Global Initiative For Chronic Obstructive Lung Disease

Global Initiative for Chronic
Obstructive
Lung
Disease
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GLOBAL STRATEGY FOR THE DIAGNOSIS,

MANAGEMENT, AND PREVENTION OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
2021 REPORT
GLOBAL INITIATIVE FOR
CHRONIC OBSTRUCTIVE LUNG
DISEASE
GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT,

AND PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
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(2021 REPORT)
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© 2020 Global Initiative for Chronic Obstructive Lung Disease, Inc.
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GOLD BOARD OF DIRECTORS GOLD SCIENCE COMMITTEE *
(2020) (2020)
Alvar Agusti, MD, Chair Claus Vogelmeier, MD, Chair Alberto Papi, MD
Respiratory Institute University of Marburg University of Ferrara
Hospital Clinic, IDIBAPS Marburg, Germany Ferrara, Italy
Univ. Barcelona and Ciberes
Barcelona, Spain Alvar Agusti, MD Ian Pavord, MA DM
Respiratory Institute, Hospital Respiratory Medicine Unit and Oxford
Richard Beasley, MD Clinic, IDIBAPS Respiratory NIHR Biomedical Research
Medical Research Institute of NZ Univ. Barcelona and Ciberes Centre, Nuffield Department of Medicine
Wellington, New Zealand Barcelona, Spain University of Oxford
Oxford, UK
Bartolome R. Celli, MD Antonio Anzueto, MD
Harvard Medical School South Texas Veterans Health Care System Nicolas Roche, MD
Boston, Massachusetts, USA University of Texas, Health Pneumologie, Hôpital Cochin,
San Antonio, Texas, USA AP-HP.Centre – Université de Paris
Rongchang Chen, MD (Descartes), UMR 1016
Shenzhen Institute of Respiratory Disease, Peter Barnes, DM, FRS Institut Cochin
Shenzhen People's Hospital National Heart & Lung Institute Paris, France
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Shenzhen, PRC Imperial College
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London, United Kingdom Don D. Sin, MD
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Gerard Criner, MD St. Paul’s Hospital
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Temple University School of Medicine Jean Bourbeau, MD University of British Columbia
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Philadelphia, Pennsylvania, USA McGill University Health Centre Vancouver, Canada
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McGill University
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David Halpin, MD Montreal, Canada O Dave Singh, MD
University of Exeter Medical School, University of Manchester
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College of Medicine and Health, Gerard Criner, MD Manchester, UK

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University of Exeter, Exeter Temple University School of Medicine

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Devon, UK Philadelphia, Pennsylvania, USA Robert Stockley, MD DSc

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University Hospital
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M. Victorina López Varela, MD David Halpin, MD Birmingham, UK

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Universidad de la República University of Exeter Medical School,

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Montevideo, Uruguay College of Medicine and Health, M. Victorina López Varela, MD

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University of Exeter, Exeter Universidad de la República

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Maria Montes de Oca, MD Devon, UK Hospital Maciel

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Hospital Universitario de Caracas Montevideo, Uruguay

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Universidad Central de Venezuela MeiLan K. Han, MD MS

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Centro Médico de Caracas University of Michigan Jørgen Vestbo, MD (retired 2019)

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Caracas, Venezuela Ann Arbor, MI, USA University of Manchester

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Manchester, England, UK
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Kevin Mortimer, MD Fernando J. Martinez, MD MS

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Liverpool School of Tropical Medicine New York-Presbyterian Hospital/ Jadwiga A. Wedzicha, MD

Liverpool, UK Weill Cornell Medical Center Imperial College London
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New York, NY, USA London, UK

Sundeep Salvi, MD
Pulmocare Research and Education Maria Montes de Oca, MD
(PURE) Foundation Hospital Universitario de Caracas
Pune, India Universidad Central de Venezuela
Centro Médico de Caracas
Claus Vogelmeier, MD Caracas, Venezuela
University of Marburg
Marburg, Germany
GOLD EXECUTIVE DIRECTOR GOLD PROJECT MANAGER EDITORIAL ASSISTANCE

Rebecca Decker, MSJ Katie Langefeld, BS Ruth Hadfield, PhD
Fontana, Wisconsin, USA Illinois, USA Macquarie University, Sydney, Australia
Michael Hess, MPH, RRT, RPFT,

Kalamazoo, MI, USA
*
Disclosure forms for GOLD Committees are posted on the GOLD Website, www.goldcopd.org
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GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD
(2021)
GOLD ASSEMBLY
The GOLD National Leaders are individuals from around the world with an interest in promoting the goals of GOLD
within their home country. The group meets periodically to share information about programs of health education,
COPD management, and prevention.
ARGENTINA Mumbai, India Islamabad, Pakistan

Dr Eduardo A. Schiavi Dr R. Narasimhan, MD POLAND
Buenos Aires, Argentina Chennai, India Paul Kuca, MD
AUSTRIA Dr Kshitij Agarwal, MD Pawel Sliwinski, MD, PhD
Dr Otto Chris Burghuber Delhi, India Warsaw, Poland
BANGLADESH INDONESIA ROMANIA
Dr Kazi S. Bennoor Prof Faisal Yunus Florin Mihaltan, MD
Dhaka, Bangladesh IRAN Ruxandra Ulmeanu, MD
BELGIUM Dr Masjedi Mohammad Reza Bucharest, Romania
Professor Wim Janssens Tehran, Iran RUSSIA
Leuven, Belgium Mohammad Ashkan Moslehi, MD Prof Zaurbek Aisanov, MD
BRAZIL Shiraz, Iran Moscow, Russia
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Jose Roberto Jardim, MD IRELAND Prof Alexandre Vizel, MD
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Aquiles Camelier, MD Timothy J. McDonnell, MD Kazan, Tatarstan Republic, Russian
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Sao Paulo, Brazil Dublin, Ireland Federation
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BULGARIA ISRAEL Svetlana Ovcharenko, MD
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Dr Yavor Ivanov Zvi G. Fridlender, MD, MSc Sergey Fedosenko, MD, PhD
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Pleven, Bulgaria Jerusalem, Israel Siberian State Medical University,
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CANADA ITALY O Tomsk, Russia
Dr Dennis E. O’Donnell Prof Lorenzo Corbetta SINGAPORE
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Kingston, Ontario, Canada Florence, Italy Kian-Chung Ong, MD

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CHILE JAPAN Wan-Cheng Tan, MD,

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Dr Manuel Barros Takahide Nagase, MD Chair, Asian Pacific COPD Roundtable

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CHINA Tokyo, Japan SLOVAK REPUBLIC

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Jiangtao Lin, MD KAZAKHSTAN Ruzena Tkacova, MD PhD

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Beijing, China Damilya Nugmanova, MD, PhD, DSci Kosice, Slovakia

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Fu-Qiang Wen, MD, PhD Almaty, Kazakhstan SLOVENIA

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COLOMBIA Tair Nurpeissov Professor Dr. Stanislav Suskovic

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Alejandro Casas, MD KOREA Golnik, Slovenia

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Vice-Director, COPD Department Yeon-Mok Oh, MD SOUTH AFRICA

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Latin American Thoracic Society Seoul, South Korea Professor Richard van Zyl-Smit
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CROATIA KUWAIT University of Cape Town and

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Neven Miculinic, MD Professor Mousa Khadadah Groote Schuur Hospital

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Zagreb, Croatia Kuwait University Cape Town, South Africa

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CZECH REPUBLIC KYRGYZSTAN SPAIN

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Stanislav Kos, MD, PhD., FCCP Talant Sooronbaev, MD Dr Patricia Sobradillo

Mirosov, Czech Republic Bishkek, Kyrgyzstan SWITZERLAND
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EGYPT LEBANON Daiana Stolz, MD

Tarek Safwat, MD, FCCP Mirna Waked, MD, FCCP Basel, Switzerland
Hisham Tarraf, MD Balamand University, Lebanon SYRIA
Cairo, Egypt MALTA Yousser Mohammad, MD
FRANCE Prof Joseph M Cacciotolo Lattakia, Syria
Prof Gaetan Deslée Pieta, Malta TRINIDAD & TOBAGO
Reims, France MOLDOVA Dr. Sateesh Madhava Sakhamuri
GEORGIA Alexandru Corlateanu, MD, PhD The University of the West Indies,
Maia Gotua, MD, PhD ERS National Delegate Trinidad and Tobago
Tbilisi, Georgia Republic of Moldova TURKEY
GREECE NORWAY Prof Dr. Hakan Gunen
Prof Konstantinos Kostikas Amund Gulsvoik, MD Malatya, Turkey
Ioannina, Greece Bergen, Norway Prof Nurdan Kokturk, MD
HONG KONG CHINA Rune Nielsen, MD, PhD Ankara, Turkey
David S.C. Hui, MD University of Bergen, Norway VIETNAM
Shatin, N.T. Hong Kong PAKISTAN Ngo Quy Chau, MD, PhD
ICELAND Prof Javaid Khan Hanoi, Vietnam
Dr Gunnar Gudmundsson Karachi, Pakistan Le Thi Tuyet Lan, MD, PhD
Reykjavik, Iceland Dr Jamil Ur Rehman Tahir Ho Chi Minh City, Vietnam
INDIA Kammanwala, Sialkot Cantt, Pakistan Sy Duong-Quy, MD, PhD, FCCP
Rohini V. Chowgule, MD Dr Mohammad Osman Yusuf Lam Dong Medical College, Vietnam
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PREFACE
The GOLD report is revised annually and has been used worldwide by healthcare professionals as a “strategy document”
and tool to implement effective management programs based on local healthcare systems.
The major change in the 2021 revision is the addition of Chapter 7 in which we summarize the relevant key points
regarding COVID-19 in the context of COPD including recommendations for remote follow-up during pandemic
restrictions. In recognition of the enormous role of COPD in LMIC countries we added references to the WHO minimum
set of interventions for the diagnosis of COPD and the management of exacerbations.
GOLD has been fortunate to have a network of international distinguished health professionals from multiple disciplines.
Many of these experts have initiated investigations of the causes and prevalence of COPD in their countries and have
developed innovative approaches for the dissemination and implementation of the GOLD management strategy. The
GOLD initiative will continue to work with National Leaders and other interested healthcare professionals to bring COPD to
the attention of governments, public health officials, healthcare workers, and the general public to raise awareness of the
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burden of COPD and to develop programs for early detection, prevention and approaches to management.
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Alvar G. Agusti, MD Claus Vogelmeier, MD

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Chair, GOLD Board of Directors Chair, GOLD Science Committee

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Hospital Clínic, Universitat de Barcelona, Department of Medicine, Pulmonary and Critical

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Villarroel 170, 08036 Barcelona, Care Medicine, University Medical Center Gießen
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Spain and Marburg, Philipps-Universität Marburg,

Baldingerstraße, 35043 Marburg, Germany
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GLOBAL STRATEGY FOR DIAGNOSIS, MANAGEMENT AND
PREVENTION OF COPD 2021 UPDATE†
METHODOLOGY
When the Global Initiative for Chronic Obstructive Lung Disease (GOLD) program was initiated in 1998, a goal was to
produce recommendations for management of COPD based on the best scientific information available. The first
report, Global Strategy for Diagnosis, Management and Prevention of COPD was issued in 2001. In 2006 and again in
2011 a complete revision was prepared based on published research. These reports, and their companion documents,
have been widely distributed and translated into many languages and can be found on the GOLD website
(www.goldcopd.org).
The GOLD Science Committee ‡ was established in 2002 to review published research on COPD management and
prevention, to evaluate the impact of this research on recommendations in the GOLD documents related to
management and prevention, and to post yearly updates on the GOLD website. Its members are recognized leaders in
COPD research and clinical practice with the scientific credentials to contribute to the task of the Committee and are
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invited to serve in a voluntary capacity.
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Updates of the 2011-revised report were released in January 2013, 2014, 2015, and 2016. The 2017 GOLD Report, the
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4th major revision of GOLD, incorporates an update of recent information that has been reviewed by the science
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committee from 2015 to 2016 and a comprehensive reassessment and revision of prior recommendations for the
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diagnosis, assessment and treatment of COPD. Updates of the 2017-revised report were made in 2018, 2019 and 2020.
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Process: To produce the GOLD report, a PubMed search (National Center for Biotechnology Information, U.S.
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National Library of Medicine, Bethesda MD, USA) was completed using search fields established by the Committee: 1)
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COPD or Chronic Obstructive Pulmonary Disease (All Fields) AND 2) Clinical Trials or Meta-analysis (All Fields) OR 3)
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articles in the top 20 medical or respiratory journals (available on request) or The Cochrane Database of Systematic
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Reviews.
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Publications in peer reviewed journals not captured by the PubMed searches may be submitted to the Chair, GOLD
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Science Committee, providing the full paper, including abstract, is submitted in (or translated into) English.
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Members of the Committee receive a summary of citations and all abstracts. Each abstract is assigned to two
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Committee members, although all members are offered the opportunity to provide input on any abstract. Members
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evaluate the abstract or, subject to her/his judgment, the full publication, by answering four specific written questions
from a short questionnaire, to indicate if the scientific data presented impacts on recommendations in the GOLD
report. If so, the member is asked to specifically identify modifications that should be made.
The GOLD Science Committee meets twice yearly to discuss each publication that was considered by at least one
member of the Committee to potentially have an impact on the management of COPD. The full Committee then
reaches a consensus on whether to include it in the report, either as a reference supporting current recommendations,
or to change the report. In the absence of consensus, disagreements are decided by an open vote of the full
† The Global Strategy for Diagnosis, Management and Prevention of COPD (updated 2021), the Pocket Guide (updated 2021) and the complete list
of references examined by the Committee is available on the GOLD website: www.goldcopd.org.
‡GOLD Science Committee Members (2020-2021): C. Vogelmeier, Chair, A. Agusti, A. Anzueto, P. Barnes, J. Bourbeau, G. Criner, P. Frith, D.
Halpin, M. Han, F. Martinez, M. Montes de Oca, A. Papi, I. Pavord, N. Roche, D. Sin, D. Singh, R. Stockley, M. Victorina Lopez Varela, J.
Wedzicha.
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Committee. Only high-quality systematic reviews and meta-analyses that provide strong evidence for changing clinical
practice are cited in the GOLD report with preference given to citing the original randomized controlled trial(s).
Recommendations by the GOLD Committees for use of any medication are based on the best evidence available from
the published literature and not on labeling directives from government regulators. The Committee does not make
recommendations for therapies that have not been approved by at least one major regulatory agency.
NEW REFERENCES
The GOLD 2021 report is a revision of the GOLD 2020 report. Following systematic literature searches and double-
blind review by the GOLD Science committee, the GOLD report has been updated to include key peer-reviewed
research publications from January 2019 to July 2020. In total, 244 new references have been added to the GOLD 2021
report.
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TABLE OF CONTENTS
PREFACE .............................................................................................................................................................................................................. IV
GLOBAL STRATEGY FOR DIAGNOSIS, MANAGEMENT AND PREVENTION OFCOPD 2021 UPDATE ........................................................................ V
METHODOLOGY ................................................................................................................................................................................................... V
NEW REFERENCES................................................................................................................................................................................................ VI
TABLE OF CONTENTS .......................................................................................................................................................................................... VII
GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD .................................................................................. 1
INTRODUCTION .................................................................................................................................................................................................... 1
BACKGROUND ...................................................................................................................................................................................................... 1
LEVELS OF EVIDENCE ............................................................................................................................................................................................ 2
REFERENCES ......................................................................................................................................................................................................... 3
CHAPTER 1: DEFINITION AND OVERVIEW ....................................................................................................................................................... 4
OVERALL KEY POINTS: ..................................................................................................................................................................................... 4

DEFINITION ........................................................................................................................................................................................................... 4
BURDEN OF COPD ................................................................................................................................................................................................. 5
Prevalence ....................................................................................................................................................................................................... 5
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Morbidity ........................................................................................................................................................................................................ 7
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Mortality ......................................................................................................................................................................................................... 7
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Economic burden............................................................................................................................................................................................. 7
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Social burden ................................................................................................................................................................................................... 7
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FACTORS THAT INFLUENCE DISEASE DEVELOPMENT AND PROGRESSION ............................................................................................................ 8
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Genetic factors ................................................................................................................................................................................................ 8
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Age and sex ..................................................................................................................................................................................................... 9

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Lung growth and development ....................................................................................................................................................................... 9

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Exposure to particles ....................................................................................................................................................................................... 9

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Socioeconomic status .................................................................................................................................................................................... 10

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Asthma and airway hyper-reactivity ............................................................................................................................................................. 10

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Chronic bronchitis ......................................................................................................................................................................................... 11

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Infections....................................................................................................................................................................................................... 12
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PATHOLOGY, PATHOGENESIS AND PATHOPHYSIOLOGY .................................................................................................................................... 12

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Pathology ...................................................................................................................................................................................................... 12
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Pathogenesis ................................................................................................................................................................................................. 12
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Pathophysiology ............................................................................................................................................................................................ 13
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REFERENCES ....................................................................................................................................................................................................... 14
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CHAPTER 2: DIAGNOSIS AND INITIAL ASSESSMENT .......................................................................................................................................20

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OVERALL KEY POINTS: ................................................................................................................................................................................... 20

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DIAGNOSIS ......................................................................................................................................................................................................... 21
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SYMPTOMS......................................................................................................................................................................................................... 21
MEDICAL HISTORY .............................................................................................................................................................................................. 23
Physical examination .................................................................................................................................................................................... 23
Spirometry ..................................................................................................................................................................................................... 23
ASSESSMENT ...................................................................................................................................................................................................... 27
Classification of severity of airflow limitation ............................................................................................................................................... 27
Assessment of symptoms .............................................................................................................................................................................. 27
Choice of thresholds ...................................................................................................................................................................................... 28
Assessment of exacerbation risk ................................................................................................................................................................... 29
Assessment of concomitant chronic diseases (comorbidities) ....................................................................................................................... 30
Combined COPD assessment ......................................................................................................................................................................... 30
Alpha-1 antitrypsin deficiency (AATD)........................................................................................................................................................... 32
Additional investigations............................................................................................................................................................................... 33
REFERENCES ....................................................................................................................................................................................................... 36
CHAPTER 3: EVIDENCE SUPPORTING PREVENTION AND MAINTENANCE THERAPY.........................................................................................40
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SMOKING CESSATION ......................................................................................................................................................................................... 40
Pharmacotherapies for smoking cessation ................................................................................................................................................... 41
VACCINATIONS ................................................................................................................................................................................................... 42
Influenza vaccine ........................................................................................................................................................................................... 42
Pneumococcal vaccine .................................................................................................................................................................................. 42
Other vaccines ............................................................................................................................................................................................... 43
PHARMACOLOGICAL THERAPY FOR STABLE COPD ............................................................................................................................................. 43
Overview of the medications......................................................................................................................................................................... 43
Bronchodilators ............................................................................................................................................................................................. 44
Antimuscarinic drugs..................................................................................................................................................................................... 46
Methylxanthines ........................................................................................................................................................................................... 46
Combination bronchodilator therapy ............................................................................................................................................................ 47
Anti-inflammatory agents ............................................................................................................................................................................. 48
Inhaled corticosteroids (ICS) .......................................................................................................................................................................... 48
Triple therapy (LABA/LAMA/ICS) ................................................................................................................................................................... 52
Oral glucocorticoids ...................................................................................................................................................................................... 52
Phosphodiesterase-4 (PDE4) inhibitors ......................................................................................................................................................... 52
Antibiotics ..................................................................................................................................................................................................... 53
Mucolytic (mucokinetics, mucoregulators) and antioxidant agents (N-acetylcysteine, carbocysteine, erdosteine) .................................... 53
Other drugs with potential to reduce exacerbations..................................................................................................................................... 53
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Issues related to inhaled delivery .................................................................................................................................................................. 54
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Other pharmacological treatments ............................................................................................................................................................... 55
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REHABILITATION, EDUCATION & SELF-MANAGEMENT ...................................................................................................................................... 56
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Pulmonary rehabilitation .............................................................................................................................................................................. 56
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Education, self-management and integrative care ....................................................................................................................................... 58
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SUPPORTIVE, PALLIATIVE, END-OF-LIFE & HOSPICE CARE .................................................................................................................................. 60
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Symptom control and palliative care ............................................................................................................................................................ 60
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Therapy relevant to all patients with COPD .................................................................................................................................................. 60

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End-of-life and hospice care .......................................................................................................................................................................... 61

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OTHER TREATMENTS .......................................................................................................................................................................................... 62

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Oxygen therapy and ventilatory support....................................................................................................................................................... 62

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Ventilatory Support ....................................................................................................................................................................................... 62

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INTERVENTIONAL THERAPY ................................................................................................................................................................................ 63

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Surgical Interventions.................................................................................................................................................................................... 63
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Bronchoscopic interventions to reduce hyperinflation in severe emphysema ............................................................................................... 64

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REFERENCES ....................................................................................................................................................................................................... 66
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CHAPTER 4: MANAGEMENT OF STABLE COPD ...............................................................................................................................................80

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INTRODUCTION .................................................................................................................................................................................................. 80
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IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS ......................................................................................................................................... 82

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Tobacco smoke.............................................................................................................................................................................................. 82
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Indoor and outdoor air pollution ................................................................................................................................................................... 82

Occupational exposures ................................................................................................................................................................................ 82
TREATMENT OF STABLE COPD: PHARMACOLOGICAL TREATMENT..................................................................................................................... 84
Algorithms for the assessment, initiation and follow-up management of pharmacological treatment ....................................................... 85
TREATMENT OF STABLE COPD: NON-PHARMACOLOGICAL TREATMENT............................................................................................................ 90
Education and self-management .................................................................................................................................................................. 91
Physical activity ............................................................................................................................................................................................. 92
Pulmonary rehabilitation programs .............................................................................................................................................................. 92
Exercise training ............................................................................................................................................................................................ 93
End-of-life and palliative care ....................................................................................................................................................................... 94
Nutritional support........................................................................................................................................................................................ 94
Vaccination ................................................................................................................................................................................................... 94
Oxygen therapy ............................................................................................................................................................................................. 95
Ventilatory support ....................................................................................................................................................................................... 96
Interventional bronchoscopy and surgery ..................................................................................................................................................... 96
MONITORING AND FOLLOW-UP ......................................................................................................................................................................... 99
Monitoring disease progression and development of complications and/or comorbidities.......................................................................... 99
Pharmacotherapy and other medical treatment .......................................................................................................................................... 99
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Comorbidities .............................................................................................................................................................................................. 100
Surgery in the COPD patient........................................................................................................................................................................ 100
REFERENCES ..................................................................................................................................................................................................... 100
CHAPTER 5: MANAGEMENT OF EXACERBATIONS ........................................................................................................................................104
OVERALL KEY POINTS: ................................................................................................................................................................................. 104

INTRODUCTION ................................................................................................................................................................................................ 104
TREATMENT OPTIONS ...................................................................................................................................................................................... 106
Treatment setting ....................................................................................................................................................................................... 106
Pharmacological treatment ........................................................................................................................................................................ 109
Respiratory support..................................................................................................................................................................................... 110
Hospital discharge and follow-up................................................................................................................................................................ 113
Prevention of exacerbations........................................................................................................................................................................ 113
REFERENCES ..................................................................................................................................................................................................... 115
CHAPTER 6: COPD AND COMORBIDITIES .....................................................................................................................................................121

INTRODUCTION ................................................................................................................................................................................................ 121
Cardiovascular diseases (CVD) .................................................................................................................................................................... 122
Heart failure ................................................................................................................................................................................................ 122
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Ischaemic heart disease (IHD) ..................................................................................................................................................................... 122
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Arrhythmias ................................................................................................................................................................................................ 122
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Peripheral vascular disease ......................................................................................................................................................................... 123
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Hypertension ............................................................................................................................................................................................... 123
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Lung cancer ................................................................................................................................................................................................. 123
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Osteoporosis ............................................................................................................................................................................................... 124
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Anxiety and depression................................................................................................................................................................................ 124
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Metabolic syndrome and diabetes .............................................................................................................................................................. 125

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Gastroesophageal reflux (GERD) ................................................................................................................................................................. 125

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Bronchiectasis ............................................................................................................................................................................................. 125

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Obstructive sleep apnea .............................................................................................................................................................................. 125

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Cognitive impairment.................................................................................................................................................................................. 126

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COPD as part of multimorbidity .................................................................................................................................................................. 126

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Other considerations ................................................................................................................................................................................... 126

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REFERENCES ..................................................................................................................................................................................................... 126

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CHAPTER 7: COVID-19 AND COPD ................................................................................................................................................................131

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INTRODUCTION ................................................................................................................................................................................................ 131

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RISK OF INFECTION WITH SARS-COV-2 .............................................................................................................................................................. 131

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INVESTIGATIONS .............................................................................................................................................................................................. 132

Testing for SARS-CoV-2 infection................................................................................................................................................................. 132
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Spirometry & pulmonary function testing ................................................................................................................................................... 133

Bronchoscopy .............................................................................................................................................................................................. 133
Radiology .................................................................................................................................................................................................... 133
PROTECTIVE STRATEGIES FOR PATIENTS WITH COPD ....................................................................................................................................... 134
DIFFERENTIATING COVID-19 INFECTION FROM DAILY SYMPTOMS OF COPD ................................................................................................... 135
MAINTENANCE PHARMACOLOGICAL TREATMENT FOR COPD DURING THE COVID-19 PANDEMIC .................................................................. 136
Use of nebulizers ......................................................................................................................................................................................... 136
NON-PHARMACOLOGICAL TREATMENT FOR COPD DURING THE COVID-19 PANDEMIC .................................................................................. 137
REVIEW OF COPD PATIENTS DURING THE COVID-19 PANDEMIC ...................................................................................................................... 137
TREATMENT OF COVID-19 IN PATIENTS WITH COPD ........................................................................................................................................ 137
EXACERBATIONS OF COPD ................................................................................................................................................................................ 138
Systemic corticosteroids .............................................................................................................................................................................. 139
Antibiotics ................................................................................................................................................................................................... 139
PULMONARY AND EXTRA-PULMONARY COMPLICATIONS ............................................................................................................................... 140
Anticoagulation ........................................................................................................................................................................................... 140
VENTILATORY SUPPORT FOR COPD PATIENTS WITH COVID-19 PNEUMONIA ................................................................................................... 140
REHABILITATION............................................................................................................................................................................................... 141
FOLLOW-UP OF COPD PATIENTS WHO DEVELOPED COVID-19 ......................................................................................................................... 141
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REMOTE COPD PATIENT FOLLOW-UP DURING COVID-19 PANDEMIC RESTRICTIONS ....................................................................................... 143
Introduction ................................................................................................................................................................................................ 143
Triage and prioritizing process .................................................................................................................................................................... 143
Consideration and instruction for remote COPD follow-up ......................................................................................................................... 144
REFERENCES ..................................................................................................................................................................................................... 147
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GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT,
AND PREVENTION OF COPD
INTRODUCTION
The aim of the GOLD Report is to provide a non-biased review of the current evidence for the assessment, diagnosis
and treatment of patients with COPD that can aid the clinician. One of the strengths of GOLD reports is the treatment
objectives. These have stood the test of time, but are organized into two groups: objectives that are directed towards
relieving and reducing the impact of symptoms, and objectives that reduce the risk of adverse health events that may
affect the patient at some point in the future (exacerbations are an example of such events). This emphasizes the need
for clinicians to focus on both the short-term and long-term impact of COPD on their patients.
A second strength of the original strategy was the simple, intuitive system for classifying COPD severity. This was based
on FEV1 and was called a staging system because it was believed, at the time, that the majority of patients followed a
path of disease progression in which the severity of COPD tracked the severity of airflow limitation. Much is now
known about the characteristics of patients in the different GOLD stages – for example, their risk of exacerbations,
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hospitalization, and death. However, at an individual patient level, FEV1 is an unreliable marker of the severity of
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breathlessness, exercise limitation, and health status impairment.
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At the time of the original report, improvement in both symptoms and health status was a GOLD treatment objective,
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but symptoms assessment did not have a direct relation to the choice of management, and health status measurement
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was a complex process largely confined to clinical studies. Now, there are simple and reliable questionnaires designed
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for use in routine daily clinical practice. These are available in many languages. These developments have enabled an
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assessment system to be developed that draws together a measure of the impact of the patient’s symptoms and an
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assessment of the patient’s risk of having a serious adverse health event to the construction of a new approach to
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management – one that matches assessment to treatment objectives. This management approach can be used in any
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clinical setting anywhere in the world and moves COPD treatment towards individualized medicine – matching the
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patient’s therapy more closely to his or her needs.

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BACKGROUND
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Chronic Obstructive Pulmonary Disease (COPD) is now one of the top three causes of death worldwide and 90% of
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these deaths occur in low- and middle-income countries (LMICs).1 More than 3 million people died of COPD in 2012
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accounting for 6% of all deaths globally. COPD represents an important public health challenge that is both preventable
and treatable. COPD is a major cause of chronic morbidity and mortality throughout the world; many people suffer
from this disease for years and die prematurely from it or its complications. Globally, the COPD burden is projected to
increase in coming decades because of continued exposure to COPD risk factors and aging of the population.2
In 1998, with the cooperation of the National Heart, Lung, and Blood Institute, National Institutes of Health and the
World Health Organization the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was implemented. Its
goals were to increase awareness of the burden of COPD and to improve prevention and management of COPD
through a concerted worldwide effort of people involved in all facets of healthcare and healthcare policy. An important
and related goal was to encourage greater research interest in this highly prevalent disease.
In 2001, GOLD released its first report, Global Strategy for the Diagnosis, Management, and Prevention of COPD. This
report was not intended to be a comprehensive textbook on COPD, but rather to summarize the current state of the
field. It was developed by individuals with expertise in COPD research and patient care and was based on the best-
validated concepts of COPD pathogenesis at that time, along with available evidence on the most appropriate
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management and prevention strategies. It provided state-of-the-art information about COPD for pulmonary specialists
and other interested physicians and served as a source document for the production of various communications for
other audiences, including an Executive Summary, a Pocket Guide for Healthcare Professionals, and a Patient Guide.
Immediately following the release of the first GOLD report in 2001, the GOLD Board of Directors appointed a Science
Committee, charged with keeping the GOLD documents up-to-date by reviewing published research, evaluating the
impact of this research on the management recommendations in the GOLD documents, and posting yearly updates of
these documents on the GOLD website.
In 2018 GOLD held a one-day summit to consider information about the epidemiology, clinical features, approaches to
prevention and control, and the availability of resources for COPD in LMICs.1 Major conclusions of the summit included that:
there are limited data about the epidemiological and clinical features of COPD in LMICs but the data available indicate there
are important differences in these features around the world; there is widespread availability of affordable tobacco products
as well as other exposures (e.g., household air pollution) thought to increase the risk of developing COPD; diagnostic
spirometry services are not widely available and there are major problems with access to affordable quality-assured
pharmacological and non-pharmacological therapies. GOLD is therefore concerned that COPD is not being taken seriously
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enough at any level, from individuals and communities, to national governments and international agencies.3 It is time for
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this to change and the GOLD Board of Directors challenge all relevant stakeholders to work together in coalition with GOLD
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to address the avoidable burden of COPD worldwide. GOLD is committed to improving the health of people at risk of and
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with COPD, wherever they happen to have been born, and wishes to do its bit to help achieve the United Nations Sustainable
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Development Goal 3.4 to reduce premature mortality from non-communicable diseases - including COPD - by one third by
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2030.4
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LEVELS OF EVIDENCE
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Levels of evidence have been assigned to evidence-based recommendations where appropriate (Table A). Evidence
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levels are indicated in boldface type enclosed in parentheses after the relevant statement e.g., (Evidence A). The
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methodological issues concerning the use of evidence from meta-analyses were carefully considered when i)
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treatment effect (or effect size) was consistent from one study to the next, and we needed to identify the common
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effect; ii) the effect varied from one study to the next, and there was a need to identify the reason for the variation.
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REFERENCES
1. Halpin DMG, Celli BR, Criner GJ, et al. The GOLD Summit on chronic obstructive pulmonary disease in low- and middle-
income countries. Int J Tuberc Lung Dis 2019; 23(11): 1131-41.
2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11):
e442.
3. Halpin DMG, Celli BR, Criner GJ, et al. It is time for the world to take COPD seriously: a statement from the GOLD board
of directors. Eur Respir J 2019; 54(1): 1900914.
4. United Nations. Sustainable Development Goals, online information available here:
https://www.un.org/sustainabledevelopment/sustainable-development-goals/ [accessed Oct 2020].
3
CHAPTER 1: DEFINITION AND OVERVIEW
OVERALL KEY POINTS:

• Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease
that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway
and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.
• The most common respiratory symptoms include dyspnea, cough and/or sputum production. These
symptoms may be under-reported by patients.
• The main risk factor for COPD is tobacco smoking but other environmental exposures such as
biomass fuel exposure and air pollution may contribute. Besides exposures, host factors predispose
individuals to develop COPD. These include genetic abnormalities, abnormal lung development and
accelerated aging.
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• COPD may be punctuated by periods of acute worsening of respiratory symptoms, called
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exacerbations.
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• In most patients, COPD is associated with significant concomitant chronic diseases, which increase
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its morbidity and mortality.
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DEFINITION
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Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that is characterized
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by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually
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caused by significant exposure to noxious particles or gases and influenced by host factors including abnormal lung
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development. Significant comorbidities may have an impact on morbidity and mortality.

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There may be significant lung pathology (e.g., emphysema) in the absence of airflow limitation that needs further
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evaluation (Figure 1.1). The chronic airflow limitation that is characteristic of COPD is caused by a mixture of small
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airways disease and parenchymal destruction (emphysema), the relative contributions of which vary from person to
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person. These changes do not always occur together, but evolve at different rates over time. Chronic inflammation
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causes structural changes, narrowing of the small airways and destruction of the lung parenchyma that leads to the
loss of alveolar attachments to the small airways and decreases lung elastic recoil. In turn, these changes diminish the
ability of the airways to remain open during expiration. A loss of small airways may also contribute to airflow limitation
and mucociliary dysfunction is a characteristic feature of the disease. Airflow limitation is usually measured by
spirometry as this is the most widely available and reproducible test of lung function. Many previous definitions of
COPD have emphasized the terms “emphysema” and “chronic bronchitis”, which are not included in the definition
used in this or earlier GOLD reports. Emphysema, or destruction of the gas-exchanging surfaces of the lung (alveoli),
is a pathological term that is often (but incorrectly) used clinically and describes only one of several structural
abnormalities present in patients with COPD. Chronic bronchitis, or the presence of cough and sputum production for
at least 3 months in each of two consecutive years, remains a clinically and epidemiologically useful term, but is present
in only a minority of subjects when this definition is used. However, when alternative definitions are used to define
chronic bronchitis, or older populations with greater levels of smoke or occupational inhalant exposure are queried,
the prevalence of chronic bronchitis is greater.1,2 It is important to recognize that chronic respiratory symptoms may
precede the development of airflow limitation and may be associated with the development of acute respiratory
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events.3 Chronic respiratory symptoms also exist in individuals with normal spirometry3,4 and a significant number of
smokers without airflow limitation have structural evidence of lung disease manifested by the varying presence of
emphysema, airway wall thickening and gas trapping.3,4
BURDEN OF COPD
COPD is a leading cause of morbidity and mortality worldwide that induces an economic and social burden that is both
substantial and increasing.5,6 COPD prevalence, morbidity and mortality vary across countries and across different
groups within countries. COPD is the result of a complex interplay of long-term cumulative exposure to noxious gases
and particles, combined with a variety of host factors including genetics, airway hyper-responsiveness and poor lung
growth during childhood.7-9 Often, the prevalence of COPD is directly related to the prevalence of tobacco smoking,
although in many countries outdoor, occupational and indoor air pollution (resulting from the burning of wood and
other biomass fuels) are major COPD risk factors.10,11 The prevalence and burden of COPD are projected to increase
over the coming decades due to continued exposure to COPD risk factors and aging of the world’s population; as
longevity increases more people will express the long-term effects of exposure to COPD risk factors.12 Information on
the burden of COPD can be found on international websites, for example the:
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• World Health Organization (WHO)13
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• World Bank/WHO Global Burden of Disease Study14
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Prevalence
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Existing COPD prevalence data vary widely due to differences in survey methods, diagnostic criteria, and analytical
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approaches.12 Importantly, all of the studies defined COPD by spirometry alone and not by the combination of
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symptoms and spirometry. The lowest estimates of prevalence are those based on self-reporting of a doctor’s
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diagnosis of COPD, or equivalent condition. For example, most national data show that < 6% of the adult population
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have been told that they have COPD.15 This is likely to be a reflection of the widespread under-recognition and under-
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diagnosis of COPD.16
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Despite the complexities, data are emerging that enable more accurate estimates of COPD prevalence. A systematic
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review and meta-analysis, including studies carried out in 28 countries between 1990 and 2004,15 provided evidence
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that the prevalence of COPD is appreciably higher in smokers and ex-smokers compared to non-smokers, in those ≥
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40 years of age compared to those < 40, and in men compared to women. The Latin American Project for the
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Investigation of Obstructive Lung Disease (PLATINO)17 examined the prevalence of post-bronchodilator airflow
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limitation among persons > 40 years in one major city from each of five Latin American countries – Brazil, Chile, Mexico,
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Uruguay, and Venezuela. In each country, the prevalence of COPD increased steeply with age, with the highest
prevalence among those > 60 years. Prevalence in the total population ranged from a low of 7.8% in Mexico City,
Mexico, to a high of 19.7% in Montevideo, Uruguay. In all five cities, the prevalence was appreciably higher in men
than in women,17 which contrasts with findings from European cities such as Salzburg, Austria.18
The Burden of Obstructive Lung Diseases (BOLD) program has also used a standardized methodology comprising
questionnaires and pre- and post-bronchodilator spirometry to assess the prevalence and risk factors for COPD in
people aged 40 and over around the world. Surveys have been completed in 29 countries and studies are on-going in
a further nine.19 BOLD reported worse lung function than earlier studies, with a prevalence of COPD grade 2 or higher
of 10.1% (SE 4.8) overall, 11.8% (SE 7.9) for men, and 8.5% (SE 5.8) for women20 and a substantial prevalence of COPD
of 3-11% among never-smokers.20 BOLD also examined the prevalence of COPD in north and sub-Saharan Africa and
Saudi Arabia and found similar results.21-24
Based on BOLD and other large scale epidemiological studies, it is estimated that the number of COPD cases was 384
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million in 2010, with a global prevalence of 11.7% (95% confidence interval (CI) 8.4%–15.0%).25 Globally, there are
around three million deaths annually.26 With the increasing prevalence of smoking in developing countries, and aging
populations in high-income countries, the prevalence of COPD is expected to rise over the next 40 years and by 2060
there may be over 5.4 million deaths annually from COPD and related conditions.27,28
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Morbidity
Morbidity measures traditionally include physician visits, emergency department visits, and hospitalizations. Although
COPD databases for these outcome parameters are less readily available and usually less reliable than mortality
databases, to date studies on the available data indicate that morbidity due to COPD increases with age,15-17 and in
patients with COPD the development of comorbidities may be seen at an earlier age.29 Morbidity from COPD may be
affected by other concomitant chronic conditions (e.g., cardiovascular disease,30 musculoskeletal impairment,
diabetes mellitus) that are related to smoking, aging and COPD. These chronic conditions may significantly impair
patient’s health status, in addition to interfering with COPD management and are major drivers of hospitalizations and
costs for patients with COPD.31
Mortality
The World Health Organization (WHO) publishes mortality statistics for selected causes of death annually for all WHO
regions; additional information is available from the WHO Evidence for Health Policy Department.32 However, data
must be interpreted with caution because of the inconsistent use of COPD terminology. In the 10th revision of the
International Statistical Classification of Diseases and Related Health Problems (ICD-10), deaths from COPD or chronic
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airways obstruction are included in the broad category of “COPD and allied conditions” (ICD-10 codes J42-46).
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Under-recognition and under-diagnosis of COPD reduces the accuracy of mortality data.33,34 Furthermore, the accuracy
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of COPD diagnosis codes recorded in administrative health databases is also uncertain.35,36 In some jurisdictions,
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reliance on administrative health data, particularly those that only record hospitalizations, may underestimate the
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burden of COPD.37 The reliability of recording of COPD-related deaths in mortality data is also problematic. Although
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COPD is often a primary cause of death, it is more likely to be listed as a contributory cause of death or omitted from
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the death certificate entirely.38 However, it is clear that COPD is one of the most important causes of death in most
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countries. For instance, in 2011, COPD was the third leading cause of death in the United States.39 This increase in
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COPD-related mortality has mainly been driven by the expanding epidemic of smoking; reduced mortality from other
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common causes of death (e.g., ischemic heart disease, infectious diseases); the aging of the world’s population,
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particularly in high-income countries; and scarcity of effective disease modifying therapies.

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Economic burden
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COPD is associated with significant economic burden. In the European Union, the total direct costs of respiratory
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disease are estimated to be about 6% of the total annual healthcare budget, with COPD accounting for 56% (38.6
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billion Euros) of the cost of respiratory disease.40 In the United States the estimated direct costs of COPD are $32 billion
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and the indirect costs $20.4 billion.41 COPD exacerbations account for the greatest proportion of the total COPD burden
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on the healthcare system. Not surprisingly, there is a striking direct relationship between the severity of COPD and the
cost of care, and the cost distribution changes as the disease progresses. For example, hospitalization and ambulatory
oxygen costs soar as COPD severity increases. Any estimate of direct medical expenditure for home-based care under-
represents the true cost of home-based care to society, because it ignores the economic value of the care provided by
family members to people with COPD.
In developing countries, direct medical costs may be less important than the impact of COPD on workplace and home
productivity. Because the healthcare sector might not provide long-term supportive care services for severely disabled
individuals, COPD may force at least two individuals to leave the workplace – the affected individual and a family
member who must now stay home to care for their disabled relative.42 Since human capital is often the most important
national asset for developing countries, the indirect costs of COPD may represent a serious threat to the economy.
Social burden
Since mortality offers only a limited perspective on the human burden of a disease, it is desirable to find other
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measures of disease burden that are consistent and measurable within and between nations. The authors of the Global
Burden of Disease (GBD) Study designed a method to estimate the fraction of mortality and disability attributable to
major diseases and injuries using a composite measure of the burden of each health problem: the Disability-Adjusted
Life Year (DALY).43 The DALYs for a specific condition are the sum of years lost because of premature mortality and
years of life lived with disability, adjusted for the severity of disability. The GBD Study found that COPD is an increasing
contributor to disability and mortality around the world. In 2005 COPD was the eighth leading cause of DALYs lost
across the world but by 2013 COPD was ranked as the fifth leading cause of DALYs lost.44 In the United States, COPD is
the second leading cause of reduced DALYs, trailing only ischemic heart disease.45
FACTORS THAT INFLUENCE DISEASE DEVELOPMENT AND

PROGRESSION
Although cigarette smoking is the most well studied COPD risk factor, it is not the only risk factor and there is consistent
evidence from epidemiologic studies that non-smokers may also develop chronic airflow limitation.20 Much of the
evidence concerning risk factors for COPD comes from cross-sectional epidemiological studies that identify
associations rather than causal relationships. Nevertheless, compared to smokers with COPD, never smokers with
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chronic airflow limitation have fewer symptoms, milder disease and lower burden of systemic inflammation.46
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Interestingly, never smokers with chronic airflow limitation do not appear to have an increased risk of lung cancer, or
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cardiovascular comorbidities, compared to those without chronic airflow limitation. However, there is evidence that
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they have an increased risk of pneumonia and mortality from respiratory failure.46
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Although several longitudinal studies of COPD have followed groups and populations for up to 20 years,7 to date no
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studies have monitored the progression of the disease through its entire course, or included the pre and perinatal
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periods that may be important in shaping an individual’s future COPD risk. Thus, the current understanding of risk
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factors for COPD is in many respects still incomplete.

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COPD results from a complex interaction between genes and the environment. Cigarette smoking is the leading
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environmental risk factor for COPD, yet even for heavy smokers, fewer than 50% develop COPD during their lifetime.47
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Although genetics may play a role in modifying the risk of COPD in smokers, there may also be other risk factors
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involved. For example, sex may influence whether a person takes up smoking or experiences certain occupational or
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environmental exposures; socioeconomic status may be linked to a child’s birth weight (as it impacts on lung growth
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and development, and in turn on susceptibility to developing the disease); and longer life expectancy will allow greater
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lifetime exposure to risk factors. Understanding the relationships and interactions between risk factors requires
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further investigation.
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Genetic factors
The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin (AATD),48 a
major circulating inhibitor of serine proteases. Although AATD deficiency is relevant to only a small part of the world’s
population, it illustrates the interaction between genes and environmental exposures that predispose an individual to
COPD. A systematic review of 20 studies in European populations found AATD PiZZ genotypes in 0.12% of COPD
patients (range 0.08-0.24%), and a prevalence ranging from 1 in 408 in Northern Europe to 1 in 1,274 in Eastern
Europe.49
A significant familial risk of airflow limitation has been observed in people who smoke and are siblings of patients with
severe COPD,50 suggesting that genetics together with environmental factors could influence this susceptibility. Single
genes, such as the gene encoding matrix metalloproteinase 12 (MMP-12) and glutathione S-transferase have been
related to a decline in lung function51 or risk of COPD.52 Several genome-wide association studies have linked genetic
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loci with COPD (or FEV1 or FEV1/FVC as the phenotype) including markers near the alpha-nicotinic acetylcholine
receptor, hedgehog interacting protein (HHIP), and several others. Nevertheless, it remains uncertain whether these
genes are directly responsible for COPD or are merely markers of causal genes.53-57
Age and sex

Age is often listed as a risk factor for COPD. It is unclear if healthy aging as such leads to COPD or if age reflects the
sum of cumulative exposures throughout life.58 Aging of the airways and parenchyma mimic some of the structural
changes associated with COPD.58 Gender related differences in immune pathways and pattern of airway damage may
be seen and might be clinically important. More work in this area is needed. In the past, most studies have reported
that COPD prevalence and mortality are greater among men than women, but later data from developed countries
has reported that the prevalence of COPD is now almost equal in men and women, probably reflecting the changing
patterns of tobacco smoking.59 Although controversial, some studies have even suggested that women are more
susceptible to the effects of tobacco smoke than men,60-62 leading to more severe disease for the equivalent quantity
of cigarettes consumed. This notion has been validated in animal studies and human pathology specimens, which have
demonstrated a greater burden of small airway disease in females compared with males with COPD despite a similar
history of tobacco smoke exposure.63,64
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Lung growth and development
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Processes occurring during gestation, birth, and exposures during childhood and adolescence affect lung growth.65,66
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Reduced maximal attained lung function (as measured by spirometry) may identify individuals who are at increased
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risk for the development of COPD.4,8 Any factor that affects lung growth during gestation and childhood has the
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potential for increasing an individual’s risk of developing COPD. For example, a large study and meta-analysis
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confirmed a positive association between birthweight and FEV1 in adulthood,67 and several studies have found an
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effect of early childhood lung infections. Factors in early life termed “childhood disadvantage factors” seem to be as
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important as heavy smoking in predicting lung function in adult life.67 One study evaluated three different longitudinal
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cohorts and found that approximately 50% of patients developed COPD due to accelerated decline in FEV1 over time,
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while the other 50% developed COPD due to abnormal lung growth and development (with normal decline in lung
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function over time; Figure 1.2).7 The Medical Research Council National Survey of Health and Development
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documented a synergistic interaction between smoking and infant respiratory infection as well as early life home
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overcrowding with lung function at age 43.68

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Exposure to particles
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Across the world, cigarette smoking is the most commonly encountered risk factor for COPD. Cigarette smokers have
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a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1,
and a greater COPD mortality rate than non-smokers.69 Other types of tobacco (e.g., pipe, cigar, water pipe)70-72 and
marijuana73 are also risk factors for COPD. Passive exposure to cigarette smoke, also known as environmental tobacco
smoke (ETS), may also contribute to respiratory symptoms and COPD74 by increasing the lung’s total burden of inhaled
particles and gases. Smoking during pregnancy may pose a risk for the fetus, by affecting lung growth and development
in utero, and possibly the priming of the immune system.75
Occupational exposures, including organic and inorganic dusts, chemical agents and fumes, are an under-appreciated
risk factor for COPD.10,76 A study of the population-based UK biobank cohort identified occupations including sculptors,
gardeners and warehouse workers that were associated with an increased COPD risk among never-smokers and never-
asthmatics.77 A cross-sectional observational study demonstrated that self-reported exposure to workplace dust and
fumes is not only associated with increased airflow limitation and respiratory symptoms, but also with more
emphysema and gas trapping, assessed by computed tomography scan, in both men and women.78 An analysis of the
large U.S. population-based National Health and Nutrition Examination Survey III survey of almost 10,000 adults aged
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30-75 years estimated the fraction of COPD attributable to workplace exposures was 19.2% overall, and 31.1% among
never-smokers.79 These estimates are consistent with a statement published by the American Thoracic Society that
concluded that occupational exposures account for 10-20% of either symptoms or functional impairment consistent
with COPD.80 The risk from occupational exposures in less regulated areas of the world is likely to be much higher than
reported in studies from Europe and North America.
Wood, animal dung, crop residues, and coal, typically burned in open fires or poorly functioning stoves, may lead to
very high levels of indoor air pollution.81 There is growing evidence that indoor biomass exposure to modern and
traditional fuels used during cooking may predispose women to develop COPD in many developing countries.82-85
Almost three billion people worldwide use biomass and coal as their main source of energy for cooking, heating, and
other household needs, so the population at risk worldwide is very large.86,87 There is a lack of research about biomass
related COPD,88 although there is limited evidence from an observational study that switching to cleaner cooking fuels
or reducing exposure may reduce COPD risk in non-smokers.89
High levels of urban air pollution are harmful to individuals with existing heart or lung disease. The role of outdoor air
pollution as a risk factor for COPD is unclear, but its role appears to be relatively small in adults compared to the role
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of cigarette smoking.10 Cross-sectional analyses have shown an association between ambient levels of particulate
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matter (PM2.5/10) and COPD prevalence.90,91 However, there is evidence that air pollution has a significant impact on
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lung maturation and development. For instance, the Children’s Health Study found that children from communities
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with the highest levels of outdoor nitrogen dioxide (NO2) and particulate matter < 2.5 μm in aerodynamic diameter
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(PM2.5) were nearly 5 times more likely to have reduced lung function (defined as FEV1 < 80% of predicted) compared
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to children from communities with the lowest levels of NO2 and PM2.5.92 Importantly, reduction in ambient NO2 and
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PM2.5 levels significantly mitigated the risk of experiencing impaired lung growth.93 However, the relative effects of
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short-term, high-peak exposures and long-term, low-level exposures are yet to be resolved.
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Socioeconomic status
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Poverty is consistently associated with airflow obstruction94 and lower socioeconomic status is associated with an
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increased risk of developing COPD.95,96 It is not clear, however, whether this pattern reflects exposures to indoor and
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outdoor air pollutants, crowding, poor nutrition, infections, or other factors related to low socioeconomic status.
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Asthma and airway hyper-reactivity

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Asthma may be a risk factor for the development of chronic airflow limitation and COPD. In a report from a longitudinal
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cohort of the Tucson Epidemiological Study of Airway Obstructive Disease, adults with asthma were found to have a
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12-fold higher risk of acquiring COPD over time compared to those without asthma, after adjusting for smoking.97
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Another longitudinal study of people with asthma found that around 20% of subjects developed irreversible airflow
limitation and reduced transfer coefficient.98 A third longitudinal study observed that self-reported asthma was
associated with excess loss of FEV1 in the general population.99 A study examining the pattern of lung-growth decline
in children with asthma found that 11% met lung function impairment consistent with the spirometric classification of
COPD in early adulthood.100 In the European Community Respiratory Health Survey, airway hyper-responsiveness was
second only to cigarette smoking as the leading risk factor for COPD, responsible for 15% of the population attributable
risk (smoking had a population attributable risk of 39%).101 The pathology of chronic airflow limitation in asthmatic
non-smokers and non-asthmatic smokers is markedly different, suggesting that the two disease entities may remain
different even when presenting with similarly reduced lung function.97,102,103 However, separating asthma from COPD
in adults may be clinically difficult at times.
Airway hyper-responsiveness can exist without a clinical diagnosis of asthma and has been shown to be an
independent predictor of COPD and respiratory mortality in population studies104,105 as well as an indicator of risk of
excess decline in lung function in patients with mild COPD.106
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Chronic bronchitis
In the seminal study by Fletcher and colleagues, chronic bronchitis was not associated with an accelerated decline in
lung function.96,107 However, subsequent studies have observed an association between mucus hypersecretion and
increased FEV1 decline,108 and in younger adults who smoke, the presence of chronic bronchitis has been associated
with an increased likelihood of developing COPD.109 Chronic bronchitis has also been associated with an increased risk
in the total number as well as severity of exacerbations.110
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Infections
A history of severe childhood respiratory infection has been associated with reduced lung function and increased
respiratory symptoms in adulthood.101 Susceptibility to infections plays a role in exacerbations of COPD but the effect
on disease development is less clear. In a large observational study Pseudomonas aeruginosa colonization
independently predicted an increased risk of hospitalization for exacerbation and all-cause mortality.111 There is
evidence that HIV patients are at increased risk of COPD compared to HIV negative controls (11 studies; pooled odds
ratio for 1.14 (95% CI 1.05,1.25)112; tuberculosis has also been identified as a risk factor for COPD.113 In addition,
tuberculosis is both a differential diagnosis for COPD and a potential comorbidity.114,115
PATHOLOGY, PATHOGENESIS AND PATHOPHYSIOLOGY

Inhalation of cigarette smoke or other noxious particles, such as smoke from biomass fuels, causes lung inflammation.
Lung inflammation is a normal response that appears to be modified in patients who develop COPD. This chronic
inflammatory response may induce parenchymal tissue destruction (resulting in emphysema), and disruption of
normal repair and defense mechanisms (resulting in small airway fibrosis). These pathological changes lead to gas
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trapping and progressive airflow limitation. A brief overview follows that describes and summarizes the pathologic
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changes in COPD, their cellular and molecular mechanisms, and how these underlie the physiological abnormalities
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and symptoms characteristic of this disease.
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Pathology
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Pathological changes characteristic of COPD are found in the airways, lung parenchyma, and pulmonary vasculature.116
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The pathological changes observed in COPD include chronic inflammation, with increased numbers of specific
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inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair.
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In general, the inflammatory and structural changes in the airways increase with disease severity and persist on
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smoking cessation. Most pathology data come from studies in smokers and the same balance of airway and
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parenchymal disease cannot necessarily be assumed when other factors are operative. Systemic inflammation may be
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present and could play a role in the multiple comorbid conditions found in patients with COPD.117
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Pathogenesis
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The inflammation observed in the respiratory tract of COPD patients appears to be a modification of the normal
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inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this
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amplified inflammation are not yet understood but may, at least in part, be genetically determined. Although some
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patients develop COPD without smoking, the nature of the inflammatory response in these patients is as yet unknown.
Oxidative stress and an excess of proteinases in the lung are likely to further modify lung inflammation. Together,
these mechanisms may lead to the characteristic pathological changes in COPD. Lung inflammation persists after
smoking cessation through unknown mechanisms, although autoantigens and perturbations in the lung microbiome
may play a role.118,119 Similar mechanisms may occur for concomitant chronic diseases.
Oxidative stress. Oxidative stress may be an important amplifying mechanism in COPD.117,120 Biomarkers of
oxidative stress (e.g., hydrogen peroxide, 8-isoprostane) are increased in the exhaled breath condensate, sputum, and
systemic circulation of COPD patients. Oxidative stress is further increased during exacerbations. Oxidants are both
generated by cigarette smoke and other inhaled particulates, and released from activated inflammatory cells such as
macrophages and neutrophils. There may also be a reduction in endogenous antioxidants in COPD patients as a result
of reduction in levels of the transcription factor Nrf2 that regulates many antioxidant genes.114,121
Protease-antiprotease imbalance. There is compelling evidence for an imbalance in the lungs of COPD patients
between proteases that break down connective tissue components and antiproteases that counterbalance this
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action.122 Increased levels of several proteases, derived from inflammatory cells and epithelial cells, have been
observed in COPD patients. There is increasing evidence that these proteases may interact with each other. Protease-
mediated destruction of elastin, a major connective tissue component in lung parenchyma, is believed to be an
important feature of emphysema but may be more difficult to establish in airway changes.123
Inflammatory cells. COPD is characterized by increased numbers of macrophages in peripheral airways, lung
parenchyma and pulmonary vessels, together with increased activated neutrophils and increased lymphocytes that
include Tc1, Th1, Th17 and ILC3 cells. In some patients, there may also be increases in eosinophils, Th2 or ILC2 cells.
All of these inflammatory cells, together with epithelial cells and other structural cells release multiple inflammatory
mediators.117 A study suggests that local IgA deficiency is associated with bacterial translocation, small airway
inflammation and airway remodeling.124
Inflammatory mediators. The wide variety of inflammatory mediators that have been shown to be increased in
COPD patients attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process
(proinflammatory cytokines), and induce structural changes (growth factors).125
Peribronchiolar and interstitial fibrosis. Peribronchiolar fibrosis and interstitial opacities have been reported in
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patients with COPD or those who are asymptomatic smokers.118,126-128 An excessive production of growth factors may
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be found in smokers or those with preceding airway inflammation who have COPD.129 Inflammation may precede the
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development of fibrosis or repeated injury of the airway wall itself may lead to excessive production of muscle and
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fibrous tissue.130 This may be a contributing factor to the development of small airways limitation and eventually the
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obliteration that may precede the development of emphysema.131
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O
Differences in inflammation between COPD and asthma. Although both COPD and asthma are associated
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with chronic inflammation of the respiratory tract, there are differences in the inflammatory cells and mediators
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N
involved in the two diseases.132 Some patients with COPD have an inflammatory pattern with increased eosinophils.133
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Pathophysiology
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There is now a good understanding of how the underlying disease process in COPD leads to the characteristic
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physiological abnormalities and symptoms. For example, inflammation and narrowing of peripheral airways leads to
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decreased FEV1.134 Parenchymal destruction due to emphysema also contributes to airflow limitation and leads to
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decreased gas transfer. There is also emerging evidence to suggest that in addition to airway narrowing, there is a loss
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of small airways, which may contribute to airflow limitation.135

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Airflow limitation and gas trapping. The extent of inflammation, fibrosis, and luminal exudates in the small
airways correlates with the reduction in the FEV1 and FEV1/FVC ratio, and probably with the accelerated decline in
FEV1 that is characteristic of COPD.134 This peripheral airway limitation progressively traps gas during expiration,
resulting in hyperinflation. Static hyperinflation reduces inspiratory capacity and is commonly associated with dynamic
hyperinflation during exercise leading to increased dyspnea and limitation of exercise capacity. These factors
contribute to impairment of the intrinsic contractile properties of respiratory muscles. It is thought that hyperinflation
develops early in the disease and is the main mechanism for exertional dyspnea.136,137 Bronchodilators acting on
peripheral airways reduce gas trapping, thereby reducing lung volumes and improving symptoms and exercise
capacity.138
Gas exchange abnormalities. Gas exchange abnormalities result in hypoxemia and hypercapnia, and have several
mechanisms in COPD. In general, gas transfer for oxygen and carbon dioxide worsens as the disease progresses.
Reduced ventilation may also be due to reduced ventilatory drive or increased dead space ventilation.137 This may lead
to carbon dioxide retention when it is combined with reduced ventilation, due to increased effort to breathe because
13
of severe limitation and hyperinflation coupled with ventilatory muscle impairment. The abnormalities in alveolar
ventilation and a reduced pulmonary vascular bed further worsen the VA/Q (ventilation perfusion ratio)
abnormalities.139
Mucus hypersecretion. Mucus hypersecretion, resulting in a chronic productive cough, is a feature of chronic
bronchitis and is not necessarily associated with airflow limitation. Conversely, not all patients with COPD have
symptomatic mucus hypersecretion. When present, mucus hypersecretion is due to an increased number of goblet
cells and enlarged submucosal glands, both because of chronic airway irritation by cigarette smoke and other noxious
agents. Several mediators and proteases stimulate mucus hypersecretion and many of them exert their effects through
the activation of epidermal growth factor receptor (EGFR).140
Pulmonary hypertension. Pulmonary hypertension may develop late in the course of COPD and is due mainly to
hypoxic vasoconstriction of the small pulmonary arteries, eventually resulting in structural changes that include intimal
hyperplasia and later smooth muscle hypertrophy/hyperplasia.141 Even in mild COPD, or in smokers susceptible to
emphysema,142,143 there are significant abnormalities in pulmonary microvascular blood flow, that worsen with disease
progression.144
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An inflammatory response in vessels, similar to that seen in the airways, is also observed in COPD, along with evidence
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of endothelial cell dysfunction. The loss of the pulmonary capillary bed in emphysema may further contribute to
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increased pressure in the pulmonary circulation. Progressive pulmonary hypertension may lead to right ventricular
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hypertrophy and eventually to right-side cardiac failure. Interestingly, the diameter of pulmonary artery as measured
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on computed tomography (CT) scans has been shown to relate to the risk of exacerbation, independent of previous
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history of exacerbations.145 This suggests that perturbations in pulmonary vasculature are major, but under-
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recognized, drivers of symptoms and exacerbations in COPD.

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N
Exacerbations. Exacerbations of respiratory symptoms triggered by respiratory infections with bacteria or viruses
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(which may coexist), environmental pollutants, or unknown factors often occur in patients with COPD; a characteristic
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response with increased inflammation occurs during episodes of bacterial or viral infection. During exacerbations there
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is increased hyperinflation and gas trapping, with reduced expiratory flow, thus accounting for increased dyspnea.146
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There is also worsening of VA/Q abnormalities that can result in hypoxemia.147 During exacerbations there is evidence
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of increased airway inflammation. Other conditions (pneumonia, thromboembolism, and acute cardiac failure) may
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mimic or aggravate an exacerbation of COPD.

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Systemic features. Most patients with COPD have concomitant chronic diseases linked to the same risk factors i.e.,
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smoking, aging, and inactivity, which may have a major impact on health status and survival.148 Airflow limitation and
particularly hyperinflation affect cardiac function and gas exchange.146 Inflammatory mediators in the circulation may
contribute to skeletal muscle wasting and cachexia, and may initiate or worsen comorbidities such as ischemic heart
disease, heart failure, osteoporosis, normocytic anemia, diabetes, and metabolic syndrome.
REFERENCES
1. American Lung Association Epidemiology and Statistics Unit. Trends in COPD (Chronic Bronchitis and Emphysema):
Morbidity and Mortality. 2013. https://www.lung.org/assets/documents/research/copd-trend-report.pdf (accessed 14
October 2019).
2. Kim V, Crapo J, Zhao H, et al. Comparison between an alternative and the classic definition of chronic bronchitis in
COPDGene. Ann Am Thorac Soc 2015; 12(3): 332-9.
3. Woodruff PG, Barr RG, Bleecker E, et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary
Function. N Engl J Med 2016; 374(19): 1811-21.
4. Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and Radiologic Disease in Smokers With Normal Spirometry. JAMA
Intern Med 2015; 175(9): 1539-49.
14
5. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in
1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2095-128.
6. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries
1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2163-96.
7. Lange P, Celli B, Agusti A, et al. Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease. N Engl J
Med 2015; 373(2): 111-22.
8. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. Poor airway function in early infancy and lung function by age
22 years: a non-selective longitudinal cohort study. Lancet 2007; 370(9589): 758-64.
9. Tashkin DP, Altose MD, Bleecker ER, et al. The lung health study: airway responsiveness to inhaled methacholine in
smokers with mild to moderate airflow limitation. The Lung Health Study Research Group. Am Rev Respir Dis 1992;
145(2 Pt 1): 301-10.
10. Eisner MD, Anthonisen N, Coultas D, et al. An official American Thoracic Society public policy statement: Novel risk
factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 182(5): 693-
718.
11. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009; 374(9691): 733-43.
12. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11):
e442.
13. World Health Organization. World Health Organization (WHO) Website. http://www.who.int (accessed Oct 2020).
14. World Health Organization. Global Burden of Disease Website. http://www.who.int/topics/global_burden_of_disease
(accessed Oct 2020).
15. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and
TE
meta-analysis. Eur Respir J 2006; 28(3): 523-32.
U
IB
16. Quach A, Giovannelli J, Cherot-Kornobis N, et al. Prevalence and underdiagnosis of airway obstruction among middle-
R
aged adults in northern France: The ELISABET study 2011-2013. Respir Med 2015; 109(12): 1553-61.
T
IS
17. Menezes AM, Perez-Padilla R, Jardim JR, et al. Chronic obstructive pulmonary disease in five Latin American cities (the
D
PLATINO study): a prevalence study. Lancet 2005; 366(9500): 1875-81.
R
18. Schirnhofer L, Lamprecht B, Vollmer WM, et al. COPD prevalence in Salzburg, Austria: results from the Burden of
O
Obstructive Lung Disease (BOLD) Study. Chest 2007; 131(1): 29-36.
PY
19. BOLD. Burden of Obstructive Lung Disease Initiative Webpage, published by Imperial College London, available here:
O
C
http://www.boldstudy.org/ [accessed Oct 2020].

T
20. Lamprecht B, McBurnie MA, Vollmer WM, et al. COPD in never smokers: results from the population-based burden of
O
N
obstructive lung disease study. Chest 2011; 139(4): 752-63.

O
21. Al Ghobain M, Alhamad EH, Alorainy HS, Al Kassimi F, Lababidi H, Al-Hajjaj MS. The prevalence of chronic obstructive
-D
pulmonary disease in Riyadh, Saudi Arabia: a BOLD study. Int J Tuberc Lung Dis 2015; 19(10): 1252-7.
L
22. Denguezli M, Daldoul H, Harrabi I, et al. COPD in Nonsmokers: Reports from the Tunisian Population-Based Burden of
IA
Obstructive Lung Disease Study. PLoS One 2016; 11(3): e0151981.

ER
23. El Rhazi K, Nejjari C, BenJelloun MC, El Biaze M, Attassi M, Garcia-Larsen V. Prevalence of chronic obstructive
AT
pulmonary disease in Fez, Morocco: results from the BOLD study. Int J Tuberc Lung Dis 2016; 20(1): 136-41.
M
24. Obaseki DO, Erhabor GE, Gnatiuc L, Adewole OO, Buist SA, Burney PG. Chronic Airflow Obstruction in a Black African
T
H
Population: Results of BOLD Study, Ile-Ife, Nigeria. COPD 2016; 13(1): 42-9.
IG
25. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-
R
analysis. J Glob Health 2015; 5(2): 020415.

PY
26. Global Burden of Disease Study Collaborators. Global, regional, and national age-sex specific all-cause and cause-
O
C
specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study
2013. Lancet 2015; 385(9963): 117-71.
27. Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur
Respir J 2006; 27(2): 397-412.
28. World Health Organization. Projections of mortality and causes of death, 2016 and 2060, online information available
here http://www.who.int/healthinfo/global_burden_disease/projections/en/ [accessed Oct 2020].
29. Divo MJ, Celli BR, Poblador-Plou B, et al. Chronic Obstructive Pulmonary Disease (COPD) as a disease of early aging:
Evidence from the EpiChron Cohort. PLoS One 2018; 13(2): e0193143.
30. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive
pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015; 3(8): 631-9.
31. Mannino DM, Higuchi K, Yu TC, et al. Economic Burden of COPD in the Presence of Comorbidities. Chest 2015; 148(1):
138-50.
32. World Health Organization. Evidence-Informed Policy Network: EVIPnet in Action. http://www.who.int/evidence
(accessed Oct 2020).
33. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a
population-based prevalence study. Lancet 2007; 370(9589): 741-50.
34. Duong M, Islam S, Rangarajan S, et al. Global differences in lung function by region (PURE): an international,
community-based prospective study. Lancet Respir Med 2013; 1(8): 599-609.
15
35. Schneider A, Gantner L, Maag I, Borst MM, Wensing M, Szecsenyi J. Are ICD-10 codes appropriate for performance
assessment in asthma and COPD in general practice? Results of a cross sectional observational study. BMC Health Serv
Res 2005; 5(1): 11.
36. Cooke CR, Joo MJ, Anderson SM, et al. The validity of using ICD-9 codes and pharmacy records to identify patients with
chronic obstructive pulmonary disease. BMC Health Serv Res 2011; 11: 37.
37. Stein BD, Bautista A, Schumock GT, et al. The validity of International Classification of Diseases, Ninth Revision, Clinical
Modification diagnosis codes for identifying patients hospitalized for COPD exacerbations. Chest 2012; 141(1): 87-93.
38. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J
2006; 28(4): 781-5.
39. Hoyert DL, Xu JQ. Deaths: preliminary data for 2011. Natl Vital Stat Rep 2011; 61(6): 1-65.
40. European Respiratory Society on behalf of the Forum of International Respiratory Societies (FIRS). The Global Impact of
Respiratory Disease, Second Edition. 2017.
https://www.who.int/gard/publications/The_Global_Impact_of_Respiratory_Disease.pdf (accessed 14 October 2019).
41. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in
the USA. Clinicoecon Outcomes Res 2013; 5: 235-45.
42. Sin DD, Stafinski T, Ng YC, Bell NR, Jacobs P. The impact of chronic obstructive pulmonary disease on work loss in the
United States. Am J Respir Crit Care Med 2002; 165(5): 704-7.
43. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease
Study. Lancet 1997; 349(9064): 1498-504.
44. GBD 2013 DALYs and HALE Collaborators, Murray CJ, Barber RM, et al. Global, regional, and national disability-adjusted
life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013:
TE
quantifying the epidemiological transition. Lancet 2015; 386(10009): 2145-91.
U
IB
45. Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.
R
JAMA 2013; 310(6): 591-608.
T
IS
46. Thomsen M, Nordestgaard BG, Vestbo J, Lange P. Characteristics and outcomes of chronic obstructive pulmonary
D
disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013; 1(7): 543-50.
R
47. Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15%. Lancet 2006; 367(9518): 1216-9.
O
48. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 2005; 365(9478): 2225-36.
PY
49. Blanco I, Diego I, Bueno P, Pérez-Holanda S, Casas-Maldonado F, Miravitlles M. Prevalence of α(1)-antitrypsin PiZZ
O
C
genotypes in patients with COPD in Europe: a systematic review. Eur Respir Rev 2020; 29(157): 200014.
T
50. McCloskey SC, Patel BD, Hinchliffe SJ, Reid ED, Wareham NJ, Lomas DA. Siblings of patients with severe chronic
O
N
obstructive pulmonary disease have a significant risk of airflow obstruction. Am J Respir Crit Care Med 2001; 164(8 Pt
O
1): 1419-24.
-D
51. Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med
L
2009; 361: 2599-608.

IA
52. Ding Z, Wang K, Li J, Tan Q, Tan W, Guo G. Association between glutathione S-transferase gene M1 and T1
ER
polymorphisms and chronic obstructive pulmonary disease risk: A meta-analysis. Clin Genet 2019; 95(1): 53-62.
AT
53. Cho MH, Boutaoui N, Klanderman BJ, et al. Variants in FAM13A are associated with chronic obstructive pulmonary
M
disease. Nat Genet 2010; 42(3): 200-2.

T
H
54. Pillai SG, Ge D, Zhu G, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD):
IG
identification of two major susceptibility loci. PLoS Genet 2009; 5(3): e1000421.
R
55. Soler Artigas M, Wain LV, Repapi E, et al. Effect of five genetic variants associated with lung function on the risk of
PY
chronic obstructive lung disease, and their joint effects on lung function. Am J Respir Crit Care Med 2011; 184(7): 786-
O
C
95.
56. Repapi E, Sayers I, Wain LV, et al. Genome-wide association study identifies five loci associated with lung function. Nat
Genet 2010; 42(1): 36-44.
57. Cho MH, McDonald ML, Zhou X, et al. Risk loci for chronic obstructive pulmonary disease: a genome-wide association
study and meta-analysis. Lancet Respir Med 2014; 2(3): 214-25.
58. Mercado N, Ito K, Barnes PJ. Accelerated ageing of the lung in COPD: new concepts. Thorax 2015; 70(5): 482-9.
59. Landis SH, Muellerova H, Mannino DM, et al. Continuing to Confront COPD International Patient Survey: methods,
COPD prevalence, and disease burden in 2012-2013. Int J Chron Obstruct Pulmon Dis 2014; 9: 597-611.
60. Foreman MG, Zhang L, Murphy J, et al. Early-onset chronic obstructive pulmonary disease is associated with female sex,
maternal factors, and African American race in the COPDGene Study. Am J Respir Crit Care Med 2011; 184(4): 414-20.
61. Lopez Varela MV, Montes de Oca M, Halbert RJ, et al. Sex-related differences in COPD in five Latin American cities: the
PLATINO study. Eur Respir J 2010; 36(5): 1034-41.
62. Silverman EK, Weiss ST, Drazen JM, et al. Gender-related differences in severe, early-onset chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2000; 162(6): 2152-8.
63. Martinez FJ, Curtis JL, Sciurba F, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med 2007;
176(3): 243-52.
64. Tam A, Churg A, Wright JL, et al. Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive
Pulmonary Disease. Am J Respir Crit Care Med 2016; 193(8): 825-34.
16
65. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory
infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991; 303(6804): 671-5.
66. Todisco T, de Benedictis FM, Iannacci L, et al. Mild prematurity and respiratory functions. Eur J Pediatr 1993; 152(1): 55-
8.
67. Lawlor DA, Ebrahim S, Davey Smith G. Association of birth weight with adult lung function: findings from the British
Women's Heart and Health Study and a meta-analysis. Thorax 2005; 60(10): 851-8.
68. Allinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D, Wedzicha JA. Combined Impact of Smoking and Early-Life
Exposures on Adult Lung Function Trajectories. Am J Respir Crit Care Med 2017; 196(8): 1021-30.
69. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow
obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009; 180(1): 3-10.
70. Raad D, Gaddam S, Schunemann HJ, et al. Effects of water-pipe smoking on lung function: a systematic review and
meta-analysis. Chest 2011; 139(4): 764-74.
71. She J, Yang P, Wang Y, et al. Chinese water-pipe smoking and the risk of COPD. Chest 2014; 146(4): 924-31.
72. Gunen H, Tarraf H, Nemati A, Al Ghobain M, Al Mutairi S, Aoun Bacah Z. Waterpipe tobacco smoking. Tuberk Toraks
2016; 64(1): 94-6.
73. Tan WC, Lo C, Jong A, et al. Marijuana and chronic obstructive lung disease: a population-based study. CMAJ 2009;
180(8): 814-20.
74. Yin P, Jiang CQ, Cheng KK, et al. Passive smoking exposure and risk of COPD among adults in China: the Guangzhou
Biobank Cohort Study. Lancet 2007; 370(9589): 751-7.
75. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy. Effects on lung function during the first 18 months
of life. Am J Respir Crit Care Med 1995; 152: 977-83.
TE
76. Paulin LM, Diette GB, Blanc PD, et al. Occupational exposures are associated with worse morbidity in patients with
U
IB
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 191(5): 557-65.
R
77. De Matteis S, Jarvis D, Darnton A, et al. The occupations at increased risk of COPD: analysis of lifetime job-histories in
T
IS
the population-based UK Biobank Cohort. Eur Respir J 2019; 54(1).
D
78. Marchetti N, Garshick E, Kinney GL, et al. Association between occupational exposure and lung function, respiratory
R
symptoms, and high-resolution computed tomography imaging in COPDGene. Am J Respir Crit Care Med 2014; 190(7):
O
756-62.
PY
79. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Association between chronic obstructive pulmonary disease and
O
C
employment by industry and occupation in the US population: a study of data from the Third National Health and
T
Nutrition Examination Survey. Am J Epidemiol 2002; 156(8): 738-46.

O
N
80. Balmes J, Becklake M, Blanc P, et al. American Thoracic Society Statement: Occupational contribution to the burden of
O
airway disease. Am J Respir Crit Care Med 2003; 167(5): 787-97.

-D
81. Orozco-Levi M, Garcia-Aymerich J, Villar J, Ramirez-Sarmiento A, Anto JM, Gea J. Wood smoke exposure and risk of
L
chronic obstructive pulmonary disease. Eur Respir J 2006; 27(3): 542-6.

IA
82. Gan WQ, FitzGerald JM, Carlsten C, Sadatsafavi M, Brauer M. Associations of ambient air pollution with chronic
ER
obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013; 187(7): 721-7.
AT
83. Ezzati M. Indoor air pollution and health in developing countries. Lancet 2005; 366(9480): 104-6.
M
84. Zhou Y, Zou Y, Li X, et al. Lung function and incidence of chronic obstructive pulmonary disease after improved cooking
T
H
fuels and kitchen ventilation: a 9-year prospective cohort study. PLoS Med 2014; 11(3): e1001621.
IG
85. Sana A, Somda SMA, Meda N, Bouland C. Chronic obstructive pulmonary disease associated with biomass fuel use in
R
women: a systematic review and meta-analysis. BMJ Open Respir Res 2018; 5(1): e000246.
PY
86. Assad NA, Balmes J, Mehta S, Cheema U, Sood A. Chronic obstructive pulmonary disease secondary to household air
O
C
pollution. Semin Respir Crit Care Med 2015; 36(3): 408-21.

87. Sherrill DL, Lebowitz MD, Burrows B. Epidemiology of chronic obstructive pulmonary disease. Clin Chest Med 1990;
11(3): 375-87.
88. Ramírez-Venegas A, Velázquez-Uncal M, Aranda-Chávez A, et al. Bronchodilators for hyperinflation in COPD associated
with biomass smoke: clinical trial. Int J Chron Obstruct Pulmon Dis 2019; 14: 1753-62.
89. Chan KH, Kurmi OP, Bennett DA, et al. Solid Fuel Use and Risks of Respiratory Diseases. A Cohort Study of 280,000
Chinese Never-Smokers. Am J Respir Crit Care Med 2019; 199(3): 352-61.
90. Liu S, Zhou Y, Liu S, et al. Association between exposure to ambient particulate matter and chronic obstructive
pulmonary disease: results from a cross-sectional study in China. Thorax 2017; 72(9): 788-95.
91. Doiron D, de Hoogh K, Probst-Hensch N, et al. Air pollution, lung function and COPD: results from the population-based
UK Biobank study. Eur Respir J 2019; 54(1).
92. Gauderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung development from 10 to 18 years of age. N
Engl J Med 2004; 351(11): 1057-67.
93. Gauderman WJ, Urman R, Avol E, et al. Association of improved air quality with lung development in children. N Engl J
Med 2015; 372(10): 905-13.
94. Townend J, Minelli C, Mortimer K, et al. The association between chronic airflow obstruction and poverty in 12 sites of
the multinational BOLD study. Eur Respir J 2017; 49(6).
17
95. Beran D, Zar HJ, Perrin C, Menezes AM, Burney P, Forum of International Respiratory Societies working group c. Burden
of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-
income countries. Lancet Respir Med 2015; 3(2): 159-70.
96. Gershon AS, Warner L, Cascagnette P, Victor JC, To T. Lifetime risk of developing chronic obstructive pulmonary disease:
a longitudinal population study. Lancet 2011; 378(9795): 991-6.
97. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126(1):
59-65.
98. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the presence of
irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up.
Thorax 2003; 58(4): 322-7.
99. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with
asthma. N Engl J Med 1998; 339(17): 1194-200.
100. McGeachie MJ, Yates KP, Zhou X, et al. Patterns of Growth and Decline in Lung Function in Persistent Childhood
Asthma. N Engl J Med 2016; 374(19): 1842-52.
101. de Marco R, Accordini S, Marcon A, et al. Risk factors for chronic obstructive pulmonary disease in a European cohort of
young adults. Am J Respir Crit Care Med 2011; 183(7): 891-7.
102. Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction
due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167(3): 418-24.
103. To T, Zhu J, Larsen K, et al. Progression from Asthma to Chronic Obstructive Pulmonary Disease. Is Air Pollution a Risk
Factor? Am J Respir Crit Care Med 2016; 194(4): 429-38.
104. Rijcken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. The relationship of nonspecific bronchial responsiveness
TE
to respiratory symptoms in a random population sample. Am Rev Respir Dis 1987; 136(1): 62-8.
U
IB
105. Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine airway hyper-responsiveness and mortality from
R
chronic obstructive pulmonary disease: a cohort study. Lancet 2000; 356(9238): 1313-7.
T
IS
106. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung
D
function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research
R
Group. Am J Respir Crit Care Med 1996; 153(6 Pt 1): 1802-11. O
107. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1(6077): 1645-8.
PY
108. Allinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D, Wedzicha JA. The Presence of Chronic Mucus Hypersecretion
O
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across Adult Life in Relation to Chronic Obstructive Pulmonary Disease Development. Am J Respir Crit Care Med 2016;
T
193(6): 662-72.
O
N
109. Guerra S, Sherrill DL, Venker C, Ceccato CM, Halonen M, Martinez FD. Chronic bronchitis before age 50 years predicts
O
incident airflow limitation and mortality risk. Thorax 2009; 64(10): 894-900.
-D
110. Kim V, Han MK, Vance GB, et al. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest
L
2011; 140(3): 626-33.

IA
111. Eklof J, Sorensen R, Ingebrigtsen TS, et al. Pseudomonas aeruginosa and risk of death and exacerbations in patients with
ER
chronic obstructive pulmonary disease: an observational cohort study of 22 053 patients. Clin Microbiol Infect 2019.
AT
112. Bigna JJ, Kenne AM, Asangbeh SL, Sibetcheu AT. Prevalence of chronic obstructive pulmonary disease in the global
M
population with HIV: a systematic review and meta-analysis. Lancet Glob Health 2018; 6(2): e193-e202.
T
H
113. Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review.
IG
Int J Infect Dis 2015; 32: 138-46.

R
114. Menezes AM, Hallal PC, Perez-Padilla R, et al. Tuberculosis and airflow obstruction: evidence from the PLATINO study in
PY
Latin America. Eur Respir J 2007; 30(6): 1180-5.

O
C
115. Jordan TS, Spencer EM, Davies P. Tuberculosis, bronchiectasis and chronic airflow obstruction. Respirology 2010; 15(4):
623-8.
116. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009; 4: 435-59.
117. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol
2016; 138(1): 16-27.
118. Sze MA, Dimitriu PA, Suzuki M, et al. Host Response to the Lung Microbiome in Chronic Obstructive Pulmonary Disease.
Am J Respir Crit Care Med 2015; 192(4): 438-45.
119. Lee SH, Goswami S, Grudo A, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med 2007;
13(5): 567-9.
120. Domej W, Oettl K, Renner W. Oxidative stress and free radicals in COPD--implications and relevance for treatment. Int J
Chron Obstruct Pulmon Dis 2014; 9: 1207-24.
121. Malhotra D, Thimmulappa R, Vij N, et al. Heightened endoplasmic reticulum stress in the lungs of patients with chronic
obstructive pulmonary disease: the role of Nrf2-regulated proteasomal activity. Am J Respir Crit Care Med 2009;
180(12): 1196-207.
122. Stockley RA. Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 1999; 160(5 Pt 2): S49-52.
123. Johnson SR. Untangling the protease web in COPD: metalloproteinases in the silent zone. Thorax 2016; 71(2): 105-6.
124. Polosukhin VV, Richmond BW, Du RH, et al. Secretory IgA Deficiency in Individual Small Airways Is Associated with
Persistent Inflammation and Remodeling. Am J Respir Crit Care Med 2017; 195(8): 1010-21.
18
125. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med 2014; 35(1):
71-86.
126. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other
fibrosing interstitial lung diseases. Hum Pathol 2008; 39(9): 1275-94.
127. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung
abnormalities. N Engl J Med 2011; 364(10): 897-906.
128. Putman RK, Hatabu H, Araki T, et al. Association Between Interstitial Lung Abnormalities and All-Cause Mortality. JAMA
2016; 315(7): 672-81.
129. Churg A, Tai H, Coulthard T, Wang R, Wright JL. Cigarette smoke drives small airway remodeling by induction of growth
factors in the airway wall. Am J Respir Crit Care Med 2006; 174(12): 1327-34.
130. Rennard SI, Wachenfeldt K. Rationale and emerging approaches for targeting lung repair and regeneration in the
treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2011; 8(4): 368-75.
131. Hogg JC, McDonough JE, Gosselink JV, Hayashi S. What drives the peripheral lung-remodeling process in chronic
obstructive pulmonary disease? Proc Am Thorac Soc 2009; 6(8): 668-72.
132. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008; 8(3): 183-92.
133. Global Initiative for Asthma. 2015 Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). 2015 (accessed 14
October 2018).
134. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N
Engl J Med 2004; 350(26): 2645-53.
135. McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary
disease. N Engl J Med 2011; 365(17): 1567-75.
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136. Ofir D, Laveneziana P, Webb KA, Lam YM, O'Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic
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patients with GOLD stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177(6): 622-9.
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137. Elbehairy AF, Ciavaglia CE, Webb KA, et al. Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive
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Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance. Am J Respir Crit Care Med 2015; 191(12): 1384-
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94.
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138. Casaburi R, Maltais F, Porszasz J, et al. Effects of tiotropium on hyperinflation and treadmill exercise tolerance in mild to
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moderate chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014; 11(9): 1351-61.
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139. Rodriguez-Roisin R, Drakulovic M, Rodriguez DA, Roca J, Barbera JA, Wagner PD. Ventilation-perfusion imbalance and
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chronic obstructive pulmonary disease staging severity. J Appl Physiol 2009; 106(6): 1902-8.
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140. Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway
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diseases. Eur Respir J 2008; 32(4): 1068-81.

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141. Sakao S, Voelkel NF, Tatsumi K. The vascular bed in COPD: pulmonary hypertension and pulmonary vascular alterations.
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Eur Respir Rev 2014; 23(133): 350-5.

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142. Iyer KS, Newell JD, Jr., Jin D, et al. Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of
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Smoking-induced Inflammatory Lung Disease. Am J Respir Crit Care Med 2016; 193(6): 652-61.
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143. Alford SK, van Beek EJ, McLennan G, Hoffman EA. Heterogeneity of pulmonary perfusion as a mechanistic image-based
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phenotype in emphysema susceptible smokers. Proc Natl Acad Sci U S A 2010; 107(16): 7485-90.
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144. Peinado VI, Pizarro S, Barbera JA. Pulmonary vascular involvement in COPD. Chest 2008; 134(4): 808-14.
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145. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med
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2012; 367(10): 913-21.

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146. Parker CM, Voduc N, Aaron SD, Webb KA, O'Donnell DE. Physiological changes during symptom recovery from
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moderate exacerbations of COPD. Eur Respir J 2005; 26(3): 420-8.

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147. Barbera JA, Roca J, Ferrer A, et al. Mechanisms of worsening gas exchange during acute exacerbations of chronic
obstructive pulmonary disease. Eur Respir J 1997; 10(6): 1285-91.
148. Miller J, Edwards LD, Agusti A, et al. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir
Med 2013; 107(9): 1376-84.
19
CHAPTER 2: DIAGNOSIS AND INITIAL ASSESSMENT
OVERALL KEY POINTS:

• COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, a
history of recurrent lower respiratory tract infections and/or a history of exposure to risk factors for
the disease.
• Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV1/FVC < 0.70
confirms the presence of persistent airflow limitation.
• The goals of COPD assessment are to determine the level of airflow limitation, the impact of disease
on the patient’s health status, and the risk of future events (such as exacerbations, hospital
admissions, or death), in order to guide therapy.
• Concomitant chronic diseases occur frequently in COPD patients, including cardiovascular disease,
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skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, anxiety, and lung cancer.
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These comorbidities should be actively sought and treated appropriately when present as they can
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influence mortality and hospitalizations independently.
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DIAGNOSIS
COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of
exposure to risk factors for the disease (Figure 2.1 and Table 2.1). Spirometry is required to make the diagnosis in this
clinical context1; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow
limitation and thus of COPD in patients with appropriate symptoms and significant exposures to noxious stimuli. The
WHO has defined a minimum set of interventions for the diagnosis of COPD in primary care.2
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SYMPTOMS
Chronic and progressive dyspnea is the most characteristic symptom of COPD. Cough with sputum production is
present in up to 30% of patients. These symptoms may vary from day-to-day3 and may precede the development of
airflow limitation by many years. Individuals, particularly those with COPD risk factors, presenting with these
symptoms should be examined to search for the underlying cause(s). These patient symptoms should be used to help
develop appropriate interventions. Significant airflow limitation may also be present without chronic dyspnea and/or
cough and sputum production and vice versa.4 Although COPD is defined on the basis of airflow limitation, in practice
the decision to seek medical help is usually determined by the impact of symptoms on a patient’s functional status. A
person may seek medical attention either because of chronic respiratory symptoms or because of an acute, transient
episode of exacerbated respiratory symptoms.
Dyspnea. Dyspnea, a cardinal symptom of COPD, is a major cause of the disability and anxiety that is associated with
the disease.5 Typical COPD patients describe their dyspnea as a sense of increased effort to breathe, chest heaviness,
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air hunger, or gasping.6 However, the terms used to describe dyspnea may vary both individually and culturally.6
Cough. Chronic cough is often the first symptom of COPD and is frequently discounted by the patient as an expected
consequence of smoking and/or environmental exposures. Initially, the cough may be intermittent, but subsequently
may be present every day, often throughout the day. Chronic cough in COPD may be productive or unproductive.7 In
some cases, significant airflow limitation may develop without the presence of a cough. Other causes of chronic cough
are listed in Table 2.2.
Sputum production. COPD patients commonly raise small quantities of tenacious sputum with coughing. Regular
production of sputum for three or more months in two consecutive years (in the absence of any other conditions that
may explain it) is the classical definition of chronic bronchitis,8 but this is a somewhat arbitrary definition that does
not reflect the entire range of sputum production that occurs in COPD. Sputum production is often difficult to evaluate
because patients may swallow sputum rather than expectorate it, a habit that is subject to significant cultural and sex
variation. Furthermore, sputum production can be intermittent with periods of flare-up interspersed with periods of
remission.9 Patients producing large volumes of sputum may have underlying bronchiectasis. The presence of purulent
sputum reflects an increase in inflammatory mediators,10,11 and its development may identify the onset of a bacterial
exacerbation, though the association is relatively weak.11,12
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Wheezing and chest tightness. Wheezing and chest tightness are symptoms that may vary between days, and
over the course of a single day. Audible wheeze may arise at the laryngeal level and need not be accompanied by
abnormalities heard on auscultation. Alternatively, widespread inspiratory or expiratory wheezes can be present on
auscultation. Chest tightness often follows exertion, is poorly localized, is muscular in character, and may arise from
isometric contraction of the intercostal muscles. An absence of wheezing or chest tightness does not exclude a
diagnosis of COPD, nor does the presence of these symptoms confirm a diagnosis of asthma.
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Additional features in severe disease. Fatigue, weight loss, muscle loss, and anorexia are common problems in
patients with severe and very severe COPD.13-15 They have prognostic importance16,17 and can also be a sign of other
diseases, such as tuberculosis or lung cancer, and therefore should always be investigated. Syncope during cough
occurs due to rapid increases in intrathoracic pressure during prolonged attacks of coughing. Coughing spells may also
cause rib fractures, which are sometimes asymptomatic. Ankle swelling may be the only indicator of the presence of
cor pulmonale. Symptoms of depression and/or anxiety merit specific enquiry when obtaining the medical history
because they are common in COPD18 and are associated with poorer health status, increased risk of exacerbations,
and emergency hospital admission.19
MEDICAL HISTORY
A detailed medical history of a new patient who is known, or suspected, to have COPD should include:
► Patient’s exposure to risk factors, such as smoking and occupational or environmental exposures.
► Past medical history, including asthma, allergy, sinusitis, or nasal polyps; respiratory infections in
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childhood; other chronic respiratory and non-respiratory diseases.
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► Family history of COPD or other chronic respiratory disease.
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► Pattern of symptom development: COPD typically develops in adult life and most patients are conscious
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of increased breathlessness, more frequent or prolonged “winter colds,” and some social restriction for
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a number of years before seeking medical help.

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► History of exacerbations or previous hospitalizations for respiratory disorder. Patients may be aware of
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periodic worsening of symptoms even if these episodes have not been identified as exacerbations of
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COPD.
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► Presence of comorbidities, such as heart disease, osteoporosis, musculoskeletal disorders, and

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malignancies that may also contribute to restriction of activity.

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► Impact of disease on patient’s life, including limitation of activity, missed work and economic impact,
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effect on family routines, feelings of depression or anxiety, well-being and sexual activity.
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► Social and family support available to the patient.

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► Possibilities for reducing risk factors, especially smoking cessation.

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Physical examination
Although an important part of patient care, a physical examination is rarely diagnostic in COPD. Physical signs of airflow
limitation are usually not present until significant impairment of lung function has occurred,20,21 and detection based
on physical examination has relatively low sensitivity and specificity. A number of physical signs may be present in
COPD, but absence does not exclude the diagnosis.
Spirometry
Spirometry is the most reproducible and objective measurement of airflow limitation. It is a noninvasive and readily
available test. Despite its good sensitivity, peak expiratory flow measurement alone cannot be reliably used as the
only diagnostic test because of its weak specificity.22,23 Good quality spirometric measurement is possible in any
healthcare setting and all healthcare workers who care for COPD patients should have access to spirometry. Some of
the factors needed to achieve accurate test results are summarized in Table 2.3.24,25
23
Spirometry should measure the volume of air forcibly exhaled from the point of maximal inspiration (forced vital
capacity, FVC) and the volume of air exhaled during the first second of this maneuver (forced expiratory volume in one
second, FEV1), and the ratio of these two measurements (FEV1/FVC) should be calculated. The ratio between FEV1 and
slow vital capacity (VC), FEV1/VC, is sometimes measured instead of the FEV1/FVC ratio. This will often lead to lower
values of the ratio, especially in pronounced airflow limitation. Spirometry measurements are evaluated by
comparison with reference values25 based on age, height, sex, and race.
A normal spirometry tracing is shown in Figure 2.2A. A spirometry tracing typical of a patient with obstructive disease
is shown in Figure 2.2B. Patients with COPD typically show a decrease in both FEV1 and FVC.
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The spirometric criterion for airflow limitation remains a post-bronchodilator fixed ratio of FEV1/FVC < 0.70. This
criterion is simple and independent of reference values, and has been used in numerous clinical trials that form the
evidence base from which most of our treatment recommendations are drawn. It should be noted that the use of the
fixed FEV1/FVC ratio to define airflow limitation may result in more frequent diagnosis of COPD in the elderly,26,27 and
less frequent diagnosis in adults < 45 years,27 especially in mild disease, compared to using a cut-off based on the lower
limit of normal (LLN) values for FEV1/FVC.
The LLN values are based on the normal distribution and classify the bottom 5% of the healthy population as abnormal.
From a scientific or clinical perspective, it is difficult to determine which of these criteria will result in optimal COPD
diagnostic accuracy. However, LLN values are highly dependent on the choice of valid reference equations using post-
bronchodilator FEV1, and there are no longitudinal studies available validating the use of the LLN, or studies using
reference equations in populations where smoking is not the major cause of COPD. Using the fixed ratio is not inferior
to LLN regarding prognosis.28
25
Normal spirometry may be defined by a new approach from the Global Lung Initiative (GLI).29,30 Using GLI equations, z
scores were calculated for FEV1, FVC, and FEV1/FVC. The diagnostic algorithm was initially based on a single threshold,
namely a z score of -1.64 (defining the LLN at the fifth percentile of the normal distribution). The results were
compared to fixed ratio data. The findings suggest that among adults with GLI-defined normal spirometry, the use of
a fixed ratio may misclassify individuals as having respiratory impairment. It is important that these findings are
reproduced in other cohorts.
The risk of misdiagnosis and over-treatment of individual patients using the fixed ratio as a diagnostic criterion is
limited, as spirometry is only one parameter for establishing the clinical diagnosis of COPD; the additional parameters
being symptoms and other risk factors. Diagnostic simplicity and consistency are crucial for the busy clinician. Thus,
GOLD favors the use of the fixed ratio over LLN.
Assessment of the presence or absence of airflow obstruction based on a single measurement of the post-
bronchodilator FEV1/FVC ratio should be confirmed by repeat spirometry on a separate occasion if the value is
between 0.6 and 0.8, as in some cases the ratio may change as a result of biological variation when measured at a
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later interval.31,32 If the initial post-bronchodilator FEV1/FVC ratio is less than 0.6 it is very unlikely to rise above 0.7
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spontaneously.31
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therapeutic decisions is no longer recommended.33 The degree of reversibility has not been shown to augment the
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diagnosis of COPD, differentiate the diagnosis from asthma, or to predict the response to long-term treatment with
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bronchodilators or corticosteroids.34
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The role of screening spirometry in the general population is controversial.35,36 In asymptomatic individuals without
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any significant exposures to tobacco or other noxious stimuli, screening spirometry is probably not indicated; whereas
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yield for COPD is relatively high and spirometry should be considered as a method for early case finding.37,38 Both FEV1
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and FVC predict all-cause mortality independent of tobacco smoking, and abnormal lung function identifies a subgroup
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of smokers at increased risk for lung cancer. This has been the basis of an argument that screening spirometry should
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be employed as a global health assessment tool.39,40 A risk score based on routine data from electronic health records
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in primary care may facilitate case-finding and be cost-effective.41,42 However, there are no data to indicate that
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screening spirometry is effective in directing management decisions or in improving COPD outcomes in patients who
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are identified before the development of significant symptoms.43 This may reflect the design and application of current
case finding instruments that have not been utilized to identify patients with undiagnosed COPD who are most likely
to benefit from existing therapies.44,45 Thus, GOLD advocates active case finding37,46,47 i.e., performing spirometry in
patients with symptoms and/or risk factors, but not screening spirometry. Systematic active case-finding in a primary
care setting via mail-out of a screening questionnaire was also found to be an effective way to identify undiagnosed
COPD patients.48
Interpretation of the severity of lung function impairment is dependent on having appropriate reference values. The
Prospective Urban and Rural Epidemiological (PURE) study analyzed pre-bronchodilator spirometry data from 153,996
healthy people with less than 5 pack-year smoking histories in 17 countries and observed wide variation in lung
function.49 For instance, compared with individuals living in North America or Europe, people living in Southeast Asia
had FEV1 values that were on average 31% lower, adjusted for age, height and sex. Similarly, those living in sub-Saharan
Africa, East Asia, Middle East and South America had FEV1 values that were on average 21%, 13%, 11%, and 6% lower
than individuals living in North America or Europe, respectively, independent of age, height, sex, and smoking status.49
Unless relevant predicted values are used the severity of airflow limitation will be overestimated.
26
ASSESSMENT
The goals of COPD assessment are to determine the level of airflow limitation, its impact on the patient’s health status
and the risk of future events (such as exacerbations, hospital admissions or death), in order to, eventually, guide
therapy.
To achieve these goals, COPD assessment must consider the following aspects of the disease separately:
► The presence and severity of the spirometric abnormality
► Current nature and magnitude of the patient’s symptoms
► History of moderate and severe exacerbations and future risk
► Presence of comorbidities
Classification of severity of airflow limitation

The classification of airflow limitation severity in COPD is shown in Table 2.4. Specific spirometric cut-points are used
for purposes of simplicity. Spirometry should be performed after the administration of an adequate dose of at least
one short-acting inhaled bronchodilator in order to minimize variability.
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It should be noted that there is only a weak correlation between FEV1, symptoms and impairment of a patient’s health
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status.50,51 For this reason, formal symptomatic assessment is required.
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Assessment of symptoms
Here we present the two measures of symptoms that are most widely used.
In the past, COPD was viewed as a disease largely characterized by breathlessness. A simple measure of breathlessness
such as the Modified British Medical Research Council (mMRC) Questionnaire52 (Table 2.5) was considered adequate
for assessment of symptoms, as the mMRC relates well to other measures of health status53 and predicts future
mortality risk.54,55
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However, it is now recognized that COPD impacts patients beyond just dyspnea.56 For this reason, a comprehensive
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assessment of symptoms is recommended rather than just a measure of breathlessness. The most comprehensive
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disease-specific health status questionnaires such as the Chronic Respiratory Questionnaire (CRQ)57 and St. George’s
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Respiratory Questionnaire (SGRQ)58 are too complex to use in routine practice, but shorter comprehensive measures
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e.g., COPD Assessment Test (CAT™) and The COPD Control Questionnaire (The CCQ©) have been developed and are
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suitable.
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COPD Assessment Test (CAT™). The COPD Assessment Test™ * is an 8-item uni-dimensional measure of health
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status impairment in COPD (Figure 2.3).59 It was developed to be applicable worldwide and validated translations are
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available in a wide range of languages. The score ranges from 0-40, correlates very closely with the SGRQ, and has
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Choice of thresholds
The CAT™ and the CCQ© provide measures of the symptomatic impact of COPD but do not categorize patients into
symptom severity groups for the purpose of treatment. The SGRQ is the most widely documented comprehensive
measure; scores < 25 are uncommon in diagnosed COPD patients61 and scores ≥ 25 are very uncommon in healthy
persons.62,63 Therefore, it is recommended that a symptom score equivalent to SGRQ score ≥ 25 should be used as the
threshold for considering regular treatment for symptoms including breathlessness, particularly since this corresponds
to the range of severity seen in patients recruited to the trials that have provided the evidence base for treatment
recommendations. The equivalent cut-point for the CAT™ is 10.64
An equivalent mMRC score cannot be calculated because a simple breathlessness cut-point cannot equate to a
* The COPD Assessment Test was developed by a multi-disciplinary group of international experts in COPD supported by GSK. COPD Assessment Test and the CAT™ logo is a trademark of the
GlaxoSmithKline group of companies. © 2009 GlaxoSmithKline. All rights reserved. GSK activities with respect to the COPD Assessment Test™ are overseen by a governance board that includes
independent external experts, one of whom chairs the board.
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comprehensive symptom score cut-point. The great majority of patients with an SGRQ of ≥ 25 will have an mMRC of
≥ 1; however patients with mMRC < 1 may also have a number of other COPD symptoms.65 For this reason, the use of
a comprehensive symptom assessment is recommended. However, because use of the mMRC is widespread, an mMRC
of ≥ 2 is still included as a threshold for separating “less breathlessness” from “more breathlessness.” Nevertheless,
users are cautioned that assessment of other symptoms is required.65
There are other scales available such as the COPD Control Questionnaire (CCQ) and the Chronic Respiratory Disease
Questionnaire (CRQ) that will not be discussed in detail.
Assessment of exacerbation risk

COPD exacerbations are defined as an acute worsening of respiratory symptoms that result in additional therapy.66-69
These events are classified as mild (treated with short acting bronchodilators (SABDs) only), moderate (treated with
SABDs plus antibiotics and/or oral corticosteroids) or severe (patient requires hospitalization or visits the emergency
room). Severe exacerbations may also be associated with acute respiratory failure. A number of large studies that
classified patients using the GOLD spirometric grading systems have been conducted.70-72 These studies demonstrate
that exacerbation rates vary greatly between patients72 and during follow-up.73 The best predictor of having frequent
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exacerbations (defined as two or more exacerbations per year) is a history of earlier treated events.72
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In addition, deteriorating airflow limitation is associated with an increasing prevalence of exacerbations,
hospitalization74 and risk of death.61,75 Hospitalization for a COPD exacerbation is associated with poor prognosis and
increased risk of death.76 There is also a significant relationship between spirometric severity and the risk of
exacerbation and death. At the population level, approximately 20% of GOLD 2 (moderate airflow limitation) patients
may experience frequent exacerbations requiring treatment with antibiotics and/or systemic corticosteroids.72 The
risk of exacerbations is significantly higher for patients with GOLD 3 (severe) and GOLD 4 (very severe). However, FEV1
by itself lacks sufficient precision (i.e., wide variation) to be used clinically as a predictor of exacerbation or mortality
in patients with COPD.75
The association between blood eosinophil count and risk of exacerbations is outlined in Chapter 3.
Assessment of concomitant chronic diseases (comorbidities)

Patients with COPD often have important concomitant chronic illnesses at the time of diagnosis and COPD represents
an important component of multimorbidity development particularly in the elderly in response to common risk factors
(e.g., aging, smoking, alcohol, diet and inactivity).76-79 COPD itself also has significant extrapulmonary (systemic) effects
including weight loss, nutritional abnormalities and skeletal muscle dysfunction. Skeletal muscle dysfunction is
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characterized by both sarcopenia (loss of muscle cells) and abnormal function of the remaining cells.80 Its causes are
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likely multifactorial (e.g., inactivity, poor diet, inflammation and hypoxia) and it can contribute to exercise intolerance
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and poor health status in patients with COPD. Importantly, skeletal muscle dysfunction is a rectifiable source of
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exercise intolerance.81
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Common comorbidities include cardiovascular disease,82 skeletal muscle dysfunction, metabolic syndrome,
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osteoporosis, depression, anxiety and lung cancer. The existence of COPD may actually increase the risk for other
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diseases; this is particularly striking for COPD and lung cancer.83,84 Whether this association is due to common risk
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factors (e.g., smoking), involvement of susceptibility genes, or impaired clearance of carcinogens is not clear.
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Comorbidities can occur in patients with mild, moderate or severe airflow limitation,61 influence mortality and
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hospitalizations independently,85 and deserve specific treatment. Therefore, comorbidities should be looked for
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routinely, and treated appropriately, in any patient with COPD. Recommendations for the diagnosis, assessment of
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severity, and management of individual comorbidities in patients with COPD are the same as for all other patients. A
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more detailed description of the management of COPD and comorbidities is provided in Chapter 6.
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Combined COPD assessment

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patient’s spirometric classification and/or risk of exacerbations. The “ABCD” assessment tool of the 2011 GOLD update
was a major step forward from the simple spirometric grading system of the earlier versions of GOLD because it
incorporated patient-reported outcomes and highlighted the importance of exacerbation prevention in the
management of COPD. However, there were some important limitations. Firstly, the ABCD assessment tool performed
no better than the spirometric grades for mortality prediction or other important health outcomes in COPD.75,86,87
Moreover, group “D” outcomes were modified by two parameters: lung function and/or exacerbation history, which
caused confusion.51 To address these and other concerns (while at the same time maintaining consistency and
simplicity for the practicing clinician), a refinement of the ABCD assessment tool is proposed that separates spirometric
grades from the “ABCD” groups. For some therapeutic recommendations, ABCD groups will be derived exclusively
from patient symptoms and their history of exacerbation. Spirometry, in conjunction with patient symptoms and
history of moderate and severe exacerbations, remains vital for the diagnosis, prognostication and consideration of
other important therapeutic approaches. This new approach to assessment is illustrated in Figure 2.4.
In the revised assessment scheme, patients should undergo spirometry to determine the severity of airflow limitation
30
(i.e., spirometric grade). They should also undergo assessment of either dyspnea using mMRC or symptoms using
CAT™. Finally, their history of moderate and severe exacerbations (including prior hospitalizations) should be
recorded.
The number provides information regarding severity of airflow limitation (spirometric grade 1 to 4) while the letter
(groups A to D) provides information regarding symptom burden and risk of exacerbation which can be used to guide
therapy. FEV1 is a very important parameter at the population-level in the prediction of important clinical outcomes
such as mortality and hospitalizations or prompting consideration for non-pharmacological therapies such as lung
volume reduction or lung transplantation. However, it is important to note that at the individual patient level, FEV1
loses precision and thus cannot be used alone to determine all therapeutic options. Furthermore, in some
circumstances, such as during hospitalization or urgent presentation to the clinic or emergency room, the ability to
assess patients based on symptoms and exacerbation history, independent of the spirometric value, allows clinicians
to initiate a treatment plan based on the revised ABCD scheme alone. This assessment approach acknowledges the
limitations of FEV1 in making treatment decisions for individualized patient care and highlights the importance of
patient symptoms and exacerbation risks in guiding therapies in COPD. The separation of airflow limitation from
clinical parameters makes it clearer what is being evaluated and ranked. This will facilitate more precise treatment
recommendations based on parameters that are driving the patient’s symptoms at any given time.
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Example: Consider two patients – both patients with FEV1 < 30% of predicted, CAT™ scores of 18 and one with no
exacerbations in the past year and the other with three moderate exacerbations in the past year. Both would have
been labelled GOLD D in the prior classification scheme. However, with the new proposed scheme, the subject with
three moderate exacerbations in the past year would be labelled GOLD grade 4, group D.
31
Individual decisions on pharmacotherapeutic approaches would use the recommendations in Chapter 4 based on the
ABCD assessment to treat the patient’s major problem at this time i.e., persistent exacerbations. The other patient,
who has had no exacerbations, would be classified as GOLD grade 4, group B. In such patients – besides
pharmacotherapy and rehabilitation – lung volume reduction, lung transplant or bullectomy may be important
considerations for therapy given their symptom burden and level of spirometric limitation.
Note: In cases where there is a marked discordance between the level of airflow limitation and the perceived
symptoms, a more detailed evaluation should be carried out to better understand lung mechanics (e.g., full lung
function tests), lung structure (e.g., computed tomography) and/or comorbidities (e.g., ischemic heart disease) that
might impact patient symptoms. In some cases, patients may endorse minimal symptoms despite demonstrating
severe airflow limitation. Adapting to the limitations induced by COPD, these patients may reduce their level of
physical activity in a way that may result in an underestimation of the symptom load. In these cases, exercise tests like
the 6-minute walking distance may reveal that the patients are severely constrained and do need more intense
treatment than the initial evaluation would have suggested.
The role of spirometry for the diagnosis, assessment and follow-up of COPD is summarized in Table 2.6.
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Alpha-1 antitrypsin deficiency (AATD)

Alpha-1 antitrypsin deficiency (AATD) screening. The World Health Organization recommends that all patients
with a diagnosis of COPD should be screened once especially in areas with high AATD prevalence.88,89 Although the
classical patient is young (< 45 years) with panlobular basal emphysema, it has become recognized that delay in
diagnosis has led to identification of some AATD patients when they are older and have a more typical distribution of
emphysema (centrilobular apical).90 A low concentration (< 20% normal) is highly suggestive of homozygous deficiency.
Family members should be screened and, together with the patient, referred to specialist centers for advice and
management (see Chapter 3).
32
Additional investigations
The following additional investigations may be considered as part of the diagnosis and assessment of COPD.
Imaging. A chest X-ray is not useful to establish a diagnosis in COPD, but it is valuable in excluding alternative
diagnoses and establishing the presence of significant comorbidities such as concomitant respiratory (pulmonary
fibrosis, bronchiectasis, pleural diseases), skeletal (e.g., kyphoscoliosis), and cardiac diseases (e.g., cardiomegaly).
Radiological changes associated with COPD include signs of lung hyperinflation (flattened diaphragm and an increase
in the volume of the retrosternal air space), hyperlucency of the lungs, and rapid tapering of the vascular markings.
Computed tomography (CT) of the chest is not routinely recommended except for detection of bronchiectasis and
COPD patients that meet the criteria for lung cancer risk assessment. The presence of emphysema in particular may
increase the risk for development of lung cancer. However, CT scanning may be helpful in the differential diagnosis
where concomitant diseases are present. In addition, if a surgical procedure such as lung volume reduction,91 or
increasingly non-surgical based lung volume reduction92 is contemplated, a chest CT scan is necessary since the
distribution of emphysema is one of the most important determinants of surgical suitability. A CT scan is also required
for patients being evaluated for lung transplantation.
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Lung volumes and diffusing capacity. COPD patients exhibit gas trapping (a rise in residual volume) from the
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early stages of the disease, and as airflow limitation worsens, static hyperinflation (an increase in total lung capacity)
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occurs. These changes can be documented by body plethysmography, or less accurately by helium dilution lung volume
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measurement. These measurements help characterize the severity of COPD but are not essential to patient
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management. Measurement of diffusing capacity (DLCO) provides information on the functional impact of emphysema
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in COPD and is often helpful in patients with breathlessness that may seem out of proportion to the degree of airflow
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limitation.
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Oximetry and arterial blood gas measurement. Pulse oximetry can be used to evaluate a patient’s arterial
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oxygen saturation and need for supplemental oxygen therapy. Pulse oximetry should be used to assess all patients
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with clinical signs suggestive of respiratory failure or right heart failure. If peripheral arterial oxygen saturation is <
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92% arterial or capillary blood gases should be assessed.93,94

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Exercise testing and assessment of physical activity. Objectively measured exercise impairment, assessed
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by a reduction in self-paced walking distance95,96 or during incremental exercise testing in a laboratory,97 is a powerful
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indicator of health status impairment and predictor of prognosis; exercise capacity may fall in the year before death.98
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Walking tests can be useful for assessing disability and risk of mortality99 and are used to assess the effectiveness of
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pulmonary rehabilitation. Both the paced shuttle walk test100 and the unpaced 6-minute walk test can be used.101,102
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As the course length has a substantial impact on the distance walked, existing reference equations established for a
30 meter course cannot be applied to predict the distance achieved on shorter courses.103 Laboratory testing using
cycle or treadmill ergometry can assist in identifying co-existing or alternative conditions e.g., cardiac diagnoses.
Monitoring of physical activity may be more relevant regarding prognosis than evaluating exercise capacity.104 This can
be conducted using accelerometers or multi-sensor instruments.
Composite scores. Several variables identify patients at increased risk for mortality including FEV1, exercise
tolerance assessed by walking distance or peak oxygen consumption, weight loss, and reduction in arterial oxygen
tension. A relatively simple approach to identifying disease severity using a combination of most of the above variables
has been proposed. The BODE (Body mass index, Obstruction, Dyspnea, and Exercise) method gives a composite score
that is a better predictor of subsequent survival than any single component.105,106 Simpler alternatives that do not
include an exercise test have been suggested but all these approaches need validation across a wide range of disease
severities and clinical settings to confirm that they are suitable for routine clinical use.107,108
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Differential diagnoses. In some patients with chronic asthma, a clear distinction from COPD is difficult using current
imaging and physiological testing techniques, since the two conditions share common traits and clinical expressions.
Most other potential differential diagnoses are easier to distinguish from COPD (Table 2.7).
Biomarkers. There is rapidly increasing interest in the use of biomarkers in COPD. Biomarkers are ‘characteristics
that are objectively measured and evaluated as an indicator of normal biological or pathogenic processes or
pharmacological responses to therapeutic interventions’. In general such data has proven difficult to interpret, largely
as a result of weak associations and lack of reproducibility between large patient cohorts109 which was further
confirmed in the SUMMIT study.110 Some studies (see Chapter 5 – Exacerbations) have indicated the use of C-reactive
protein (CRP) and procalcitonin111 in reducing antibiotic usage during exacerbations, although the observed sputum
color remains highly sensitive and specific for a high bacterial load during such episodes.
At present the assessment of eosinophils provides the best guidance to the use of corticosteroids109 especially in the
prevention of some exacerbations (see Chapter 3 – Inhaled Corticosteroids).
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Continued cautious and realistic interpretation of the role of biomarkers in the management of identified clinical traits
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is required.
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Other considerations. It is clear that some patients without evidence of airflow limitation have evidence of
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structural lung disease on chest imaging (emphysema, gas trapping, airway wall thickening) that is consistent with
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what is found in patients with COPD. Such patients may report exacerbations of respiratory symptoms or even require
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treatment with respiratory medications on a chronic basis. Whether these patients have acute or chronic bronchitis,
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a persistent form of asthma or an earlier presentation of what will become COPD as it is currently defined, is unclear
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at present and will require further study.

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REFERENCES
1. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a
population-based prevalence study. Lancet 2007; 370(9589): 741-50.
2. World Health Organization. WHO package of essential noncommunicable (PEN) disease interventions for primary health
care. Geneva. Licence: CC BY-NC-SA 3.0 IGO, online document available here:
https://www.who.int/publications/i/item/who-package-of-essential-noncommunicable-(pen)-disease-interventions-
for-primary-health-care [accessed Oct 2020].
3. Kessler R, Partridge MR, Miravitlles M, et al. Symptom variability in patients with severe COPD: a pan-European cross-
sectional study. Eur Respir J 2011; 37(2): 264-72.
4. Montes de Oca M, Perez-Padilla R, Talamo C, et al. Acute bronchodilator responsiveness in subjects with and without
airflow obstruction in five Latin American cities: the PLATINO study. Pulm Pharmacol Ther 2010; 23(1): 29-35.
5. Miravitlles M, Worth H, Soler Cataluna JJ, et al. Observational study to characterise 24-hour COPD symptoms and their
relationship with patient-reported outcomes: results from the ASSESS study. Respir Res 2014; 15: 122.
6. Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz A. The language of breathlessness. Use of verbal
descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 1991; 144(4): 826-32.
7. Cho SH, Lin HC, Ghoshal AG, et al. Respiratory disease in the Asia-Pacific region: Cough as a key symptom. Allergy
Asthma Proc 2016; 37(2): 131-40.
8. Medical Research Council Committee on the Aetiology of Chronic Bronchitis. Definition and classification of chronic
bronchitis for clinical and epidemiological purposes. A report to the Medical Research Council by their Committee on
TE
the Aetiology of Chronic Bronchitis. Lancet 1965; 1(7389): 775-9.
U
9. Allinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D, Wedzicha JA. The Presence of Chronic Mucus Hypersecretion
IB
across Adult Life in Relation to Chronic Obstructive Pulmonary Disease Development. Am J Respir Crit Care Med 2016;
TR
193(6): 662-72.
IS
10. Soler N, Esperatti M, Ewig S, Huerta A, Agusti C, Torres A. Sputum purulence-guided antibiotic use in hospitalised
D
R
patients with exacerbations of COPD. Eur Respir J 2012; 40(6): 1344-53.O
11. Brusse-Keizer MG, Grotenhuis AJ, Kerstjens HA, et al. Relation of sputum colour to bacterial load in acute exacerbations
PY
of COPD. Respir Med 2009; 103(4): 601-6.

O
12. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute
C
exacerbations of COPD. Chest 2000; 117(6): 1638-45.

T
O
13. von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia
N
Sarcopenia Muscle 2010; 1(1): 1-5.

O
-D
14. Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. Prevalence and characteristics of
nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993; 147(5):
L
IA
1151-6.
ER
15. Attaway AH, Welch N, Hatipoglu U, Zein JG, Dasarathy S. Muscle loss contributes to higher morbidity and mortality in
AT
COPD: An analysis of national trends. Respirology 2020: online ahead of print; 10.1111/resp.13877.
M
16. Rutten EP, Calverley PM, Casaburi R, et al. Changes in body composition in patients with chronic obstructive pulmonary
T
disease: do they influence patient-related outcomes? Ann Nutr Metab 2013; 63(3): 239-47.
H
IG
17. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive
R
pulmonary disease. Am J Clin Nutr 2005; 82(1): 53-9.

PY
18. Hanania NA, Mullerova H, Locantore NW, et al. Determinants of depression in the ECLIPSE chronic obstructive
O
pulmonary disease cohort. Am J Respir Crit Care Med 2011; 183(5): 604-11.
C
19. Blakemore A, Dickens C, Chew-Graham CA, et al. Depression predicts emergency care use in people with chronic
obstructive pulmonary disease: a large cohort study in primary care. Int J Chron Obstruct Pulmon Dis 2019; 14: 1343-53.
20. Holleman DR, Jr., Simel DL. Does the clinical examination predict airflow limitation? JAMA 1995; 273(4): 313-9.
21. Kesten S, Chapman KR. Physician perceptions and management of COPD. Chest 1993; 104(1): 254-8.
22. Colak Y, Nordestgaard BG, Vestbo J, Lange P, Afzal S. Prognostic significance of chronic respiratory symptoms in
individuals with normal spirometry. Eur Respir J 2019; 54(3).
23. Jackson H, Hubbard R. Detecting chronic obstructive pulmonary disease using peak flow rate: cross sectional survey.
BMJ 2003; 327(7416): 653-4.
24. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26(2): 319-38.
25. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26(5): 948-68.
26. van Dijk W, Tan W, Li P, et al. Clinical relevance of fixed ratio vs lower limit of normal of FEV1/FVC in COPD: patient-
reported outcomes from the CanCOLD cohort. Ann Fam Med 2015; 13(1): 41-8.
27. Guder G, Brenner S, Angermann CE, et al. "GOLD or lower limit of normal definition? A comparison with expert-based
diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study". Respir Res 2012; 13(1): 13.
28. Bhatt SP, Balte PP, Schwartz JE, et al. Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization
and Mortality. JAMA 2019; 321(24): 2438-47.
29. Vaz Fragoso CA, McAvay G, Van Ness PH, et al. Phenotype of normal spirometry in an aging population. Am J Respir Crit
Care Med 2015; 192(7): 817-25.
36
30. Vaz Fragoso CA, McAvay G, Van Ness PH, et al. Phenotype of Spirometric Impairment in an Aging Population. Am J
Respir Crit Care Med 2016; 193(7): 727-35.
31. Aaron SD, Tan WC, Bourbeau J, et al. Diagnostic Instability and Reversals of Chronic Obstructive Pulmonary Disease
Diagnosis in Individuals with Mild to Moderate Airflow Obstruction. Am J Respir Crit Care Med 2017; 196(3): 306-14.
32. Schermer TR, Robberts B, Crockett AJ, et al. Should the diagnosis of COPD be based on a single spirometry test? NPJ
Prim Care Respir Med 2016; 26: 16059.
33. Albert P, Agusti A, Edwards L, et al. Bronchodilator responsiveness as a phenotypic characteristic of established chronic
obstructive pulmonary disease. Thorax 2012; 67(8): 701-8.
34. Hansen JE, Porszasz J. Counterpoint: Is an increase in FEV(1) and/or FVC >/= 12% of control and >/= 200 mL the best
way to assess positive bronchodilator response? No. Chest 2014; 146(3): 538-41.
35. Siu AL, Bibbins-Domingo K, Grossman DC, et al. Screening for Chronic Obstructive Pulmonary Disease: US Preventive
Services Task Force Recommendation Statement. JAMA 2016; 315(13): 1372-7.
36. Qaseem A, Snow V, Shekelle P, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a
clinical practice guideline from the American College of Physicians. Ann Intern Med 2007; 147(9): 633-8.
37. Hill K, Goldstein RS, Guyatt GH, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among
patients at risk in primary care. CMAJ 2010; 182(7): 673-8.
38. Lopez Varela MV, Montes de Oca M, Rey A, et al. Development of a simple screening tool for opportunistic COPD case
finding in primary care in Latin America: The PUMA study. Respirology 2016; 21(7): 1227-34.
39. Tammemagi MC, Lam SC, McWilliams AM, Sin DD. Incremental value of pulmonary function and sputum DNA image
cytometry in lung cancer risk prediction. Cancer Prev Res (Phila) 2011; 4(4): 552-61.
40. de-Torres JP, Wilson DO, Sanchez-Salcedo P, et al. Lung cancer in patients with chronic obstructive pulmonary disease.
TE
Development and validation of the COPD Lung Cancer Screening Score. Am J Respir Crit Care Med 2015; 191(3): 285-91.
U
IB
41. Haroon S, Adab P, Riley RD, Fitzmaurice D, Jordan RE. Predicting risk of undiagnosed COPD: development and validation
R
of the TargetCOPD score. Eur Respir J 2017; 49(6).
T
IS
42. Lambe T, Adab P, Jordan RE, et al. Model-based evaluation of the long-term cost-effectiveness of systematic case-
D
finding for COPD in primary care. Thorax 2019; 74(8): 730-9.
R
43. U.S. Preventive Services Task Force, Siu AL, Bibbins-Domingo K, et al. Screening for Chronic Obstructive Pulmonary
O
Disease: US Preventive Services Task Force Recommendation Statement. JAMA 2016; 315(13): 1372-7.
PY
44. Tan WC, Sin DD, Bourbeau J, et al. Characteristics of COPD in never-smokers and ever-smokers in the general
O
C
population: results from the CanCOLD study. Thorax 2015; 70(9): 822-9.
T
45. Han MK, Steenrod AW, Bacci ED, et al. Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight
O
N
from Screening Tools and Epidemiologic Studies. Chronic Obstr Pulm Dis (Miami) 2015; 2(2): 103-21.
O
46. Dirven JA, Tange HJ, Muris JW, van Haaren KM, Vink G, van Schayck OC. Early detection of COPD in general practice:
-D
implementation, workload and socioeconomic status. A mixed methods observational study. Prim Care Respir J 2013;
L
22(3): 338-43.
IA
47. Le Rouzic O, Roche N, Cortot AB, et al. Defining the "Frequent Exacerbator" Phenotype in COPD: A Hypothesis-Free
ER
Approach. Chest 2018; 153(5): 1106-15.

AT
48. Jordan RE, Adab P, Sitch A, et al. Targeted case finding for chronic obstructive pulmonary disease versus routine
M
practice in primary care (TargetCOPD): a cluster-randomised controlled trial. Lancet Respir Med 2016; 4(9): 720-30.
T
H
49. Duong M, Islam S, Rangarajan S, et al. Global differences in lung function by region (PURE): an international,
IG
community-based prospective study. Lancet Respir Med 2013; 1(8): 599-609.

R
50. Jones PW. Health status and the spiral of decline. COPD 2009; 6(1): 59-63.
PY
51. Han MK, Muellerova H, Curran-Everett D, et al. GOLD 2011 disease severity classification in COPDGene: a prospective
O
C
cohort study. Lancet Respir Med 2013; 1(1): 43-50.

52. Fletcher CM. Standardised questionnaire on respiratory symptoms: a statement prepared and approved by the MRC
Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960; 2: 1662.
53. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC)
dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54(7):
581-6.
54. Sundh J, Janson C, Lisspers K, Stallberg B, Montgomery S. The Dyspnoea, Obstruction, Smoking, Exacerbation (DOSE)
index is predictive of mortality in COPD. Prim Care Respir J 2012; 21(3): 295-301.
55. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in
patients with COPD. Chest 2002; 121(5): 1434-40.
56. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001; 56(11): 880-7.
57. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic
lung disease. Thorax 1987; 42(10): 773-8.
58. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow
limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992; 145(6): 1321-7.
59. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD
Assessment Test. Eur Respir J 2009; 34(3): 648-54.
37
60. Karloh M, Fleig Mayer A, Maurici R, Pizzichini MM, Jones PW, Pizzichini E. The COPD Assessment Test: What Do We
Know So Far?: A Systematic Review and Meta-Analysis About Clinical Outcomes Prediction and Classification of Patients
Into GOLD Stages. Chest 2016; 149(2): 413-25.
61. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11:
122.
62. Nishimura K, Mitsuma S, Kobayashi A, et al. COPD and disease-specific health status in a working population. Respir Res
2013; 14: 61.
63. Miravitlles M, Soriano J, Garcia-Rio F, et al. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life
and daily life activities. Thorax 2009; 64: 863-8.
64. Jones PW, Tabberer M, Chen WH. Creating scenarios of the impact of COPD and their relationship to COPD Assessment
Test (CAT) scores. BMC Pulm Med 2011; 11: 42.
65. Jones PW, Adamek L, Nadeau G, Banik N. Comparisons of health status scores with MRC grades in COPD: implications
for the GOLD 2011 classification. Eur Respir J 2013; 42(3): 647-54.
66. Hurst JR, Wedzicha JA. What is (and what is not) a COPD exacerbation: thoughts from the new GOLD guidelines. Thorax
2007; 62(3): 198-9.
67. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007; 370(9589): 786-96.
68. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157(5 Pt 1): 1418-22.
69. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl 2003; 41: 46s-53s.
70. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive
pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374(9696):
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1171-8.
U
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71. Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic
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obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009; 10:
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IS
59.
D
72. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J
R
Med 2010; 363(12): 1128-38. O
73. Han MK, Quibrera PM, Carretta EE, et al. Frequency of exacerbations in patients with chronic obstructive pulmonary
PY
disease: an analysis of the SPIROMICS cohort. Lancet Respir Med 2017; 5(8): 619-26.
O
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74. Mullerova H, Maselli DJ, Locantore N, et al. Hospitalized exacerbations of COPD: risk factors and outcomes in the
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ECLIPSE cohort. Chest 2015; 147(4): 999-1007.

O
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75. Soriano JB, Lamprecht B, Ramirez AS, et al. Mortality prediction in chronic obstructive pulmonary disease comparing
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the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data. Lancet Respir Med 2015; 3(6):
-D
443-50.
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76. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute
IA
exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60(11): 925-31.
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77. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and
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asthma in primary care. Chest 2005; 128(4): 2099-107.

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78. National Institute for Health and Care Excellence. Multimorbidity: clinical assessment and management; NICE guideline
T
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[NG56]Published date: 21 September 2016. 2016. https://www.nice.org.uk/guidance/ng56 (accessed Oct 2020).

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79. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and
R
systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187(7):
PY
728-35.
O
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80. Wagner PD. Possible mechanisms underlying the development of cachexia in COPD. Eur Respir J 2008; 31(3): 492-501.
81. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society
statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2014; 189(9): e15-62.
82. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive
pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015; 3(8): 631-9.
83. Brenner DR, Boffetta P, Duell EJ, et al. Previous lung diseases and lung cancer risk: a pooled analysis from the
International Lung Cancer Consortium. Am J Epidemiol 2012; 176(7): 573-85.
84. Fry JS, Hamling JS, Lee PN. Systematic review with meta-analysis of the epidemiological evidence relating FEV1 decline
to lung cancer risk. BMC Cancer 2012; 12: 498.
85. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular
disease in COPD. Eur Respir J 2008; 32(4): 962-9.
86. Goossens LM, Leimer I, Metzdorf N, Becker K, Rutten-van Molken MP. Does the 2013 GOLD classification improve the
ability to predict lung function decline, exacerbations and mortality: a post-hoc analysis of the 4-year UPLIFT trial. BMC
Pulm Med 2014; 14: 163.
87. Kim J, Yoon HI, Oh YM, et al. Lung function decline rates according to GOLD group in patients with chronic obstructive
pulmonary disease. Int J Chron Obstruct Pulmon Dis 2015; 10: 1819-27.
88. WHO meeting participants. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health
Organ 1997; 75(5): 397-415.
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89. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of
pulmonary disease in alpha1-antitrypsin deficiency. Eur Respir J 2017; 50(5).
90. Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences
lung function impairment. Am J Respir Crit Care Med 2004; 170(11): 1172-8.
91. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical
therapy for severe emphysema. N Engl J Med 2003; 348(21): 2059-73.
92. Klooster K, ten Hacken NH, Hartman JE, Kerstjens HA, van Rikxoort EM, Slebos DJ. Endobronchial Valves for Emphysema
without Interlobar Collateral Ventilation. N Engl J Med 2015; 373(24): 2325-35.
93. Amalakanti S, Pentakota MR. Pulse Oximetry Overestimates Oxygen Saturation in COPD. Respir Care 2016; 61(4): 423-7.
94. Kelly AM, McAlpine R, Kyle E. How accurate are pulse oximeters in patients with acute exacerbations of chronic
obstructive airways disease? Respir Med 2001; 95(5): 336-40.
95. Durheim MT, Smith PJ, Babyak MA, et al. Six-minute-walk distance and accelerometry predict outcomes in chronic
obstructive pulmonary disease independent of Global Initiative for Chronic Obstructive Lung Disease 2011 Group. Ann
Am Thorac Soc 2015; 12(3): 349-56.
96. Pinto-Plata VM, Cote C, Cabral H, Taylor J, Celli BR. The 6-min walk distance: change over time and value as a predictor
of survival in severe COPD. Eur Respir J 2004; 23(1): 28-33.
97. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive
pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003; 167(4): 544-9.
98. Polkey MI, Spruit MA, Edwards LD, et al. Six-minute-walk test in chronic obstructive pulmonary disease: minimal
clinically important difference for death or hospitalization. Am J Respir Crit Care Med 2013; 187(4): 382-6.
99. Celli B, Tetzlaff K, Criner G, et al. The 6-Minute-Walk Distance Test as a Chronic Obstructive Pulmonary Disease
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Stratification Tool. Insights from the COPD Biomarker Qualification Consortium. Am J Respir Crit Care Med 2016;
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194(12): 1483-93.
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100. Revill SM, Morgan MD, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: a new field test for the
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assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax 1999; 54(3): 213-22.
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101. Casanova C, Cote CG, Marin JM, et al. The 6-min walking distance: long-term follow up in patients with COPD. Eur Respir
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J 2007; 29(3): 535-40. O
102. Puente-Maestu L, Palange P, Casaburi R, et al. Use of exercise testing in the evaluation of interventional efficacy: an
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official ERS statement. Eur Respir J 2016; 47(2): 429-60.

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103. Beekman E, Mesters I, Hendriks EJ, et al. Course length of 30 metres versus 10 metres has a significant influence on six-
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minute walk distance in patients with COPD: an experimental crossover study. J Physiother 2013; 59(3): 169-76.
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104. Waschki B, Kirsten A, Holz O, et al. Physical activity is the strongest predictor of all-cause mortality in patients with
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COPD: a prospective cohort study. Chest 2011; 140(2): 331-42.

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105. Guerra B, Haile SR, Lamprecht B, et al. Large-scale external validation and comparison of prognostic models: an
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application to chronic obstructive pulmonary disease. BMC Med 2018; 16(1): 33.
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106. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in
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chronic obstructive pulmonary disease. N Engl J Med 2004; 350(10): 1005-12.

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107. Jones RC, Donaldson GC, Chavannes NH, et al. Derivation and validation of a composite index of severity in chronic
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obstructive pulmonary disease: the DOSE Index. Am J Respir Crit Care Med 2009; 180(12): 1189-95.
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108. Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of the prognostic assessment of patients with chronic
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obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet 2009; 374(9691): 704-11.
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109. Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic Obstructive Pulmonary Disease Biomarkers and Their
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Interpretation. Am J Respir Crit Care Med 2019; 199(10): 1195-204.

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110. Celli BR, Anderson JA, Brook R, et al. Serum biomarkers and outcomes in patients with moderate COPD: a substudy of
the randomised SUMMIT trial. BMJ Open Respir Res 2019; 6(1): e000431.
111. Ni W, Bao J, Yang D, et al. Potential of serum procalcitonin in predicting bacterial exacerbation and guiding antibiotic
administration in severe COPD exacerbations: a systematic review and meta-analysis. Infect Dis (Lond) 2019; 51(9): 639-
50.
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CHAPTER 3: EVIDENCE SUPPORTING PREVENTION AND
MAINTENANCE THERAPY
OVERALL KEY POINTS:

• Smoking cessation is key. Pharmacotherapy and nicotine replacement reliably increase long-term
smoking abstinence rates. Legislative smoking bans and counseling, delivered by healthcare
professionals, improve quit rates.
• The effectiveness and safety of e-cigarettes as a smoking cessation aid is uncertain at present.
• Pharmacological therapy can reduce COPD symptoms, reduce the frequency and severity of
exacerbations, and improve health status and exercise tolerance. Recent data suggest beneficial
effects on mortality.
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• Each pharmacological treatment regimen should be individualized and guided by the severity of
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symptoms, risk of exacerbations, side-effects, comorbidities, drug availability and cost, and the
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patient’s response, preference and ability to use various drug delivery devices.
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• Inhaler technique needs to be assessed regularly.
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• Influenza vaccination decreases the incidence of lower respiratory tract infections.
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• Pneumococcal vaccination decreases lower respiratory tract infections.

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• CDC recommends the Tdap vaccination (dTaP/dTPa) in COPD patients to protect against pertussis,
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tetanus and diphtheria, in those who were not vaccinated in adolescence.

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• Pulmonary rehabilitation improves symptoms, quality of life, and physical and emotional participation
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in everyday activities.
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• In patients with severe resting chronic hypoxemia, long-term oxygen therapy improves survival.
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• In patients with stable COPD and resting or exercise-induced moderate desaturation, long-term
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oxygen treatment should not be prescribed routinely. However, individual patient factors must be
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• In patients with severe chronic hypercapnia and a history of hospitalization for acute respiratory
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failure, long-term non-invasive ventilation may decrease mortality and prevent re-hospitalization.
• In select patients with advanced emphysema refractory to optimized medical care, surgical or
bronchoscopic interventional treatments may be beneficial.
• Palliative approaches are effective in controlling symptoms in advanced COPD.
This chapter summarizes the evidence about the effectiveness and safety of maintenance and prevention strategies
in COPD. The way in which the evidence is translated into clinical practice is provided in Chapter 4.
SMOKING CESSATION
Smoking cessation has the greatest capacity to influence the natural history of COPD. If effective resources and time
are dedicated to smoking cessation, long-term quit success rates of up to 25% can be achieved.1 Besides individual
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approaches to smoking cessation, legislative smoking bans are effective in increasing quit rates and reducing harm
from second-hand smoke exposure.2
Pharmacotherapies for smoking cessation

Nicotine replacement products. Nicotine replacement therapy (nicotine gum, inhaler, nasal spray, transdermal
patch, sublingual tablet, or lozenge) reliably increases long-term smoking abstinence rates3-5 and is significantly more
effective than placebo. Medical contraindications to nicotine replacement therapy include recent myocardial
infarction or stroke.6,7 The contraindication to nicotine replacement therapy after acute coronary syndrome remains
unclear and the evidence suggests that this treatment should be started > 2 weeks after a cardiovascular event.8
Continuous chewing of nicotine gum produces secretions that are swallowed rather than absorbed through the buccal
mucosa resulting in little absorption and potentially causing nausea. Acidic beverages, particularly coffee, juices, and
soft drinks, interfere with the absorption of nicotine.
Electronic cigarettes (e-cigarettes, vaping) have been evaluated with regard to smoking cessation, although efficacy
remains controversial.9,10 E-cigarettes provide a vaporized and doseable nicotine inhalation and have increased in
usage as an alternative to cigarettes for those wishing to quit but also as a rising trend for younger previous never
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smokers. E-cigarettes have been available for over 15 years and may contain not only the nicotine but also other
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chemicals, such as vegetable glycine, propylene glycol various flavoring agents, volatile carbonyls, diacetyl, reactive
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oxygen species, furones and metals, the long-term health effects of which are largely unknown.
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What is known has been reported mainly as individual or series of case reports of the acute effects of e-cigarettes,
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including vaping-associated lung injury. Severe acute lung injury, eosinophilic pneumonia, alveolar hemorrhage,
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respiratory bronchiolitis and other forms of lung abnormalities have been reportedly linked to e-cigarette use, and
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occasionally death.11-14 The U.S. Centers for Disease Control (CDC), the U.S. Food and Drug Administration (FDA), state
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and other clinical and public health partners investigated an outbreak of e-cigarette, or vaping, product use-associated
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lung injury (EVALI). As of February 18, 2020, a total of 2,807 cases of lung illness and 68 deaths had been associated
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with using e-cigarette products (devices, liquids, refill pods, and/or cartridges).14 Patients were reported to have had
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clinical improvement with systemic glucocorticoid therapy and the majority received prolonged courses.13 Laboratory
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data have shown that vitamin E acetate, an additive in some THC-containing e-cigarettes, was strongly linked to the
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EVALI outbreak.15 Following the identification of vitamin E acetate as a primary cause of EVALI there has been a decline
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in new cases since September 2019.

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Neutrophilic inflammation of the airways, airways irritability, ciliary paresis and increased mucus hypersecretion are
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seen in animal models and in vitro human airway studies similar to changes induced by cigarette smoke and recognised
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features of COPD. These data are summarized in a review by Gotts and colleagues,16 although it is likely to be many
years before the long-term risks of vaping, including risks of cancer, are clarified, particularly in patients with COPD or
whether this is an independent risk factor for developing COPD. 11-14
Pharmacological products. Varenicline,17 bupropion,18 and nortriptyline19 have been shown to increase long-term
quit rates,19 but should always be used as a component of a supportive intervention program rather than a sole
intervention for smoking cessation. The effectiveness of the antihypertensive drug clonidine is limited by side effects.19
Recommendations for treating tobacco use and dependence are summarized in Chapter 4.
A five-step program for intervention (Table 3.1)3,5,20 provides a helpful strategic framework to guide healthcare
providers interested in helping their patients stop smoking.3,5,21 Because tobacco dependence is a chronic disease,3,5
clinicians should recognize that relapse is common and reflects the chronic nature of dependence and addiction, and
does not represent failure on the part of the patient or the clinician.
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Counseling delivered by physicians and other health professionals significantly increases quit rates over self-initiated
strategies.22 Even brief (3-minute) periods of counseling urging a smoker to quit improve smoking cessation rates.22
There is a relationship between counseling intensity and cessation success.23 Ways to intensify treatment include
increasing the length of the treatment session, the number of treatment sessions, and the number of weeks over
which the treatment is delivered. Sustained quit rates of 10.9% at 6 months have been achieved when clinician
tutorials and feedback are linked to counseling sessions.24 Financial incentive models for smoking cessation have also
been reported to be effective in facilitating smoking cessation. In general, incentive programs were more effective
than usual care in increasing smoking cessation rates at 6 months.25 The combination of pharmacotherapy and
behavioral support increases smoking cessation rates.26
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VACCINATIONS
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Influenza vaccine
Influenza vaccination can reduce serious illness (such as lower respiratory tract infections requiring hospitalization)27
and death in COPD patients.28-31 Only a few studies have evaluated exacerbations and they have shown significant
reduction in the total number of exacerbations per vaccinated subject compared with those who received placebo.28
Vaccines containing either killed or live inactivated viruses are recommended32 as they are more effective in elderly
patients with COPD.33 Findings from a population-based study suggested that COPD patients, particularly the elderly,
had decreased risk of ischemic heart disease when they were vaccinated with influenza vaccine over many years.34
Occurrence of adverse reactions is generally mild and transient.
Pneumococcal vaccine
Pneumococcal vaccinations, PCV13 and PPSV23, are recommended for all patients ≥ 65 years of age (Table 3.2). The
PPSV23 is also recommended for younger COPD patients with significant comorbid conditions including chronic heart
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or lung disease.35 Specific data on the effects of PPSV and PCV in COPD patients are limited and contradictory.36 A
systematic review of injectable vaccines in COPD patients identified twelve randomized studies for inclusion and
observed injectable polyvalent pneumococcal vaccination provides significant protection against community-acquired
pneumonia, although no evidence indicates that vaccination reduced the risk of confirmed pneumococcal pneumonia,
which was a relatively rare event. Vaccination reduced the likelihood of a COPD exacerbation, and moderate-quality
evidence suggests the benefits of pneumococcal vaccination in COPD patients. Evidence was insufficient for
comparison of different pneumococcal vaccine types.37 PPSV23 has been shown to reduce the incidence of
community-acquired pneumonia in COPD patients < 65 years, with an FEV1 < 40% predicted, or comorbidities
(especially cardiac comorbidities).38 The PCV13 has been shown to exhibit at least the same or greater immunogenicity
than the PPSV23 up to two years after vaccination in COPD patients.39 In a large RCT PCV13 demonstrated significant
efficacy for the prevention of vaccine-type community-acquired pneumonia (45.6%) and vaccine-type invasive
pneumococcal disease (75%) among adults ≥ 65 years and the efficacy persisted for at least 4 years.40
Other vaccines
In adults with COPD the US Centers for Disease Control (CDC) recommends the Tdap vaccination (also called
dTaP/dTPa) to protect against pertussis (whooping cough), tetanus and diphtheria, in those who were not vaccinated
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in adolescence. 41,42
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PHARMACOLOGICAL THERAPY FOR STABLE COPD
Overview of the medications

Pharmacological therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations,
and improve exercise tolerance and health status. To date, there is no conclusive clinical trial evidence that any existing
medications for COPD modify the long-term decline in lung function.43-47 Post-hoc evidence of such an effect with long-
acting bronchodilators and/or inhaled corticosteroids48,49 requires confirmation in specifically designed trials.
The classes of medications commonly used to treat COPD are shown in Table 3.3. The choice within each class depends
on the availability and cost of medication and favorable clinical response balanced against side effects. Each treatment
regimen needs to be individualized as the relationship between severity of symptoms, airflow limitation, and severity
of exacerbations can differ between patients. The WHO has defined a minimum set of interventions for the
43
management of stable COPD in primary care.50
Bronchodilators
Bronchodilators are medications that increase FEV1 and/or change other spirometric variables. They act by altering
airway smooth muscle tone and the improvements in expiratory flow reflect widening of the airways rather than
changes in lung elastic recoil. Bronchodilators tend to reduce dynamic hyperinflation at rest and during exercise,51,52
and improve exercise performance. The extent of these changes, especially in patients with severe and very severe
COPD, is not easy to predict from the improvement in FEV1 measured at rest.53,54
Bronchodilator dose-response (FEV1 change) curves are relatively flat with all classes of bronchodilators.55-61 Increasing
the dose of either a beta2-agonist or an anticholinergic by an order of magnitude, especially when given by a nebulizer,
appears to provide subjective benefit in acute episodes62 but is not necessarily helpful in stable disease.63
Bronchodilator medications in COPD are most often given on a regular basis to prevent or reduce symptoms. Toxicity
is also dose-related (Table 3.3). Use of short acting bronchodilators on a regular basis is not generally recommended.
Beta2-agonists. The principal action of beta2-agonists is to relax airway smooth muscle by stimulating beta2-
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adrenergic receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstriction. There
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are short-acting (SABA) and long-acting (LABA) beta2-agonists. The effect of SABAs usually wears off within 4 to 6
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hours.57,58 Regular and as-needed use of SABAs improve FEV1 and symptoms.64 For single-dose, as-needed use in COPD,
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there appears to be no advantage in routinely using levalbuterol over conventional bronchodilators.65 LABAs show
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duration of action of 12 or more hours and do not preclude additional benefit from as-needed SABA therapy.66
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Formoterol and salmeterol are twice-daily LABAs that significantly improve FEV1 and lung volumes, dyspnea, health
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status, exacerbation rate and number of hospitalizations,67 but have no effect on mortality or rate of decline of lung
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function. Indacaterol is a once daily LABA that improves breathlessness,68,69 health status69 and exacerbation rate.69
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Some patients experience cough following the inhalation of indacaterol. Oladaterol and vilanterol are additional once
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daily LABAs that improve lung function and symptoms.70,71

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Adverse effects. Stimulation of beta2-adrenergic receptors can produce resting sinus tachycardia and has the
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potential to precipitate cardiac rhythm disturbances in susceptible patients. Exaggerated somatic tremor is
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troublesome in some older patients treated with higher doses of beta2-agonists, regardless of route of administration.
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Although hypokalemia can occur, especially when treatment is combined with thiazide diuretics,72 and oxygen
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consumption can be increased under resting conditions in patients with chronic heart failure,73 these metabolic effects
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decrease over time (i.e., show tachyphylaxis). Mild falls in partial pressure of oxygen (PaO2) can occur after
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administration of both SABAs and LABAs74 but the clinical significance of these changes is uncertain. Despite prior
concerns related to the use of beta2-agonists in the management of asthma, no association between beta2-agonist use
and loss of lung function or increased mortality has been reported in COPD.67,75,76
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Antimuscarinic drugs
Antimuscarinic drugs block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors expressed in
airway smooth muscle.77 Short-acting antimuscarinics (SAMAs), namely ipratropium and oxitropium, also block the
inhibitory neuronal receptor M2, which potentially can cause vagally induced bronchoconstriction.78 Long-acting
muscarinic antagonists (LAMAs), such as tiotropium, aclidinium, glycopyrronium bromide (also known as
glycopyrrolate) and umeclidinium have prolonged binding to M3 muscarinic receptors, with faster dissociation from
M2 muscarinic receptors, thus prolonging the duration of bronchodilator effect.77
A systematic review of randomized controlled trials concluded that ipratropium, a short acting muscarinic antagonist,
alone provided small benefits over short-acting beta2-agonist in terms of lung function, health status and requirement
for oral steroids.79 Among LAMAs, some are administered once a day (tiotropium and umeclidinium), others twice a
day (aclidinium), and some are approved for once daily dosing in some countries and twice daily dosing in others
(glycopyrronium).77,80 LAMA treatments (tiotropium) improve symptoms and health status.77,81 They also improve the
effectiveness of pulmonary rehabilitation82,83 and reduce exacerbations and related hospitalizations.81 Clinical trials
have shown a greater effect on exacerbation rates for LAMA treatment (tiotropium) versus LABA treatment.84,85 In a
long-term clinical trial of 5,993 patients with COPD, tiotropium added to other standard therapies had no effect on
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the rate of lung function decline.47 However, a study conducted in patients with early stage COPD defined by low
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symptom burden and mild to moderate airflow obstruction treated with tiotropium showed an increase in FEV1,
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reduction in moderate but not severe exacerbations, and attenuation of the post-bronchodilator, but not pre-
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bronchodilator decline in FEV1.86
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Adverse effects. Inhaled anticholinergic drugs are poorly absorbed which limits the troublesome systemic effects
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observed with atropine.77,87 Extensive use of this class of agents in a wide range of doses and clinical settings has shown
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them to be very safe. The main side effect is dryness of mouth.78,88 Although occasional urinary symptoms have been
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reported, there are no data to prove a true causal relationship.89 Some patients using ipratropium report a bitter,
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metallic taste. An unexpected small increase in cardiovascular events in COPD patients regularly treated with
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ipratropium bromide has been reported.90,91 In a large, long-term clinical trial in COPD patients, tiotropium added to
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other standard therapies had no effect on cardiovascular risk.47 Although there were some initial concerns regarding
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the safety of tiotropium delivery via the Respimat®92 inhaler, the findings of a large trial observed no difference in
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mortality or exacerbation rates when comparing tiotropium in a dry-powder inhaler and the Respimat® inhaler.93
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There are less safety data available for the other LAMAs, but the rate of anti-cholinergic side effects for drugs in this
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class appears to be low and generally similar. Use of solutions with a facemask can precipitate acute glaucoma,
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probably as a direct result of the contact between the solution and the eye.94-96
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Methylxanthines
Controversy remains about the exact effects of xanthine derivatives. They may act as non-selective phosphodiesterase
inhibitors, but have also been reported to have a range of non-bronchodilator actions, the significance of which is
disputed.97-99 Data on duration of action for conventional, or even slow-release, xanthine preparations are lacking in
COPD.
Theophylline, the most commonly used methylxanthine, is metabolized by cytochrome P450 mixed function oxidases.
Clearance of the drug declines with age. Many other physiological variables and drugs modify theophylline
metabolism. Enhanced inspiratory muscle function has been reported in patients treated with methylxanthines,97 but
whether this reflects a reduction in gas trapping or a primary effect on the respiratory skeletal muscles is not clear. All
studies that have shown efficacy of theophylline in COPD were performed with sustained-release preparations.
There is evidence for a modest bronchodilator effect compared with placebo in stable COPD.100 Addition of
theophylline to salmeterol produces a greater improvement in FEV1 and breathlessness than salmeterol alone.101,102
46
There is limited and contradictory evidence regarding the effect of low-dose theophylline on exacerbation rates.103,104
A study that investigated the effectiveness of adding low-dose theophylline to ICS in COPD patients at increased risk
of exacerbation showed no difference compared with placebo in the number of COPD exacerbations over a one-year
period.105
Adverse effects. Toxicity is dose-related, which is a particular problem with xanthine derivatives because their
therapeutic ratio is small and most of the benefit occurs only when near-toxic doses are given.98,100 Methylxanthines
are non-specific inhibitors of all phosphodiesterase enzyme subsets, which explains their wide range of toxic effects.
Problems include the development of palpitations caused by atrial and ventricular arrhythmias (which can prove fatal)
and grand mal convulsions (which can occur irrespective of prior epileptic history). Other side effects include
headaches, insomnia, nausea, and heartburn, and these may occur within the therapeutic range of serum levels of
theophylline. These medications have significant interactions with commonly used medications such as erythromycin
(but not azithromycin), certain quinolone antibiotics (ciprofloxacin, but not ofloxacin), allopurinol, cimetidine (but not
ranitidine), serotonin uptake inhibitors (fluvoxamine) and the 5-lipoxygenase inhibitor zileuton.
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Combination bronchodilator therapy

Combining bronchodilators with different mechanisms and durations of action may increase the degree of
bronchodilation with a lower risk of side-effects compared to increasing the dose of a single bronchodilator.106,107
Combinations of SABAs and SAMAs are superior compared to either medication alone in improving FEV1 and
symptoms. 108 Treatment with formoterol and tiotropium in separate inhalers has a bigger impact on FEV1 than either
component alone.109 There are numerous combinations of a LABA and LAMA in a single inhaler available (Table 3.3).
These combinations improve lung function compared to placebo106; this improvement is consistently greater than long
acting bronchodilator monotherapy effects although the magnitude of improvement is less than the fully additive
effect predicted by the individual component responses.110 In studies where patient reported outcomes (PROs) are
the primary endpoint or in pooled analyses, combination bronchodilators have a greater impact on PROs compared to
monotherapies.111-114 In one clinical trial, combination LABA/LAMA treatment had the greatest improvement in quality
of life compared to placebo or its individual bronchodilator components in patients with a greater baseline symptom
47
burden.115 A clinical trial showed that LABA/LAMA improved lung function and symptoms versus long-acting
bronchodilator monotherapy in symptomatic patients with low exacerbation risk and not receiving inhaled
corticosteroids.116 These clinical trials deal with group mean data, but symptom responses to LABA/LAMA
combinations are best evaluated on an individual patient basis. A lower dose, twice daily regimen for a LABA/LAMA
has also been shown to improve symptoms and health status in COPD patients117 (Table 3.4). These findings have been
shown in people across different ethnic groups (Asian as well as European).118
Most studies with LABA/LAMA combinations have been performed in patients with a low rate of exacerbations. One
study in patients with a history of exacerbations indicated that a combination of long-acting bronchodilators is more
effective than long-acting bronchodilator monotherapy for preventing exacerbations.119 Another large study found
that combining a LABA with a LAMA did not reduce exacerbation rate as much as expected compared with a LAMA
alone.120 Another study in patients with a history of exacerbations confirmed that a combination LABA/LAMA
decreased exacerbations to a greater extent than an LABA/ICS combination.121 However, another study in a population
with high exacerbation risk (≥ 2 exacerbations and/or 1 hospitalization in the previous year) reported that LABA/ICS
decreased exacerbations to a greater extent than an LABA/LAMA combination at higher blood eosinophil
concentrations (see Chapter 2).122 A large observational pharmaco-epidemiological study found similar effectiveness
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of LABA/LAMA and LABA/ICS but a significantly higher risk of pneumonia in those treated with LABA/ICS.123
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Anti-inflammatory agents
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To date, exacerbations (e.g., exacerbation rate, patients with at least one exacerbation, time-to-first exacerbation)
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represent the main clinically relevant end-point used for efficacy assessment of drugs with anti-inflammatory effects
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(Table 3.5).
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Inhaled corticosteroids (ICS)

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Preliminary general considerations. In vitro evidence suggests that COPD-associated inflammation has limited
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responsiveness to corticosteroids. Moreover, some drugs including beta2-agonists, theophylline or macrolides may
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partially facilitate corticosteroid sensitivity in COPD.124,125 The clinical relevance of this effect has not yet been fully
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established.
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In vivo data suggest that the dose-response relationships and long-term (> 3 years) safety of inhaled corticosteroids
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(ICS) in patients with COPD are unclear and require further investigation.109 Because the effects of ICS in COPD can be
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modulated by the concomitant use of long-acting bronchodilators, these two therapeutic options are discussed
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separately.
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Both current and ex-smokers with COPD benefit from ICS use in terms of lung function and exacerbation rates,
although the magnitude of the effect is lower in heavy or current smokers compared to light or ex-smokers. 122,126
Efficacy of ICS (alone). Most studies have found that regular treatment with ICS alone does not modify the long-
term decline of FEV1 nor mortality in patients with COPD.127 Studies and meta-analyses assessing the effect of regular
treatment with ICS alone on mortality in patients with COPD have not provided conclusive evidence of benefit.127 In
the TORCH trial, a trend toward higher mortality was observed for patients treated with fluticasone propionate alone
compared to those receiving placebo or salmeterol plus fluticasone propionate combination.128 However, an increase
in mortality was not observed in COPD patients treated with fluticasone furoate in the Survival in Chronic Obstructive
Pulmonary Disease with Heightened Cardiovascular Risk (SUMMIT) trial.129 However, in moderate COPD, fluticasone
furoate alone or in combination with vilanterol was associated with slower decline in FEV1 compared with placebo or
vilanterol alone by on average 9 ml/year.130 A number of studies have investigated whether there is a relationship
between ICS treatment and risk of lung cancer with conflicting results.131
48
ICS in combination with long-acting bronchodilator therapy. In patients with moderate to very severe COPD
and exacerbations, an ICS combined with a LABA is more effective than either component alone in improving lung
function, health status and reducing exacerbations.132,133 Clinical trials powered on all-cause mortality as the primary
outcome failed to demonstrate a statistically significant effect of combination therapy on survival.128,129
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Most studies that found a beneficial effect of LABA/ICS fixed dose combination (FDC) over LABA alone on exacerbation
rate, recruited patients with a history of at least one exacerbation in the previous year.132 A pragmatic RCT conducted
in a primary healthcare setting in the United Kingdom compared a LABA/ICS combination with usual care. Findings
showed an 8.4% reduction in moderate-to-severe exacerbations (primary outcome) and a significant improvement in
CAT™ score, with no difference in the rate of healthcare contacts or pneumonias. However, basing recommendations
on these results is difficult because of the heterogeneity of treatments reported in the usual care group, the higher
rate of treatment changes in the group receiving the LABA/ICS combination of interest, and the medical practice
patterns unique to the UK region where the study was conducted.134
Blood eosinophil count. A number of studies have shown that blood eosinophil counts predict the magnitude of
the effect of ICS (added on top of regular maintenance bronchodilator treatment) in preventing future
exacerbations.122,135-139 There is a continuous relationship between blood eosinophil counts and ICS effects; no and/or
small effects are observed at lower eosinophil counts, with incrementally increasing effects observed at higher
eosinophil counts. Data modelling indicates that ICS containing regimens have little or no effect at a blood eosinophil
count < 100 cells/µL,135 therefore this threshold can be used to identify patients with a low likelihood of treatment
benefit with ICS. The threshold of a blood eosinophil count > 300 cells/µL identifies the top of the continuous
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relationship between eosinophils and ICS, and can be used to identify patients with the greatest likelihood of
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treatment benefit with ICS. These thresholds of < 100 cells/µL and > 300 cells/µL should be regarded as estimates,
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rather than precise cut-off values, that can predict different probabilities of treatment benefit. All in all, therefore,
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blood eosinophil counts can help clinicians estimate the likelihood of a beneficial preventive response to the addition
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of ICS to regular bronchodilator treatment, and thus can be used as a biomarker in conjunction with clinical assessment
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when making decisions regarding ICS use.
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Sources of evidence include: 1) Post-hoc analyses comparing LABA/ICS versus LABA135,136,138; 2) Pre-specified analyses
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comparing triple therapy versus LABA/LAMA or LAMA122,137,139 and, 3) other analyses comparing LABA/ICS versus
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LABA/LAMA140 or studying ICS withdrawal.141-143

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The treatment effect of ICS containing regimens (LABA/LAMA/ICS and LABA/ICS vs LABA/LAMA) is higher in patients
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with high exacerbation risk (≥ 2 exacerbations and / or 1 hospitalization in the previous year).121,122,137 Thus, the use of
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blood eosinophil counts to predict ICS effects should always be combined with clinical assessment of exacerbation risk
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(as indicated by the previous history of exacerbations). Other factors (smoking status, ethnicity, geographical location)
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could influence the relationship between ICS effect and blood eosinophil count, but remains to be further explored.
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The mechanism for an increased ICS effect in COPD patients with higher blood eosinophil counts remains unclear.
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The repeatability of blood eosinophil counts in a large primary care population appears reasonable,144 although greater
variability is observed at higher thresholds.145 Better reproducibility is observed at the lower thresholds (e.g., 100
cells/µL).146
Cohort studies have produced differing results with regard to the ability of blood eosinophils to predict future
exacerbation outcomes, with either no relationship147 or a positive relationship reported.148,149 Differences between
studies are likely to be related to different previous exacerbation histories and ICS use. There is insufficient evidence
to recommend that blood eosinophils should be used to predict future exacerbation risk on an individual basis in COPD
patients.
Factors to consider when initiating ICS treatment in combination with one or two long-acting bronchodilators are
shown in Figure 3.1.150
Adverse effects. There is high quality evidence from randomized controlled trials (RCTs) that ICS use is associated
with higher prevalence of oral candidiasis, hoarse voice, skin bruising and pneumonia.127 This excess risk has been
50
confirmed in ICS studies using fluticasone furoate, even at low doses.151 Patients at higher risk of pneumonia include
those who currently smoke, are aged ≥ 55 years, have a history of prior exacerbations or pneumonia, a body mass
index (BMI) < 25 kg/m2, a poor MRC dyspnea grade and/or severe airflow limitation.152,153 Independent of ICS use,
there is evidence that a blood eosinophil count < 2% increases the risk of developing pneumonia.154 In studies of
patients with moderate COPD, ICS by itself or in combination with a LABA did not increase the risk of pneumonia.129,153
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Results from RCTs have yielded varied results regarding the risk of decreased bone density and fractures with ICS
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treatment, which may be due to differences in study designs and/or differences between ICS compounds.45,151,155-157
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Results of observational studies suggest that ICS treatment could also be associated with increased risk of
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diabetes/poor control of diabetes,158 cataracts,159 and mycobacterial infection160 including tuberculosis.161,162 In the
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absence of RCT data on these issues, it is not possible to draw firm conclusions.163 An increased risk of tuberculosis
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has been found in both observational studies and a meta-analysis of RCTs.124,125

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Withdrawal of ICS. Results from withdrawal studies provide equivocal results regarding consequences of
withdrawal on lung function, symptoms and exacerbations.164-168 Some studies, but not all, have shown an increase in
exacerbations and/or symptoms following ICS withdrawal, while others have not. There has been evidence for a
modest decrease in FEV1 (approximately 40 mL) with ICS withdrawal,168 which could be associated with increased
baseline circulating eosinophil level.141 A study examining ICS withdrawal on a background of dual bronchodilator
therapy demonstrated that both FEV1 loss and an increase in exacerbation frequency associated with ICS withdrawal
was greatest among patients with a blood eosinophil count ≥ 300 cells/µl at baseline.143 Differences between studies
may relate to differences in methodology, including the use of background long-acting bronchodilator medication(s)
which may minimize any effect of ICS withdrawal.
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Triple therapy (LABA/LAMA/ICS)
The step up in inhaled treatment to LABA plus LAMA plus ICS (triple therapy) can occur by various approaches169 and
has been shown to improve lung function, patient reported outcomes and reduce exacerbations when compared to
LAMA alone, LABA/LAMA and LABA/ICS.122,137,139,170-177
A post-hoc pooled analysis of three triple therapy clinical trials in COPD patients with severe airflow limitation and a
history of exacerbations showed a non-significant trend for lower mortality (assessed as a safety outcome) with triple
inhaled therapy compared to non-ICS based treatments.178 Two large one-year randomized controlled trials reviewed
below (named IMPACT and ETHOS) provide new evidence on mortality reduction with fixed-dose inhaled triple
combinations compared to dual bronchodilation.179,180 Both trials compared a fixed triple (LABA/LAMA/ICS)
combination (at two ICS dosages in ETHOS) to two dual therapy options (LABA/LAMA and LABA/ICS). They were
enriched for symptomatic patients with a history of frequent and/or severe exacerbations. The majority of patients
were receiving open triple or LABA/ICS based therapy before study randomization. While mortality was not a primary
endpoint for either study, it was a pre-specified outcome; vital status was rigorously collected so that missing data
was minimal. Both studies performed intention to treat analyses. In IMPACT (n=10,355), mortality in the triple therapy
arm was significantly lower compared to the dual bronchodilation arm,179 with similar findings observed in ETHOS
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(n=8,509) with the higher dose ICS (but not the lower dose).180 For both studies, there were no differences versus
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LABA/ICS.
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Together these results suggest a beneficial effect of fixed-dose triple inhaled therapy versus fixed-dose LABA/LAMA
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combinations on mortality in symptomatic COPD patients with a history of frequent and/or severe exacerbations who
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were previously receiving maintenance therapy with triple therapy, LABA/ICS or single or dual long-acting
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bronchodilators. Further analyses or studies may help determining whether other specific patient subgroups
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demonstrate a greater survival benefit.

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Oral glucocorticoids
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Oral glucocorticoids have numerous side effects, including steroid myopathy181 which can contribute to muscle
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weakness, decreased functionality, and respiratory failure in subjects with very severe COPD. Systemic glucocorticoids
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for treating acute exacerbations in hospitalized patients, or during emergency department visits, have been shown to
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reduce the rate of treatment failure, the rate of relapse and improve lung function and breathlessness.182 Conversely,
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prospective studies on the long-term effects of oral glucocorticoids in stable COPD are limited.183,184 Therefore, while
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oral glucocorticoids play a role in the acute management of exacerbations, they have no role in the chronic daily
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treatment in COPD because of a lack of benefit balanced against a high rate of systemic complications.
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Phosphodiesterase-4 (PDE4) inhibitors

Efficacy. The principal action of PDE4 inhibitors is to reduce inflammation by inhibiting the breakdown of intracellular
cyclic AMP.185 Roflumilast is a once daily oral medication with no direct bronchodilator activity. Roflumilast reduces
moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis, severe
to very severe COPD, and a history of exacerbations.186 The effects on lung function are also seen when roflumilast is
added to long-acting bronchodilators,187 and in patients who are not controlled on fixed-dose LABA/ICS
combinations.188 The beneficial effects of roflumilast have been reported to be greater in patients with a prior history
of hospitalization for an acute exacerbation.189,190 There has been no study directly comparing roflumilast with an
inhaled corticosteroid.
Adverse effects. PDE4 inhibitors have more adverse effects than inhaled medications for COPD.191 The most
frequent are diarrhea, nausea, reduced appetite, weight loss, abdominal pain, sleep disturbance, and headache.
Adverse effects have led to increased withdrawal rates from clinical trials. Adverse effects seem to occur early during
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treatment, are reversible, and diminish over time with continued treatment. In controlled studies an average
unexplained weight loss of 2 kg has been seen and weight monitoring during treatment is advised, in addition to
avoiding roflumilast treatment in underweight patients. Roflumilast should also be used with caution in patients with
depression.
Antibiotics
In older studies prophylactic, continuous use of antibiotics had no effect on the frequency of exacerbations in
COPD192,193 and a study that examined the efficacy of chemoprophylaxis undertaken in winter months over a period of
5 years concluded that there was no benefit.194 Later studies have shown that regular use of some antibiotics may
reduce exacerbation rate.195,196
Azithromycin (250 mg/day or 500 mg three times per week) or erythromycin (250 mg two times per day) for one year
in patients prone to exacerbations reduced the risk of exacerbations compared to usual care.197-199 Azithromycin use
was associated with an increased incidence of bacterial resistance, prolongation of QTc interval, and impaired hearing
tests.199 A post-hoc analysis suggests lesser benefit in active smokers.190 There are no data showing the efficacy or
safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one-year of treatment.
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Pulse therapy with moxifloxacin (400 mg/day for 5 days every 8 weeks) in patients with chronic bronchitis and frequent
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exacerbations had no beneficial effect on exacerbation rate overall.200
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Mucolytic (mucokinetics, mucoregulators) and antioxidant agents (N-acetylcysteine,
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carbocysteine, erdosteine)
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In COPD patients not receiving inhaled corticosteroids, regular treatment with mucolytics such as carbocysteine and
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N-acetylcysteine (NAC) may reduce exacerbations and modestly improve health status.201-204 In contrast, it has been
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shown that erdosteine may have a significant effect on (mild) exacerbations irrespective of concurrent treatment with
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ICS. Due to the heterogeneity of studied populations, treatment dosing and concomitant treatments, currently
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available data do not allow one to identify precisely the potential target population for antioxidant agents in COPD.205
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Other drugs with potential to reduce exacerbations

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Two RCTs in COPD patients performed before 2005 that investigated the use of an immunoregulator reported a
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decrease in the severity and frequency of exacerbations.206,207 Additional studies are needed to examine the long-term
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effects of this therapy in patients receiving currently recommended COPD maintenance therapy.
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More recently four large phase 3 studies have investigated the efficacy of the anti-IL-5 monoclonal antibody
mepolizumab208 and the anti-IL-5 receptor-α antibody benralizumab209 in patients with severe COPD, recurrent
exacerbations and peripheral blood evidence of eosinophilic inflammation despite high intensity inhaled therapy. The
studies showed a 15-20% reduction in the rate of severe exacerbations but the effect was not always statistically
significant and it was variable between studies and doses. There was no effect on FEV1 or quality of life scores and no
consistent relationship between the response to treatment and the peripheral blood eosinophil count. A post-hoc
analysis of the mepolizumab trial showed greater benefit and more clear evidence of a blood eosinophil related
treatment effect against oral corticosteroid treated exacerbations raising the possibility that this treatment might find
a role in a highly selected subgroup of patients with eosinophilic COPD and frequent requirement for oral
corticosteroids. Further studies are required to investigate this possibility.
Nedocromil and leukotriene modifiers have not been tested adequately in COPD patients and the available evidence
does not support their use. 210,211
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There was no evidence of benefit, and some evidence of harm, including malignancy and pneumonia, following
treatment with an anti-TNF-alpha antibody (infliximab) in moderate to severe COPD.212
An RCT of the selective β1 receptor blocker metoprolol in patients with moderate or severe COPD, who did not have
an established indication for beta-blocker use, showed it did not delay the time until the first COPD exacerbation
compared placebo group and hospitalization for exacerbation was more common among the patients treated with
metoprolol.213 There is no evidence that beta-blockers should be used in patients with COPD who do not have a
cardiovascular indication for their use.
Simvastatin did not prevent exacerbations in patients with COPD who had no metabolic or cardiovascular indication
for statin treatment.214 An association between statin use and improved outcomes (including decreased exacerbations
and mortality) has been reported in observational studies of patients with COPD who received them for cardiovascular
and metabolic indications.215
There is no evidence that supplementation with vitamin D has a positive impact on exacerbations in unselected
patients.216 In a meta-analysis vitamin D supplementation reduced exacerbation rates in patients with low baseline
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vitamin D levels.217
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Issues related to inhaled delivery
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When a treatment is given by the inhaled route the importance of education and training in inhaler device technique
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cannot be over-emphasized. Inhalation devices include nebulizers, metered-dose inhalers (MDIs) used without
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spacers, soft-mist inhalers and breath-actuated devices i.e., breath-actuated MDIs (BAIs) and single-dose and multi-
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dose dry powder inhalers (DPIs).218 In multi-dose DPIs, the powder is contained in a reservoir or in individual blisters.218
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All classes of inhaled drugs are not available in all types of device. Particles > 5 microns (µm) are most likely to be
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deposited in the oropharynx. For drug delivery to the lower respiratory tract and lungs, particle size (mass-median
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aerodynamic diameter) can be fine (2-5 µm) or extra-fine (< 2 µm), which influences the total respirable fraction
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(particles < 5 µm) and the amount and site of drug deposition (more peripheral deposition with extra-fine particles).218
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Randomized controlled trials have not identified superiority of one device/formulation.218 However, patients included
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in these trials are usually those who master inhalation technique and receive proper education and follow-up
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regarding this issue, and therefore may not be reflective of normal clinical practice. On average more than two thirds
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of patients make at least one error in using an inhalational device.219-222 A rigorous, prospective observational study of
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COPD patients discharged from the hospital confirmed appropriate adherence to the use of a DPI in only 23% of
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patients.223
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Observational studies have identified a significant relationship between poor inhaler use and symptom control in
patients with COPD.220 Determinants of poor inhaler technique in asthma and COPD patients include: older age, use
of multiple devices, and lack of previous education on inhaler technique.224 In such populations, education improves
inhalation technique in some but not all patients,224 especially when the “teach-back” approach (patients being asked
to show how the device has to be used) is implemented.225 It is important to check that patients continue to use their
device correctly. Lack of placebo devices within clinical areas is often a limitation and barrier to providing quality
inhaler technique instruction to patients. Encouraging a patient to bring their own devices to clinic is a useful
alternative. Those who do not reach mastery may require a change in inhalational delivery device. Pharmacist-led
interventions226 and lay health coaching227 can improve inhalation technique and adherence in COPD patients.
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The main errors in delivery device use relate to problems with inspiratory flow, inhalation duration, coordination, dose
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preparation, exhalation maneuver prior to inhalation and breath-holding following dose inhalation (Table 3.6).223
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Specific instructions are available for each type of device.218 Observational studies in patients with COPD show that,
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although the type and frequency of inhalation errors vary between devices depending on their characteristics, there
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is no device obviating the need to explain, demonstrate and regularly check inhalation technique.228-234 Strategies for
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inhaler choice based on patients’ characteristics have been proposed by experts and consensus-based taskforces
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(Table 3.6), but none have yet been prospectively tested.218,234,235 There is no evidence for superiority of nebulized
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therapy over hand-held devices in patients who are able to use these devices properly.
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Other pharmacological treatments

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Other pharmacological treatments for COPD are summarized in Table 3.7.

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Alpha-1 antitrypsin augmentation therapy. The logical approach to minimize the development and progression
of lung disease in AATD patients is alpha-1-antitrypsin augmentation. Such therapy has been available in many, though
not all, countries since the 1980s. Because AATD is rare, formal clinical trials to assess efficacy with conventional
spirometric outcome have never been undertaken. However, a wealth of observational studies suggest a reduction in
spirometric progression in treated versus non-treated patients236 and that this reduction is most effective for patients
with FEV1 35-49% predicted.237 Never or ex-smokers with an FEV1 of 35-60% predicted have been suggested as those
55
most suitable for AATD augmentation therapy (Evidence B).
Studies using sensitive parameters of emphysema progression determined by CT scans have provided evidence for an
effect on preserving lung tissue compared to placebo.238-240 Based on the last trial the indications for therapy have
been extended to include "those patients with evidence of progressive lung disease despite other optimal therapy."
However, not all patients with AATD develop or persist with rapid spirometric progression especially following smoking
cessation.241 Since the purpose of augmentation therapy is to preserve lung function and structure it seems logical to
reserve such expensive therapy for those with evidence of continued and rapid progression following smoking
cessation.241
The indication for AAT augmentation is emphysema although there are no fixed criteria for diagnosis or confirmation.
The evidence for augmentation therapy efficacy varies according to the outcome studied.242 Intravenous
augmentation therapy has been recommended for individuals with alpha-1 antitrypsin deficiency (AATD) and an FEV1
≤ 65% predicted based on previous observational studies. However, the last study powered on CT scan as an outcome
has recommended that all patients with evidence of progressive lung disease should be considered for those with lung
disease related to AATD, and an FEV1 > 65%. Individual discussion is recommended with consideration of the cost of
therapy and lack of evidence for much benefit.243 The main limitation for this therapy is very high cost and lack of
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availability in many countries.
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Antitussives. The role of antitussives in patients with COPD is inconclusive.244
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Vasodilators. Vasodilators have not been properly assessed in COPD patients with severe/disproportionate
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pulmonary hypertension. Inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of
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ventilation-perfusion balance and is contraindicated in stable COPD.245 Studies have shown that sildenafil does not
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improve the results of rehabilitation in patients with COPD and moderately increases pulmonary artery pressure.246
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Tadalafil does not appear improve exercise capacity or health status in COPD patients with mild pulmonary
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hypertension.247
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REHABILITATION, EDUCATION & SELF-MANAGEMENT

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Pulmonary rehabilitation
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Pulmonary rehabilitation is defined as “a comprehensive intervention based on thorough patient assessment followed
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by patient-tailored therapies that include, but are not limited to, exercise training, education, self-management
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intervention aiming at behavior change, designed to improve the physical and psychological condition of people with
chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviors.”248
Pulmonary rehabilitation should be considered part of integrated patient management, and usually includes a range
of healthcare professionals to ensure optimum coverage of the many aspects involved.249 Patients should undergo
careful assessment prior to enrollment, including identification of the patient’s goals, specific healthcare needs,
smoking status, nutritional health, self-management capacity, health literacy, psychological health status and social
circumstances, comorbid conditions as well as exercise capabilities and limitations.250,251 Optimum benefits are
achieved from programs lasting 6 to 8 weeks. Available evidence indicates that there are no additional benefits from
extending pulmonary rehabilitation to 12 weeks.251 Supervised exercise training at least twice weekly is recommended,
and this can include any regimen from endurance training, interval training, resistance/strength training; upper and
lower limbs ideally should be included as well as walking exercise; flexibility, inspiratory muscle training and
neuromuscular electrical stimulation can also be incorporated. In all cases the rehabilitation intervention (content,
scope, frequency, and intensity) should be individualized to maximize personal functional gains.251 When the
56
intervention includes ongoing feedback (telephone calls, biofeedback provided via pedometer and progressive goal
setting) but the program is not supervised, it is no more effective in improving physical activity than a walking program
with no feedback.252 The importance of long-term behavior change to improve physical functionality, and reduce the
psychological impact of COPD, should be emphasized to the patient.
The benefits to COPD patients from pulmonary rehabilitation are considerable (Table 3.8), and rehabilitation has been
shown to be the most effective therapeutic strategy to improve shortness of breath, health status and exercise
tolerance.253 Pulmonary rehabilitation is appropriate for most patients with COPD; improved functional exercise
capacity and health related quality of life have been demonstrated across all grades of COPD severity, although the
evidence is especially strong in patients with moderate to severe disease. Even patients with chronic hypercapnic
failure show benefit.254
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Exercise-induced oxygen desaturation can be a problem among COPD patients without chronic hypoxemia. During
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pulmonary rehabilitation it is common practice to supplement oxygen during exercise training with the aim of
facilitating higher exercise intensity. There was little support for oxygen supplementation during exercise training for
individuals with COPD from a 2007 systematic review,255 but most evidence was limited by low study quality. A large
RCT,256 with blinding of participants, trainers and assessors, demonstrated that COPD patients training with either
supplemental oxygen or medical air had significantly improved exercise capacity and health-related quality of life; no
greater benefit with oxygen was observed. The incidence and severity of adverse events were similar in both groups.
In patients with severe COPD on long-term oxygen therapy (LTOT) in whom exercise training is done with oxygenation
systems, there has been increased interest in using an alternative tool, namely nasally administered mixtures of
humidified air-oxygen blends at flow rates of 20-60 L/min (HFNT). HFNT may reduce respiratory muscle load and
respiratory rate, while increasing expiratory time.257 In an RCT, the delivery of HFNT during training sessions, as
compared with usual oxygen, was not associated with a greater improvement in endurance time, the primary
outcome, or in health status.258 However, a greater improvement in 6-minute walking distance (6MWD) test was
observed with HFNT. The proportion of patients reaching the minimal clinically important difference (MCID) in
endurance time and 6MWD was also significantly higher with HFNT. Finally, there was no significant difference
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between the two therapies in patients’ satisfaction. Further studies are needed to evaluate the efficacy of this
treatment.
Limited data exist regarding the effectiveness of pulmonary rehabilitation after an acute exacerbation of COPD, but
systematic reviews have shown that among those patients who have had a recent exacerbation (≤ 2 weeks from prior
hospitalization), pulmonary rehabilitation can reduce readmissions and mortality.259 However, initiating pulmonary
rehabilitation before the patient’s discharge may compromise survival through unknown mechanisms.260 Pulmonary
rehabilitation also ranks as one of the most cost-effective treatment strategies.249
There are many challenges with pulmonary rehabilitation. Referral of patients who might benefit, uptake and
completion of pulmonary rehabilitation is frequently limited, partly through provider ignorance as well as patients’
lack of awareness of availability or benefits. The recommended length of pulmonary rehabilitation (minimum of 6
weeks) could also be a limitation in many countries due to funding constraints of insurance companies and/or national
health funds. Virtual reality pulmonary rehabilitation could be an alternative combined or not with traditional exercise
training; this may be of particular interest in countries where the length of pulmonary rehabilitation programs is
limited to less than 4 weeks.261 Another challenge is encouraging sustained long-term physical activity. Although the
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approach may need to be personalized, behavioral lifestyle physical activity intervention has shown promising results
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i.e., the potential to decrease sedentarity and increase physical activity in patients with moderate to severe COPD.262
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A major barrier to full participation is access, which is particularly limited by geography, culture, finances, transport
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and other logistics.248,263,264
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Pulmonary rehabilitation can be conducted at a range of sites.248 Community-based and home-based programs have
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been shown to be as effective as hospital-based programs in randomized controlled trials,265,266 as long as the
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frequency and intensity are equivalent.267 There is also evidence that standardized home-based pulmonary
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rehabilitation programs improve dyspnea in COPD patients.268 However, in real life, traditional pulmonary
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rehabilitation with supervision remains the standard of care and first-line option, with home-based exercise likely to
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be a less effective alternative for patients with COPD who are unable to attend pulmonary rehabilitation.269 Another
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challenge is that the benefits of rehabilitation tend to wane over time. There is insufficient evidence, with conflicting
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research findings in the 11 available RCTs, to recommend continuation of lower intensity or lower frequency exercise
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programs with the aim of maintaining benefit long-term. However, if such programs are available they should target
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health behavior taking into account the patient’s own preferences, needs and personal goals.251,270 Pulmonary
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rehabilitation may help reduce anxiety and depression symptoms.271

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Education, self-management and integrative care

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Education. Patient “education” often takes the form of providers giving information and advice, and assumes that
knowledge will lead to behavior change. Although enhancing patient knowledge is an important step towards behavior
change, didactic group sessions are insufficient for promoting self-management skills. Topics such as smoking
cessation, correct use of inhaler devices, early recognition of exacerbation, decision-making and taking action, and
when to seek help, surgical interventions, considering advance directives, and others will be better dealt with using
self-management interventions. Personalized education and training that takes into account specific issues relating to
the individual patients, and that aims to enhance long-term functionality and appropriate health behaviors are likely
to benefit patients more. These are addressed under self-management.
Self-management. A recent Delphi process has resulted in a conceptual definition for COPD self-management
interventions: “A COPD self-management intervention is structured but personalized and often multi-component, with
goals of motivating, engaging and supporting the patients to positively adapt their health behavior(s) and develop
skills to better manage their disease.”272 The process requires iterative interactions between patients and healthcare
professionals who are competent in delivering self-management interventions. Behavior change techniques are used
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to elicit patient motivation, confidence and competence. Literacy sensitive approaches are used to enhance
comprehensibility.272
Systematic reviews have provided evidence that self-management interventions improve outcomes in COPD. Cochrane
reviews on COPD self-management have reported that self-management interventions that include written negotiated
action plans for worsening symptoms lead to a lower probability of both respiratory-related hospitalization and all
cause hospitalizations. A Cochrane review on COPD self-management interventions that includes action plans for
exacerbations demonstrated lower probability of respiratory-related hospital admissions and improvements in health
related quality of life.273 There have been concerns that health benefits from such self-management programs in COPD
could be counterbalanced by increased mortality.274,275 The Cochrane review and another meta-analysis, however,
reported no impact of self-management interventions on overall mortality.273,276 The Cochrane review did find a small,
but statistically significant, higher respiratory related mortality rate in the self-management intervention group as
compared to usual care. However, the authors also indicate the results should be interpreted with caution as
misclassification in cause of death is common, the overall effect was dominated by two studies, and no effect on all-
cause mortality was seen in the overall analysis. Furthermore, two independent, well designed studies, the COMET277
and the PIC-COPD,278 have shown the potential for reduction in mortality from integrated case management with self-
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management interventions. The program in these two studies may have promoted earlier appropriate treatment for
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exacerbations, which could have prevented some fatal complications.
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An RCT has shown that implementation of a comprehensive 3-month program to improve long-term self-management
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of patients recently discharged from hospital with COPD exacerbation resulted in nearly two-fold higher rates of COPD-
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related hospitalizations and emergency visits over 6 months. These data suggest that self-management strategies in
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recently hospitalized patients may lead to increased health care service utilization compared with usual care.279
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There remain problems with heterogeneity among interventions, consistency of their application, specifics of the
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intervention, patient populations, follow-up times and outcome measures that make generalization difficult in real
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life. It is also challenging to formulate clear recommendations regarding the most effective form and content of a self-
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management intervention in COPD given the range of heterogeneity across studies, and lack of precise definitions of
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self-management components (e.g., skills taught) and fidelity measures. The recent conceptual definition should help
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redress these deficiencies. For example, in the definition it is mentioned that: “The process requires iterative
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interactions between patients and healthcare professionals who are competent in delivering self-management
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interventions.” Having proper health coaching is important to improve self-management abilities. In patients with
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COPD admitted for an exacerbation, a study has reported the positive effect of health coaching, commencing at the
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time of hospital discharge, on reducing risk of re-hospitalization and emergency department visits.280 Furthermore,
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this randomized study indicated that health coaching delivered by a respiratory therapist or nurse may improve self-
management abilities as demonstrated by meaningful improvements in Chronic Respiratory Disease Questionnaire
mastery scores.281
Integrated care programs. COPD is a complex disease that requires the input of multiple care providers who need
to work together closely. In principle, use of a formal structured program that determines how each component is
delivered should make care more efficient and effective, but the evidence for this is divided. A meta-analysis of small
trials concluded that an integrated care program improved a number of clinical outcomes, although not mortality.282
In contrast, a large multicenter study in primary care within an existing well-organized system of care did not confirm
this.283 Besides, delivering integrated interventions by telemedicine did not show a significant effect.284,285 The
pragmatic conclusion is that well organized care is important, but there may be no advantage in structuring it tightly
into a formalized program. Furthermore, integrated care needs to be individualized to the stage of the person’s illness
and health literacy.
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SUPPORTIVE, PALLIATIVE, END-OF-LIFE & HOSPICE CARE
Symptom control and palliative care

Palliative care is a broad term that encompasses approaches to symptom control as well as management of terminal
patients close to death. The goal of palliative care is to prevent and relieve suffering, and to support the best possible
quality of life for patients and their families, regardless of the stage of disease or the need for other therapies.286 COPD
is a highly symptomatic disease and has many elements such as fatigue, dyspnea, depression, anxiety, insomnia that
require symptom-based palliative treatments. There is evidence that patients with COPD are less likely to receive such
services compared to patients with lung cancer.287,288 Palliative care expands traditional disease-model medical
treatment to increase the focus on the goals of enhancing quality of life, optimizing function, helping with decision-
making about end-of-life care, and providing emotional and spiritual support to patients and their families.286 Palliative
approaches are essential in the context of end-of-life care as well as hospice care (a model for delivery of end-of-life
care for patients who are terminally ill and predicted to have less than 6 months to live). Increasingly, palliative care
teams are available for consultation for hospitalized patients.289 Availability for outpatient palliative care consultation
is less common, and has been shown to improve quality of life, reduce symptoms and even prolong survival for patients
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with advanced lung cancer.288
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Therapy relevant to all patients with COPD
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Even when receiving optimal medical therapy many patients with COPD continue to experience distressing
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breathlessness, impaired exercise capacity, fatigue, and suffer panic, anxiety and depression.264 Some of these
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symptoms can be improved by wider use of palliative therapies that in the past have often been restricted to end-of-
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life situations.
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Palliative treatment of dyspnea. Opiates,290-292 neuromuscular electrical stimulation (NMES),292,293 chest wall
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vibration (CWV)292 and fans blowing air onto the face292,294,295 can relieve breathlessness. Immediate-release morphine
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extended exercise endurance time in over half of patients with advanced COPD, although further research is required
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to determine what patient characteristics predict response.296 Oxygen may offer some benefit even if the patient is
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not hypoxemic (Sp02 > 92%).297 Pulmonary rehabilitation is effective and in severe cases non-invasive ventilation can
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also reduce daytime breathlessness. Acupuncture and acupressure are other non-pharmacological approaches in
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patients with advanced COPD that may improve breathlessness and quality of life.298 Refractory dyspnea may be more
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effectively managed with a multidisciplinary integrated palliative and respiratory care service.299
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There is no evidence for a beneficial effect of benzodiazepines300 and there is not enough data to recommend
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distractive auditory stimuli (music), relaxation, counseling and support, with or without breathing relaxation training,
or psychotherapy.301
Nutritional support. Low BMI and particularly low fat free mass is associated with worse outcomes in people with
COPD.302 In malnourished patients with COPD, nutritional supplementation promotes significant weight gain and leads
to significant improvements in respiratory muscle strength and overall health-related quality of life.303 Nutritional
antioxidant supplementation (vitamin C and E, zinc, and selenium) has been shown to improve antioxidant deficits,
quadriceps strength, and serum total protein, without further improvement in quadriceps endurance. Only in
malnourished patients has nutritional supplementation demonstrated significant improvements for 6-minute walk
test, respiratory muscle strength and health status.304 A 12-month nutritional intervention in muscle wasted patients
had no effect on physical capacity but physical activity was significantly higher.305
Panic, anxiety & depression. The causes of depression and anxiety symptoms in people with COPD are
multifactorial and include behavioral, social and biological factors.306 Pulmonary rehabilitation may help reduce
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anxiety symptoms. The efficacy of antidepressants in patients with COPD has been inconclusive, possibly as a result of
methodological issues in the published trials. Cognitive behavioral therapy and mind-body interventions (e.g.,
mindfulness-based therapy, yoga, and relaxation) can reduce anxiety and depression; mind-body interventions also
improve physical outcomes such as lung function, dyspnea, exercise capacity and fatigue in people with COPD and
psychological problems.307
Fatigue. Fatigue in people with COPD can be improved by self-management education, pulmonary rehabilitation,
nutritional support and mind-body interventions.308
End-of-life and hospice care

In many patients, the disease trajectory in COPD is marked by a gradual decline in health status and increasing
symptoms, punctuated by acute exacerbations that are associated with an increased risk of dying.309 Although
mortality rates following hospitalization for an acute exacerbation of COPD are declining,310 reported rates still vary
from 23%311 to 80%.312 Progressive respiratory failure, cardiovascular diseases, malignancies and other diseases are
the primary cause of death in patients with COPD hospitalized for an exacerbation.312 In qualitative studies, as well as
describing the high symptom burden, patients with COPD and their families describe a need for a better understanding
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of their condition and the psychological impact of living and dying with COPD.313 Palliative care is a broad term that
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includes approaches to symptom control as well as management of terminal patients close to death. Palliative care,
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end-of-life care, and hospice care are important components of the care of patients with advanced COPD.
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End-of-life care should also include discussions with patients and their families about their views on resuscitation,
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advance directives and place of death preferences.314 At an individual level, prediction of 6-month survival in patients
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with COPD is unreliable and therefore early discussion of these issues is important together with phased introduction
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of supportive care.315 Hospitalization may be a trigger to initiate discussion of advance care planning. Patients and
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their families live with uncertainty about the timing of death and fear death will result from worsening dyspnea and
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suffocation.316 Good advance care planning can reduce anxiety for patients and their families by talking about death
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and dying and offering emotional support. It can also ensure that care is consistent with their wishes and avoids
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unnecessary, unwanted and costly invasive approaches.317,318

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For patients with very advanced or terminal illness, hospice services may provide additional benefit. Hospice services
often focus on patients with severe disability or symptom burden and may provide these services within the patient’s
home or in hospice beds in dedicated hospice units or other institutions such as hospitals or nursing homes.
Organizations such as the National Hospice and Palliative Care Organization319 provide guidance for selecting patients
with non-cancer diseases like COPD for access to hospice services (for example, disabling dyspnea at rest that is poorly
responsive to bronchodilators and progression of advanced disease demonstrated by increasing hospitalizations or
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emergency department visits).287,288 These guidelines discuss the difficulties in accurately predicting the prognosis of
patients with advanced COPD, but recognize the appropriateness of providing hospice services for some of these
patients.286 Key points for palliative, end-of-life and hospice care in COPD are summarized in Table 3.9.
OTHER TREATMENTS
Oxygen therapy and ventilatory support

Oxygen therapy. The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory
failure has been shown to increase survival in patients with severe resting hypoxemia.320 Long-term oxygen therapy
does not lengthen time to death or first hospitalization or provide sustained benefit for any of the measured outcomes
in patients with stable COPD and resting or exercise-induced moderate arterial oxygen desaturation.321 Breathlessness
may be relieved in COPD patients who are either mildly hypoxemic, or non-hypoxemic but do not otherwise qualify
for home oxygen therapy, when oxygen is given during exercise training; however, studies have shown no
improvement of breathlessness in daily life and no benefit on health related quality of life (Table 3.10).321,322 There are
contradictory studies although the majority do not demonstrate changes.323
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Although air travel is safe for most patients with chronic respiratory failure who are on long-term oxygen therapy,324
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patients should ideally maintain an in-flight PaO2 of at least 6.7 kPa (50 mmHg). Studies indicate that this can be
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achieved in those with moderate to severe hypoxemia at sea level by supplementary oxygen at 3 liters/min by nasal
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cannula or 31% by Venturi facemask.325 Those with a resting oxygen saturation > 95% and 6-minute walk oxygen
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saturation > 84% may travel without further assessment,326 although it is important to emphasize that resting
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oxygenation at sea level does not exclude the development of severe hypoxemia when travelling by air.324 Careful
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consideration should be given to any comorbidity that may impair oxygen delivery to tissues (e.g., cardiac impairment,
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anemia). Also, walking along the aisle may profoundly aggravate hypoxemia.327
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Ventilatory Support
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During exacerbations of COPD. Noninvasive ventilation (NIV) in the form of noninvasive positive pressure
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ventilation (NPPV) is the standard of care for decreasing morbidity and mortality in patients hospitalized with an
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exacerbation of COPD and acute respiratory failure328-331(see also Chapter 5).

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Stable patient. In patients with both COPD and obstructive sleep apnea there are clear benefits associated with the
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use of continuous positive airway pressure (CPAP) to improve both survival and the risk of hospital admissions.332
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Whether to use NPPV chronically at home to treat patients with acute on chronic respiratory failure following
hospitalization remains undetermined and outcome may be affected by persistent hypercapnia.333 A multicenter (13
sites) prospective RCT of COPD patients (n=116) with persistent hypercapnia (PaCO2 >53 mmHg) after 2-4 weeks of
hospital discharge because an acute episode of exacerbation, compared the effects of home noninvasive ventilation
(NIV) plus oxygen compared to home oxygen alone on time to readmission or death.333 Patients with BMI >35 kg/m2,
obstructive sleep apnea syndrome, or other causes of respiratory failure were excluded. Of 2,021 patients screened,
only 124 (6%) were eligible. Results showed that adding home NIV to oxygen therapy significantly prolonged the time
to readmission or death within 12 months.333 A systematic review and meta-analysis of these studies confirms that
NIV decreases mortality and risk of hospitalization. The best candidate subgroups (by recent hospitalization history or
PaCO2) remain unclear.331
Two previous retrospective studies334,335 and two of three RCTs333,336-339 reported reductions in re-hospitalization and
improved survival with using NPPV post-hospitalization. Two studies reported decreases in mortality and
hospitalization rates while another showed no benefit of NPPV for survival. Several factors may account for
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discrepancies: differences in patient selection, underpowered studies, NPPV settings incapable of achieving adequate
ventilation, and poor adherence with NPPV therapy.340 NPPV when indicated should be instituted and monitored
under the direction of personnel familiar with the process and the devices utilized.341,342 In patients with both COPD
and obstructive sleep apnea there are clear benefits associated with the use of continuous positive airway pressure
(CPAP) to improve both survival and the risk of hospital admissions.332
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INTERVENTIONAL THERAPY
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Surgical Interventions
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Lung volume reduction surgery (LVRS). LVRS is a surgical procedure in which parts of the lungs are resected to
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reduce hyperinflation,343 making respiratory muscles more effective pressure generators by improving their
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mechanical efficiency.344,345 LVRS increases the elastic recoil pressure of the lung and thus improves expiratory flow
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rates and reduces exacerbations.346,347 In an RCT that included severe emphysema patients, with an upper-lobe
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emphysema and low post-rehabilitation exercise capacity, LVRS resulted in improved survival when compared to
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medical treatment.348 In similar patients with high post-pulmonary rehabilitation exercise capacity, no difference in
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survival was noted after LVRS, although health status and exercise capacity improved. LVRS has been demonstrated
to result in higher mortality than medical management in severe emphysema patients with an FEV1 ≤ 20% predicted
and either homogeneous emphysema high resolution computed tomography or a DLCO of ≤ 20% of predicted.349 A
prospective economic analysis indicated that LVRS is costly relative to healthcare programs that do not include
surgery.350
Bullectomy. Bullectomy is an older surgical procedure for bullous emphysema. Removal of a large bulla that does
not contribute to gas exchange and is, or has been, responsible for complications decompresses the adjacent lung
parenchyma. In selected patients with relatively preserved underlying lung, bullectomy is associated with decreased
dyspnea, improved lung function and exercise tolerance.351 Pulmonary hypertension, hypercapnia and severe
emphysema are not absolute contraindications for bullectomy.
Lung transplantation. In appropriately selected patients with very severe COPD, lung transplantation has been
shown to improve health status and functional capacity but not prolong survival.351-353 Over 70% of lung transplants
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conducted in COPD patients are double lung transplants; the remainder are single lung transplants.354 Bilateral lung
transplantation has been reported to provide longer survival than single lung transplantation in COPD patients,
especially those < 60 years of age.355 The median survival for lung transplantation in all COPD patients has increased
to 5.5 years; it is 7 years in those receiving a bilateral lung transplant and 5 years in those receiving a single lung
transplant.354
Lung transplantation is limited by the shortage of donor organs and cost. The complications most commonly seen in
COPD patients after lung transplantation are acute rejection, bronchiolitis obliterans, opportunistic infections and
lymphoproliferative disease.356
Bronchoscopic interventions to reduce hyperinflation in severe emphysema

Due to the morbidity and mortality associated with LVRS, less invasive bronchoscopic approaches to lung reduction
have been examined.357 These include a variety of different bronchoscopic procedures.357 Although these techniques
differ markedly from one another they are similar in their objective to decrease thoracic volume to improve lung, chest
wall and respiratory muscle mechanics.
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Prospective studies have shown that the use of bronchial stents is not effective.358 A multicenter study examining the
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effects of a lung sealant to create lung reduction was discontinued prematurely; while the study reported significant
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benefits in some physiologic parameters, the intervention was associated with significant morbidity and mortality.359
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A large prospective multicenter RCT of endobronchial valve placement showed statistically significant improvements
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in FEV1 and 6-minute walk distance compared to control therapy at 6 months post intervention.360 However, the
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magnitude of the observed improvements was not clinically meaningful. Subsequently, efficacy of the same
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endobronchial valve has been studied in patients with heterogeneous,361 or heterogeneous and homogenous
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emphysema362 with mixed outcomes. Non-significant increases in median FEV1 at three months post valve
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implantation in one study was attributed to valve placement in some patients with interlobar collateral ventilation.361
Another study showed significant increases in FEV1 and 6-minute walk distance in subjects selected for the absence of
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interlobar collateral ventilation compared to the control group at 6 months.362 Adverse effects in the endobronchial
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valve treatment group in both studies included pneumothorax, valve removal or valve replacement.362 Greater benefit
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was shown in patents with heterogeneous compared to those with homogenous emphysema.362 An RCT of
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endobronchial valve placement compared with usual care conducted only in homogenous emphysematous patients
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without interlobar collateral ventilation reported improvements in FEV1, 6-minute walk distance and health status at
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6 months with targeted lobe reduction in 97% of subjects as measured by volumetric CT (mean reduction 1,195 ml).363
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A large multicenter, prospective, RCT of endobronchial valve treatment in patients with heterogeneous emphysema
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distribution and little to no collateral ventilation, demonstrated significant clinically meaningful benefits over current
standard care in lung function, dyspnea, exercise capacity, and quality of life out to at least 12-months post-
procedure.364 Pneumothorax was seen in 26.6% of subjects treated with the endobronchial valve usually within the
first 72 hours of the procedure (76%).363-365 Another large multicenter prospective RCT using a different type of
endobronchial valve in patients selected for targeted lobe treatment based on fissure integrity assessed by high
resolution chest CT showed a significant between-group increase in mean FEV1 from baseline (0.101L) and a 25.7%
between-group difference in FEV1 responder rates (improvement ≥15%). These results persisted at 12 months. The
endobronchial valve treated group also had significant reductions in hyperinflation and dyspnea. Improved health
status and quality of life was also observed. Consistent with prior studies, pneumothorax occurred in 25.5% of
endobronchial valve treated patients; the majority occurred in the first three days following the procedure during the
period of average hospitalization. Early-onset pneumothorax in the endobronchial valve treatment group likely results
from lung conformation changes due to acute volume reduction in the emphysematous targeted lobe by valve therapy
that triggers rapid ipsilateral non-targeted lobe expansion, a recognized indicator of successful target lobe occlusion
in patients with intact fissures or absence of collateral ventilation.366 The occurrence of pneumothorax highlights the
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need for physicians performing this procedure to have expertise in the management of procedural complications.366
After the post-procedural period however, patients treated with the endobronchial valve compared to usual care tend
to have a lower number of exacerbations and episodes of respiratory failure. A comparison of treatment benefits and
complications associated with endobronchial valve placement compared to LVRS show comparable benefits with
endobronchial valve treatment but with fewer complications.364 Endobronchial valve therapy is now clinically available
and approved for treatment in many countries in the treatment of patients who have intact fissures or lack of collateral
ventilation.364,367,368
Other bronchoscopic lung volume reduction techniques do not depend upon the presence of intact fissures or absence
of collateral ventilation. In a prospective RCT, targeted thermal vapour ablation of more diseased segments resulted
in clinically meaningful and statistically significant improvements in lung function and health status at 6 months. COPD
exacerbation was the most common serious adverse event. Durability of these changes was subsequently reported at
12 months follow-up.369,370 This therapy has limited clinical availability.
Two multicenter trials have examined nitinol coils implanted into the lung compared to usual care on changes in 6-
minute walk distance, lung function and health status in patients with advanced homogenous and heterogeneous
emphysema. Both studies reported an increase in 6-minute walk distance with coil treatment compared to control
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and smaller improvements in FEV1, and quality of life measured by St George’s Respiratory Questionnaire.371,372 Major
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complications included pneumonia, pneumothorax, hemoptysis and COPD exacerbations occurring more frequently
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in the coil group.372 This therapy has limited clinical availability.
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Additional data are needed to define the optimal bronchoscopic lung volume technique to produce bronchoscopic
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lung volume reduction in patients who lack fissure integrity, or exhibit collateral ventilation, and to refine the
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procedure to reduce complications and improve longer term clinical outcomes.372

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Key points for interventional therapy in stable COPD are summarized in Table 3.11.
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REFERENCES
1. van Eerd EA, van der Meer RM, van Schayck OC, Kotz D. Smoking cessation for people with chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2016; (8): CD010744.
2. Frazer K, Callinan JE, McHugh J, et al. Legislative smoking bans for reducing harms from secondhand smoke exposure,
smoking prevalence and tobacco consumption. Cochrane Database Syst Rev 2016; 2: CD005992.
3. The Tobacco Use and Dependence Clinical Practice Guideline Panel. A clinical practice guideline for treating tobacco use
and dependence: A US Public Health Service report. JAMA 2000; 283(24): 3244-54.
4. van der Meer RM, Wagena EJ, Ostelo RW, Jacobs JE, van Schayck CP. Smoking cessation for chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2003; (2): CD002999.
5. U.S. Public Health Service. A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S.
Public Health Service report. Am J Prev Med 2008; 35(2): 158-76.
6. Okuyemi KS, Nollen NL, Ahluwalia JS. Interventions to facilitate smoking cessation. Am Fam Physician 2006; 74(2): 262-
71.
7. Fiore MC, Bailey WC, Cohen SJ. Smoking Cessation: information for specialists. Rockville, MD; 1996.
8. Lee PN, Fariss MW. A systematic review of possible serious adverse health effects of nicotine replacement therapy.
Arch Toxicol 2017; 91(4): 1565-94.
9. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet
TE
2013; 382(9905): 1629-37.
U
10. Hajek P, Phillips-Waller A, Przulj D, et al. E-cigarettes compared with nicotine replacement therapy within the UK Stop
IB
Smoking Services: the TEC RCT. Health Technol Assess 2019; 23(43): 1-82.
TR
11. He T, Oks M, Esposito M, Steinberg H, Makaryus M. "Tree-in-Bloom": Severe Acute Lung Injury Induced by Vaping
IS
Cannabis Oil. Ann Am Thorac Soc 2017; 14(3): 468-70.
D
12. Henry TS, Kanne JP, Kligerman SJ. Imaging of Vaping-Associated Lung Disease. N Engl J Med 2019; 381(15): 1486-7.
R
13. O
Layden JE, Ghinai I, Pray I, et al. Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report. N
PY
Engl J Med 2020; 382(10): 903-16.

O
14. Centers for Disease Control and Prevention; U.S. Department of Health & Human Services. Outbreak of Lung Injury
C
Associated with E-Cigarette Use, or Vaping https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-

T
O
disease.html [accessed Oct 2020].

N
15. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI. N
O
Engl J Med 2020; 382(8): 697-705.

-D
16. Gotts JE, Jordt SE, McConnell R, Tarran R. What are the respiratory effects of e-cigarettes? BMJ 2019; 366: l5275.
L
IA
17. Tashkin DP, Rennard S, Hays JT, Ma W, Lawrence D, Lee TC. Effects of varenicline on smoking cessation in patients with
ER
mild to moderate COPD: a randomized controlled trial. Chest 2011; 139(3): 591-9.
18. Tashkin D, Kanner R, Bailey W, et al. Smoking cessation in patients with chronic obstructive pulmonary disease: a
AT
double-blind, placebo-controlled, randomised trial. Lancet 2001; 357(9268): 1571-5.

M
19. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and
T
H
network meta-analysis. Cochrane Database Syst Rev 2013; 5(5): CD009329.

IG
20. The tobacco use and dependence clinical practice guideline panel s, and consortium representatives,. A clinical practice
R
PY
guideline for treating tobacco use and dependence. JAMA 2000; 28: 3244-54.
O
21. Glynn TJ, Manley M, Smoking T, Cancer P. How to help your patients stop smoking: a National Cancer Institute manual
C
for physicians. [Bethesda, Md.]: Smoking, Tobacco, and Cancer Program, Division of Cancer Prevention and Control,
National Cancer Institute, U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health;
1990.
22. Stead LF, Buitrago D, Preciado N, Sanchez G, Hartmann-Boyce J, Lancaster T. Physician advice for smoking cessation.
Cochrane Database Syst Rev 2013; 5(5): CD000165.
23. Kottke TE, Battista RN, DeFriese GH, Brekke ML. Attributes of successful smoking cessation interventions in medical
practice. A meta-analysis of 39 controlled trials. JAMA 1988; 259(19): 2883-9.
24. Katz DA, Muehlenbruch DR, Brown RL, Fiore MC, Baker TB, Group ASCGS. Effectiveness of implementing the agency for
healthcare research and quality smoking cessation clinical practice guideline: a randomized, controlled trial. J Natl
Cancer Inst 2004; 96(8): 594-603.
25. Halpern SD, French B, Small DS, et al. Randomized trial of four financial-incentive programs for smoking cessation. N
Engl J Med 2015; 372(22): 2108-17.
26. Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking
cessation. Cochrane Database Syst Rev 2016; 3: CD008286.
27. Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness
in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 2004;
125(6): 2011-20.
66
28. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2006; (1): CD002733.
29. Wongsurakiat P, Lertakyamanee J, Maranetra KN, Jongriratanakul S, Sangkaew S. Economic evaluation of influenza
vaccination in Thai chronic obstructive pulmonary disease patients. J Med Assoc Thai 2003; 86(6): 497-508.
30. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against
influenza among elderly persons living in the community. N Engl J Med 1994; 331(12): 778-84.
31. Fiore AE, Shay DK, Broder K, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the
Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009; 58(RR-8): 1-52.
32. Edwards KM, Dupont WD, Westrich MK, Plummer WD, Jr., Palmer PS, Wright PF. A randomized controlled trial of cold-
adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 1994; 169(1): 68-76.
33. Hak E, van Essen GA, Buskens E, Stalman W, de Melker RA. Is immunising all patients with chronic lung disease in the
community against influenza cost effective? Evidence from a general practice based clinical prospective cohort study in
Utrecht, The Netherlands. J Epidemiol Community Health 1998; 52(2): 120-5.
34. Huang CL, Nguyen PA, Kuo PL, Iqbal U, Hsu YH, Jian WS. Influenza vaccination and reduction in risk of ischemic heart
disease among chronic obstructive pulmonary elderly. Comput Methods Programs Biomed 2013; 111(2): 507-11.
35. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent
pneumococcal polysaccharide vaccine among adults aged >/=65 years: recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014; 63(37): 822-5.
36. Walters JA, Smith S, Poole P, Granger RH, Wood-Baker R. Injectable vaccines for preventing pneumococcal infection in
patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2010; (11): CD001390.
37. Walters JA, Tang JN, Poole P, Wood-Baker R. Pneumococcal vaccines for preventing pneumonia in chronic obstructive
TE
pulmonary disease. Cochrane Database Syst Rev 2017; 1: CD001390.
U
IB
38. Alfageme I, Vazquez R, Reyes N, et al. Clinical efficacy of anti-pneumococcal vaccination in patients with COPD. Thorax
R
2006; 61(3): 189-95.
T
IS
39. Dransfield MT, Harnden S, Burton RL, et al. Long-term comparative immunogenicity of protein conjugate and free
D
polysaccharide pneumococcal vaccines in chronic obstructive pulmonary disease. Clin Infect Dis 2012; 55(5): e35-44.
R
40. Bonten MJ, Huijts SM, Bolkenbaas M, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in
O
adults. N Engl J Med 2015; 372(12): 1114-25.
PY
41. Centers for Disease Control and Prevention Mortality and Morbidity Weekly Report. Use of Tetanus Toxoid, Reduced
O
C
Diphtheria Toxoid, and Acellular Pertussis Vaccines: Updated Recommendations of the Advisory Committee on
T
Immunization Practices — United States, 2019, online article available here:

O
N
https://www.cdc.gov/mmwr/volumes/69/wr/mm6903a5.htm [accessed Sept 2020].

O
42. Centers for Disease Control and Prevention. Lung Disease including Asthma and Adult Vaccination, 2016, online
-D
information available here: https://www.cdc.gov/vaccines/adults/rec-vac/health-conditions/lung-disease.html

L
[accessed Sept 2020].

IA
43. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled
ER
study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE
AT
trial. BMJ 2000; 320(7245): 1297-303.

M
44. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic
T
H
bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272(19): 1497-505.
IG
45. Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic
R
obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive
PY
Pulmonary Disease. N Engl J Med 1999; 340(25): 1948-53.

O
C
46. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate
chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353(9167): 1819-23.
47. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med
2008; 359(15): 1543-54.
48. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive
pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374(9696):
1171-8.
49. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic
obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008; 178(4): 332-8.
50. World Health Organization. WHO package of essential noncommunicable (PEN) disease interventions for primary health
care. Geneva. Licence: CC BY-NC-SA 3.0 IGO, online document available here:
https://www.who.int/publications/i/item/who-package-of-essential-noncommunicable-(pen)-disease-interventions-
for-primary-health-care [accessed Oct 2020].
51. O'Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in
COPD. Eur Respir J 2004; 23(6): 832-40.
52. O'Donnell DE, Sciurba F, Celli B, et al. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise
endurance in COPD. Chest 2006; 130(3): 647-56.
53. Berger R, Smith D. Effect of inhaled metaproterenol on exercise performance in patients with stable "fixed" airway
obstruction. Am Rev Respir Dis 1988; 138(3): 624-9.
67
54. Hay JG, Stone P, Carter J, et al. Bronchodilator reversibility, exercise performance and breathlessness in stable chronic
obstructive pulmonary disease. Eur Respir J 1992; 5(6): 659-64.
55. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airways
disease. BMJ 1988; 297(6662): 1506-10.
56. Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers GW, Donohue JF. Dose response to ipratropium as a nebulized
solution in patients with chronic obstructive pulmonary disease. A three-center study. Am Rev Respir Dis 1989; 139(5):
1188-91.
57. Higgins BG, Powell RM, Cooper S, Tattersfield AE. Effect of salbutamol and ipratropium bromide on airway calibre and
bronchial reactivity in asthma and chronic bronchitis. Eur Respir J 1991; 4(4): 415-20.
58. Vathenen AS, Britton JR, Ebden P, Cookson JB, Wharrad HJ, Tattersfield AE. High-dose inhaled albuterol in severe
chronic airflow limitation. Am Rev Respir Dis 1988; 138(4): 850-5.
59. Donohue JF, Anzueto A, Brooks J, Mehta R, Kalberg C, Crater G. A randomized, double-blind dose-ranging study of the
novel LAMA GSK573719 in patients with COPD. Respir Med 2012; 106(7): 970-9.
60. Donohue JF, Kalberg C, Shah P, et al. Dose response of umeclidinium administered once or twice daily in patients with
COPD: a pooled analysis of two randomized, double-blind, placebo-controlled studies. J Clin Pharmacol 2014; 54(11):
1214-20.
61. Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh CJ. The risks and benefits of indacaterol--
the FDA's review. N Engl J Med 2011; 365(24): 2247-9.
62. O'Driscoll BR, Kay EA, Taylor RJ, Weatherby H, Chetty MC, Bernstein A. A long-term prospective assessment of home
nebulizer treatment. Respir Med 1992; 86(4): 317-25.
63. Jenkins SC, Heaton RW, Fulton TJ, Moxham J. Comparison of domiciliary nebulized salbutamol and salbutamol from a
TE
metered-dose inhaler in stable chronic airflow limitation. Chest 1987; 91(6): 804-7.
U
IB
64. Sestini P, Renzoni E, Robinson S, Poole P, Ram FS. Short-acting beta 2 agonists for stable chronic obstructive pulmonary
R
T
IS
65. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of nebulized levalbuterol in stable COPD. Chest 2003; 124(3): 844-
D
9.
R
66. Cazzola M, Rogliani P, Ruggeri P, et al. Chronic treatment with indacaterol and airway response to salbutamol in stable
O
COPD. Respir Med 2013; 107(6): 848-53.
PY
67. Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane
O
C
Database Syst Rev 2013; 10(10): CD010177.

T
68. Han J, Dai L, Zhong N. Indacaterol on dyspnea in chronic obstructive pulmonary disease: a systematic review and meta-
O
N
analysis of randomized placebo-controlled trials. BMC Pulm Med 2013; 13: 26.
O
69. Geake JB, Dabscheck EJ, Wood-Baker R, Cates CJ. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta(2)-
-D
agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015; 1: CD010139.
L
70. Koch A, Pizzichini E, Hamilton A, et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered
IA
via Respimat(R) versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate
ER
48-week studies. Int J Chron Obstruct Pulmon Dis 2014; 9: 697-714.

AT
71. Kempsford R, Norris V, Siederer S. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well
M
tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD. Pulm
T
H
Pharmacol Ther 2013; 26(2): 256-64.

IG
72. Lipworth BJ, McDevitt DG, Struthers AD. Hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy.
R
Protection by conventional doses of spironolactone but not triamterene. Chest 1990; 98(4): 811-5.
PY
73. Uren NG, Davies SW, Jordan SL, Lipkin DP. Inhaled bronchodilators increase maximum oxygen consumption in chronic
O
C
left ventricular failure. Eur Heart J 1993; 14(6): 744-50.

74. Khoukaz G, Gross NJ. Effects of salmeterol on arterial blood gases in patients with stable chronic obstructive pulmonary
disease. Comparison with albuterol and ipratropium. Am J Respir Crit Care Med 1999; 160(3): 1028-30.
75. McGarvey L, Niewoehner D, Magder S, et al. One-Year Safety of Olodaterol Once Daily via Respimat(R) in Patients with
GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis. COPD 2015; 12(5): 484-93.
76. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-
daily formoterol in COPD. Thorax 2010; 65(6): 473-9.
77. Melani AS. Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol 2015; 8(4): 479-501.
78. Barnes P. Bronchodilators: basic pharmacology. In: Calverley PMA, Pride NB, eds. Chronic Obstructive Pulmonary
Disease. London: Chapman and Hall; 1995: 391-417.
79. Appleton S, Jones T, Poole P, et al. Ipratropium bromide versus long-acting beta-2 agonists for stable chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2006; (3): CD006101.
80. Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the
ATTAIN study. Eur Respir J 2012; 40(4): 830-6.
81. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database
Syst Rev 2014; 7(7): CD009285.
82. Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination
of tiotropium and rehabilitative exercise training in COPD patients. Int J Chron Obstruct Pulmon Dis 2008; 3(1): 127-36.
68
83. Casaburi R, Kukafka D, Cooper CB, Witek TJ, Jr., Kesten S. Improvement in exercise tolerance with the combination of
tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005; 127(3): 809-17.
84. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N
Engl J Med 2011; 364(12): 1093-103.
85. Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic
obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med 2013;
1(7): 524-33.
86. Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med 2017;
377(10): 923-35.
87. Tashkin DP. Long-acting anticholinergic use in chronic obstructive pulmonary disease: efficacy and safety. Curr Opin
Pulm Med 2010; 16(2): 97-105.
88. Disse B, Speck GA, Rominger KL, Witek TJ, Jr., Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical
profile in obstructive lung disease. Life Sci 1999; 64(6-7): 457-64.
89. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest 2006; 130(6): 1695-703.
90. Anthonisen NR, Connett JE, Enright PL, Manfreda J, Lung Health Study Research G. Hospitalizations and mortality in the
Lung Health Study. Am J Respir Crit Care Med 2002; 166(3): 333-9.
91. Michele TM, Pinheiro S, Iyasu S. The safety of tiotropium--the FDA's conclusions. N Engl J Med 2010; 363(12): 1097-9.
92. Verhamme KM, Afonso A, Romio S, Stricker BC, Brusselle GG, Sturkenboom MC. Use of tiotropium Respimat Soft Mist
Inhaler versus HandiHaler and mortality in patients with COPD. Eur Respir J 2013; 42(3): 606-15.
93. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med 2013;
369(16): 1491-501.
TE
94. Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol causing closed-angle glaucoma.
U
IB
Lancet 1984; 2(8404): 691.
R
95. Mulpeter KM, Walsh JB, O'Connor M, O'Connell F, Burke C. Ocular hazards of nebulized bronchodilators. Postgrad Med
T
IS
J 1992; 68(796): 132-3.
D
96. Hall SK. Acute angle-closure glaucoma as a complication of combined beta-agonist and ipratropium bromide therapy in
R
the emergency department. Ann Emerg Med 1994; 23(4): 884-7. O
97. Aubier M. Pharmacotherapy of respiratory muscles. Clin Chest Med 1988; 9(2): 311-24.
PY
98. McKay SE, Howie CA, Thomson AH, Whiting B, Addis GJ. Value of theophylline treatment in patients handicapped by
O
C
chronic obstructive lung disease. Thorax 1993; 48(3): 227-32.

T
99. Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med 1988; 9(2): 325-36.
O
N
100. Ram FS, Jones PW, Castro AA, et al. Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database
O
Syst Rev 2002; (4): CD003902.

-D
101. ZuWallack RL, Mahler DA, Reilly D, et al. Salmeterol plus theophylline combination therapy in the treatment of COPD.
L
Chest 2001; 119(6): 1661-70.

IA
102. Zacarias EC, Castro AA, Cendon S. Effect of theophylline associated with short-acting or long-acting inhaled beta2-
ER
agonists in patients with stable chronic obstructive pulmonary disease: a systematic review. J Bras Pneumol 2007;
AT
33(2): 152-60.
M
103. Cosio BG, Shafiek H, Iglesias A, et al. Oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Does Not
T
H
Reduce Exacerbations in Patients With Severe COPD: A Pilot Clinical Trial. Chest 2016; 150(1): 123-30.
IG
104. Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-
R
controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 2006; 11(5):
PY
603-10.
O
C
105. Devereux G, Cotton S, Fielding S, et al. Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in
Patients With COPD: A Randomized Clinical Trial. JAMA 2018; 320(15): 1548-59.
106. Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in
COPD. Pulm Pharmacol Ther 2010; 23(4): 257-67.
107. Ray R, Tombs L, Naya I, Compton C, Lipson DA, Boucot I. Efficacy and safety of the dual bronchodilator combination
umeclidinium/vilanterol in COPD by age and airflow limitation severity: A pooled post hoc analysis of seven clinical
trials. Pulm Pharmacol Ther 2019; 57: 101802.
108. Gross N, Tashkin D, Miller R, Oren J, Coleman W, Linberg S. Inhalation by nebulization of albuterol-ipratropium
combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary
disease. Dey Combination Solution Study Group. Respiration 1998; 65(5): 354-62.
109. Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment
of COPD. COPD 2009; 6(1): 17-25.
110. Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-
agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015; 10(10): CD008989.
111. van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination
therapy on patient-centred outcomes. Prim Care Respir J 2012; 21(1): 101-8.
112. Mahler DA, Decramer M, D'Urzo A, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in
COPD: the BLAZE study. Eur Respir J 2014; 43(6): 1599-609.
69
113. Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of
life. Respir Med 2015; 109(10): 1312-9.
114. Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in
COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies
(ACLIFORM and AUGMENT). Respir Res 2015; 16: 92.
115. Martinez FJ, Fabbri LM, Ferguson GT, et al. Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol
Metered Dose Inhaler in COPD. Chest 2017; 152(6): 1169-78.
116. Maltais F, Bjermer L, Kerwin EM, et al. Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol
monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial.
Respir Res 2019; 20(1): 238.
117. Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate)
versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care
Med 2015; 192(9): 1068-79.
118. Bai C, Ichinose M, Lee SH, et al. Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with
chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2017; 12: 3329-39.
119. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the
dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind,
parallel-group study. Lancet Respir Med 2013; 1(3): 199-209.
120. Calverley PMA, Anzueto AR, Carter K, et al. Tiotropium and olodaterol in the prevention of chronic obstructive
pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial.
Lancet Respir Med 2018; 6(5): 337-44.
TE
121. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl
U
IB
J Med 2016; 374(23): 2222-34.
R
122. Lipson DA, Barnhart F, Brealey N, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N
T
IS
Engl J Med 2018; 378(18): 1671-80.
D
123. Suissa S, Dell'Aniello S, Ernst P. Comparative Effectiveness and Safety of LABA-LAMA vs LABA-ICS Treatment of COPD in
R
Real-World Clinical Practice. Chest 2019; 155(6): 1158-65. O
124. Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov 2013; 12(7):
PY
543-59.
O
C
125. Boardman C, Chachi L, Gavrila A, et al. Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulm
T
Pharmacol Ther 2014; 29(2): 129-43.

O
N
126. Sonnex K, Alleemudder H, Knaggs R. Impact of smoking status on the efficacy of inhaled corticosteroids in chronic
O
obstructive pulmonary disease: a systematic review. BMJ Open 2020; 10(4): e037509.
-D
127. Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease.
L
Cochrane Database Syst Rev 2012; 7(7): CD002991.

IA
128. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive
ER
pulmonary disease. N Engl J Med 2007; 356(8): 775-89.

AT
129. Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary
M
disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet 2016;
T
H
387(10030): 1817-26.
IG
130. Calverley PMA, Anderson JA, Brook RD, et al. Fluticasone Furoate, Vilanterol, and Lung Function Decline in Patients with
R
Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk. Am J Respir Crit Care Med 2018;
PY
197(1): 47-55.
O
C
131. Suissa S, Dell'Aniello S, Gonzalez AV, Ernst P. Inhaled corticosteroid use and the incidence of lung cancer in COPD. Eur
Respir J 2020; 55(2): 1901720.
132. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-
acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 9(9): CD006829.
133. Nannini LJ, Poole P, Milan SJ, Kesterton A. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler
versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013; 8(8):
CD006826.
134. Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. N
Engl J Med 2016; 375(13): 1253-60.
135. Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with
chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med 2018; 6(2):
117-26.
136. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood Eosinophils: A Biomarker of Response to Extrafine
Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 192(4): 523-5.
137. Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic
obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet 2018;
391(10125): 1076-84.
70
138. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to
the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a
secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3(6): 435-42.
139. Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist
therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled
trial. Lancet 2017; 389(10082): 1919-29.
140. Roche N, Chapman KR, Vogelmeier CF, et al. Blood Eosinophils and Response to Maintenance Chronic Obstructive
Pulmonary Disease Treatment. Data from the FLAME Trial. Am J Respir Crit Care Med 2017; 195(9): 1189-97.
141. Watz H, Tetzlaff K, Wouters EF, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary
disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 2016;
4(5): 390-8.
142. Calverley PMA, Tetzlaff K, Vogelmeier C, et al. Eosinophilia, Frequent Exacerbations, and Steroid Response in Chronic
Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2017; 196(9): 1219-21.
143. Chapman KR, Hurst JR, Frent SM, et al. Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in
Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical
Trial. Am J Respir Crit Care Med 2018; 198(3): 329-39.
144. Landis SH, Suruki R, Hilton E, Compton C, Galwey NW. Stability of Blood Eosinophil Count in Patients with COPD in the
UK Clinical Practice Research Datalink. COPD 2017; 14(4): 382-8.
145. Oshagbemi OA, Burden AM, Braeken DCW, et al. Stability of Blood Eosinophils in Patients with Chronic Obstructive
Pulmonary Disease and in Control Subjects, and the Impact of Sex, Age, Smoking, and Baseline Counts. Am J Respir Crit
Care Med 2017; 195(10): 1402-4.
TE
146. Southworth T, Beech G, Foden P, Kolsum U, Singh D. The reproducibility of COPD blood eosinophil counts. Eur Respir J
U
IB
2018; 52(1).
R
147. Casanova C, Celli BR, de-Torres JP, et al. Prevalence of persistent blood eosinophilia: relation to outcomes in patients
T
IS
with COPD. Eur Respir J 2017; 50(5).
D
148. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood Eosinophils and Exacerbations in Chronic
R
Obstructive Pulmonary Disease. The Copenhagen General Population Study. Am J Respir Crit Care Med 2016; 193(9):
O
965-74.
PY
149. Yun JH, Lamb A, Chase R, et al. Blood eosinophil count thresholds and exacerbations in patients with chronic
O
C
obstructive pulmonary disease. J Allergy Clin Immunol 2018; 141(6): 2037-47.e10.

T
150. Agusti A, Fabbri LM, Singh D, et al. Inhaled corticosteroids in COPD: friend or foe? Eur Respir J 2018; 52(6).
O
N
151. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only
O
for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials.
-D
Lancet Respir Med 2013; 1(3): 210-23.

L
152. Crim C, Dransfield MT, Bourbeau J, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with
IA
vilanterol alone in patients with COPD. Ann Am Thorac Soc 2015; 12(1): 27-34.
ER
153. Crim C, Calverley PMA, Anderson JA, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol in COPD
AT
patients with moderate airflow limitation: The SUMMIT trial. Respir Med 2017; 131: 27-34.
M
154. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic
T
H
obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med 2016; 4(9): 731-41.
IG
155. Johnell O, Pauwels R, Lofdahl CG, et al. Bone mineral density in patients with chronic obstructive pulmonary disease
R
treated with budesonide Turbuhaler. Eur Respir J 2002; 19(6): 1058-63.

PY
156. Ferguson GT, Calverley PM, Anderson JA, et al. Prevalence and progression of osteoporosis in patients with COPD:
O
C
results from the TOwards a Revolution in COPD Health study. Chest 2009; 136(6): 1456-65.
157. Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-
analysis of randomised controlled trials and observational studies. Thorax 2011; 66(8): 699-708.
158. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med 2010;
123(11): 1001-6.
159. Wang JJ, Rochtchina E, Tan AG, Cumming RG, Leeder SR, Mitchell P. Use of inhaled and oral corticosteroids and the
long-term risk of cataract. Ophthalmology 2009; 116(4): 652-7.
160. Andrejak C, Nielsen R, Thomsen VO, Duhaut P, Sorensen HT, Thomsen RW. Chronic respiratory disease, inhaled
corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax 2013; 68(3): 256-62.
161. Dong YH, Chang CH, Lin Wu FL, et al. Use of inhaled corticosteroids in patients with COPD and the risk of TB and
influenza: A systematic review and meta-analysis of randomized controlled trials. Chest 2014; 145(6): 1286-97.
162. Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax
2013; 68(12): 1105-13.
163. Price D, Yawn B, Brusselle G, Rossi A. Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care
Respir J 2013; 22(1): 92-100.
164. Nadeem NJ, Taylor SJ, Eldridge SM. Withdrawal of inhaled corticosteroids in individuals with COPD--a systematic review
and comment on trial methodology. Respir Res 2011; 12: 107.
71
165. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002;
166(10): 1358-63.
166. Wouters EF, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone
treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial.
Thorax 2005; 60(6): 480-7.
167. Kunz LI, Postma DS, Klooster K, et al. Relapse in FEV1 Decline After Steroid Withdrawal in COPD. Chest 2015; 148(2):
389-96.
168. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N
Engl J Med 2014; 371(14): 1285-94.
169. Brusselle G, Price D, Gruffydd-Jones K, et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing
pathways in the UK. Int J Chron Obstruct Pulmon Dis 2015; 10: 2207-17.
170. Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 180(8): 741-50.
171. Singh D, Brooks J, Hagan G, Cahn A, O'Connor BJ. Superiority of "triple" therapy with salmeterol/fluticasone propionate
and tiotropium bromide versus individual components in moderate to severe COPD. Thorax 2008; 63(7): 592-8.
172. Jung KS, Park HY, Park SY, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in
COPD: a randomized controlled study. Respir Med 2012; 106(3): 382-9.
173. Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of adding fluticasone
propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med 2012; 106(1): 91-101.
174. Frith PA, Thompson PJ, Ratnavadivel R, et al. Glycopyrronium once-daily significantly improves lung function and health
TE
status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled
U
IB
trial. Thorax 2015; 70(6): 519-27.
R
175. Lipson DA, Barnacle H, Birk R, et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive
T
IS
Pulmonary Disease. Am J Respir Crit Care Med 2017; 196(4): 438-46.
D
176. Siler TM, Kerwin E, Singletary K, Brooks J, Church A. Efficacy and Safety of Umeclidinium Added to Fluticasone
R
Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies. COPD 2016; 13(1): 1-
O
10.
PY
177. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-
O
C
agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised
T
controlled trial. Lancet 2016; 388(10048): 963-73.

O
N
178. Vestbo J, Fabbri L, Papi A, et al. Inhaled corticosteroid containing combinations and mortality in COPD. Eur Respir J
O
2018; 52(6): 1801230.

-D
179. Lipson DA, Crim C, Criner GJ, et al. Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol
L
in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2020; 201(12): 1508-16.
IA
180. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-
ER
Severe COPD. N Engl J Med 2020; 383(1): 35-48.

AT
181. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the
M
economic implications of steroid use. Respir Med 2009; 103(7): 975-94.

T
H
182. Walters JA, Tan DJ, White CJ, Gibson PG, Wood-Baker R, Walters EH. Systemic corticosteroids for acute exacerbations of
IG
chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014; (9): CD001288.
R
183. Renkema TE, Schouten JP, Koeter GH, Postma DS. Effects of long-term treatment with corticosteroids in COPD. Chest
PY
1996; 109(5): 1156-62.

O
C
184. Rice KL, Rubins JB, Lebahn F, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized
trial. Am J Respir Crit Care Med 2000; 162(1): 174-8.
185. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary
disease. Br J Pharmacol 2011; 163(1): 53-67.
186. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two
randomised clinical trials. Lancet 2009; 374(9691): 685-94.
187. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary
disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374(9691): 695-703.
188. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in
patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a
multicentre randomised controlled trial. Lancet 2015; 385(9971): 857-66.
189. Rabe KF, Calverley PMA, Martinez FJ, Fabbri LM. Effect of roflumilast in patients with severe COPD and a history of
hospitalisation. Eur Respir J 2017; 50(1).
190. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in
response to daily azithromycin therapy. Am J Respir Crit Care Med 2014; 189(12): 1503-8.
191. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane
Database Syst Rev 2013; 11(11): CD002309.
72
192. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis. Influence of penicillin and tetracycline administered daily, or
intermittently for exacerbations. A report to the Research Committee of the British Tuberculosis Association by its
Bronchitis Subcommittee. Br Med J 1961; 2(5258): 979-85.
193. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis. Influence of daily penicillin and tetracycline on exacerbations
and their cost. Br Med J 1960; 1(5169): 297-303.
194. Johnston RN, McNeill RS, Smith DH, et al. Five-year winter chemoprophylaxis for chronic bronchitis. BMJ 1969; 4(678):
265-9.
195. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane
Database Syst Rev 2013; (11): CD009764.
196. Ni W, Shao X, Cai X, et al. Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary
disease exacerbation: a meta-analysis. PLoS One 2015; 10(3): e0121257.
197. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is
associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;
178(11): 1139-47.
198. Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of
chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet
Respir Med 2014; 2(5): 361-8.
199. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;
365(8): 689-98.
200. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive
pulmonary disease: a randomized controlled trial. Respir Res 2010; 11: 10.
TE
201. Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-
U
IB
analysis. Eur Respir Rev 2015; 24(137): 451-61.
R
202. Poole P, Chong J, Cates CJ. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary
T
IS
D
203. Dal Negro RW, Wedzicha JA, Iversen M, et al. Effect of erdosteine on the rate and duration of COPD exacerbations: the
R
RESTORE study. Eur Respir J 2017; 50(4). O
204. Rogliani P, Matera MG, Page C, Puxeddu E, Cazzola M, Calzetta L. Efficacy and safety profile of mucolytic/antioxidant
PY
agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-
O
C
acetylcysteine. Respir Res 2019; 20(1): 104.

T
205. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive
O
N
pulmonary disease. Cochrane Database Syst Rev 2019; 5: CD001287.

O
206. Collet JP, Shapiro P, Ernst P, Renzi T, Ducruet T, Robinson A. Effects of an immunostimulating agent on acute
-D
exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering
L
Committee and Research Group. Prevention of Acute Respiratory Infection by an Immunostimulant. Am J Respir Crit
IA
Care Med 1997; 156(6): 1719-24.

ER
207. Li J, Zheng JP, Yuan JP, Zeng GQ, Zhong NS, Lin CY. Protective effect of a bacterial extract against acute exacerbation in
AT
patients with chronic bronchitis accompanied by chronic obstructive pulmonary disease. Chin Med J (Engl) 2004;
M
117(6): 828-34.
T
H
208. Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J
IG
Med 2017; 377(17): 1613-29.

R
209. Criner GJ, Celli BR, Brightling CE, et al. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med 2019;
PY
381(11): 1023-34.
O
C
210. Lee JH, Kim HJ, Kim YH. The Effectiveness of Anti-leukotriene Agents in Patients with COPD: A Systemic Review and
Meta-analysis. Lung 2015; 193(4): 477-86.
211. Liu L, Wang JL, Xu XY, Feng M, Hou Y, Chen L. Leukotriene receptor antagonists do not improve lung function decline in
COPD: a meta-analysis. Eur Rev Med Pharmacol Sci 2018; 22(3): 829-34.
212. Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2007; 175(9): 926-34.
213. Dransfield MT, Voelker H, Bhatt SP, et al. Metoprolol for the Prevention of Acute Exacerbations of COPD. N Engl J Med
2019; 381(24): 2304-14.
214. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N
Engl J Med 2014; 370(23): 2201-10.
215. Ingebrigtsen TS, Marott JL, Nordestgaard BG, Lange P, Hallas J, Vestbo J. Statin use and exacerbations in individuals with
chronic obstructive pulmonary disease. Thorax 2015; 70(1): 33-40.
216. Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive
pulmonary disease: a randomized trial. Ann Intern Med 2012; 156(2): 105-14.
217. Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-
analysis of individual participant data from randomised controlled trials. Thorax 2019; 74(4): 337-45.
218. Laube BL, Janssens HM, de Jongh FH, et al. What the pulmonary specialist should know about the new inhalation
therapies. Eur Respir J 2011; 37(6): 1308-31.
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Global Initiative for Chronic

GLOBAL STRATEGY FOR THE DIAGNOSIS,

GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT,

© 2020 Global Initiative for Chronic Obstructive Lung Disease, Inc.

College of Medicine and Health, Gerard Criner, MD Manchester, UK

University of Exeter, Exeter Temple University School of Medicine

Devon, UK Philadelphia, Pennsylvania, USA Robert Stockley, MD DSc

M. Victorina López Varela, MD David Halpin, MD Birmingham, UK

Universidad de la República University of Exeter Medical School,

Montevideo, Uruguay College of Medicine and Health, M. Victorina López Varela, MD

University of Exeter, Exeter Universidad de la República

Maria Montes de Oca, MD Devon, UK Hospital Maciel

Hospital Universitario de Caracas Montevideo, Uruguay

Universidad Central de Venezuela MeiLan K. Han, MD MS

Centro Médico de Caracas University of Michigan Jørgen Vestbo, MD (retired 2019)

Caracas, Venezuela Ann Arbor, MI, USA University of Manchester

Kevin Mortimer, MD Fernando J. Martinez, MD MS

Liverpool School of Tropical Medicine New York-Presbyterian Hospital/ Jadwiga A. Wedzicha, MD

New York, NY, USA London, UK

GOLD EXECUTIVE DIRECTOR GOLD PROJECT MANAGER EDITORIAL ASSISTANCE

Michael Hess, MPH, RRT, RPFT,

ARGENTINA Mumbai, India Islamabad, Pakistan

Kingston, Ontario, Canada Florence, Italy Kian-Chung Ong, MD

CHILE JAPAN Wan-Cheng Tan, MD,

Dr Manuel Barros Takahide Nagase, MD Chair, Asian Pacific COPD Roundtable

CHINA Tokyo, Japan SLOVAK REPUBLIC

Jiangtao Lin, MD KAZAKHSTAN Ruzena Tkacova, MD PhD

Beijing, China Damilya Nugmanova, MD, PhD, DSci Kosice, Slovakia

Fu-Qiang Wen, MD, PhD Almaty, Kazakhstan SLOVENIA

COLOMBIA Tair Nurpeissov Professor Dr. Stanislav Suskovic

Alejandro Casas, MD KOREA Golnik, Slovenia

Vice-Director, COPD Department Yeon-Mok Oh, MD SOUTH AFRICA

CROATIA KUWAIT University of Cape Town and

Neven Miculinic, MD Professor Mousa Khadadah Groote Schuur Hospital

Zagreb, Croatia Kuwait University Cape Town, South Africa

CZECH REPUBLIC KYRGYZSTAN SPAIN

Stanislav Kos, MD, PhD., FCCP Talant Sooronbaev, MD Dr Patricia Sobradillo

EGYPT LEBANON Daiana Stolz, MD

Alvar G. Agusti, MD Claus Vogelmeier, MD

Chair, GOLD Board of Directors Chair, GOLD Science Committee

Hospital Clínic, Universitat de Barcelona, Department of Medicine, Pulmonary and Critical

Spain and Marburg, Philipps-Universität Marburg,

CHAPTER 1: DEFINITION AND OVERVIEW ....................................................................................................................................................... 4

OVERALL KEY POINTS: ..................................................................................................................................................................................... 4

Age and sex ..................................................................................................................................................................................................... 9

Lung growth and development ....................................................................................................................................................................... 9

Exposure to particles ....................................................................................................................................................................................... 9

Socioeconomic status .................................................................................................................................................................................... 10

Asthma and airway hyper-reactivity ............................................................................................................................................................. 10

Chronic bronchitis ......................................................................................................................................................................................... 11

PATHOLOGY, PATHOGENESIS AND PATHOPHYSIOLOGY .................................................................................................................................... 12

CHAPTER 2: DIAGNOSIS AND INITIAL ASSESSMENT .......................................................................................................................................20

OVERALL KEY POINTS: ................................................................................................................................................................................... 20

CHAPTER 3: EVIDENCE SUPPORTING PREVENTION AND MAINTENANCE THERAPY.........................................................................................40

OVERALL KEY POINTS: ................................................................................................................................................................................... 40

Therapy relevant to all patients with COPD .................................................................................................................................................. 60

End-of-life and hospice care .......................................................................................................................................................................... 61

OTHER TREATMENTS .......................................................................................................................................................................................... 62

Oxygen therapy and ventilatory support....................................................................................................................................................... 62