Document Oz0LydrabR1ZyBvw5me3gVY2M

IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP GLOBAL INITIATIVE FOR CHRONIC OBSTRUCTIVE LUNG DISEASE GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (2023 REPORT) UTE TRIB DIS Y OR COP T NO - DO ERIALS MAT YRIGHT COP 2022, 2023 Global Initiative for Chronic Obstructive Lung Disease, Inc. i GOLD BOARD OF DIRECTORS (2022) GOLD SCIENCE COMMITTEE* (2022) Alvar Agusti, MD, Chair Respiratory Institute Hospital Clinic, IDIBAPS Univ. Barcelona and Ciberes Barcelona, Spain Richard Beasley, MD Medical Research Institute of NZ Wellington, New Zealand Claus Vogelmeier, MD, Chair University of Marburg Marburg, Germany Alvar Agusti, MD Respiratory Institute Hospital Clinic, IDIBAPS Univ. Barcelona and Ciberes Barcelona, Spain Bartolome R. Celli, MD Antonio Anzueto, MD Harvard Medical School South Texas Veterans Health Care System Boston, Massachusetts, USA University of Texas, Health San Antonio, Texas, USA Gerard Criner, MD Temple University School of Medicine Peter Barnes, DM, FRS Philadelphia, Pennsylvania, USA National Heart & Lung Institute Imperial College David Halpin, MD London, United Kingdom University of Exeter Medical School College of Medicine and Health Jean Bourbeau, MD University of Exeter, Exeter R Devon, UK Y O M. Victorina Lpez Varela, MD OP Universidad de la Repblica C Hospital Maciel T Montevideo, Uruguay McGill University Health Centre McGill University Montreal, Canada Gerard Criner, MD Temple University School of Medicine Philadelphia, Pennsylvania, USA O NO Maria Montes de Oca, MD D Hospital Universitario de Caracas S - Universidad Central de Venezuela L Centro Mdico de Caracas IA Caracas, Venezuela David Halpin, MD University of Exeter Medical School College of Medicine and Health University of Exeter, Exeter Devon, UK ATER Kevin Mortimer, MD M Liverpool University Hospitals NHS Foundation T Trust, UK/National Heart and Lung Institute, IGH Imperial College London, UK/School of Clinical R Medicine, College of Health Sciences, Y University of Kwazulu-Natal, South Africa COP Sundeep Salvi, MD MeiLan K. Han, MD MS University of Michigan Ann Arbor, MI, USA Fernando J. Martinez, MD MS Weill Cornell Medical Center/ New York-Presbyterian Hospital New York, NY, USA Pulmocare Research and Education (PURE) Foundation Maria Montes de Oca, MD Pune, India Hospital Universitario de Caracas Universidad Central de Venezuela Claus Vogelmeier, MD Centro Mdico de Caracas University of Marburg Caracas, Venezuela Marburg, Germany Alberto Papi, MD University of Ferrara Ferrara, Italy Ian Pavord, DM FMedSci Respiratory Medicine Unit and Oxford Respiratory NIHR Biomedical Research Centre, Nuffield Department of Medicine University of Oxford Oxford, UK Nicolas Roche, MD Pneumologie, Hpital Cochin AP-HP.Centre - Universit Paris Cit UMR 1016 DISTRIBUTE Institut Cochin Paris, France Don D. Sin, MD St. Paul's Hospital University of British Columbia Vancouver, Canada Dave Singh, MD University of Manchester Manchester, UK Robert Stockley, MD DSc University Hospital Birmingham, UK M. Victorina Lpez Varela, MD Universidad de la Repblica Hospital Maciel Montevideo, Uruguay Jadwiga A. Wedzicha, MD National Heart & Lung Institute Imperial College London London, UK GOLD EXECUTIVE DIRECTOR Katie Langefeld, BS Illinois, USA EDITORIAL ASSISTANCE Ruth Hadfield, PhD Macquarie University AIHI Sydney, Australia GRAPHIC DESIGN Wendy Stasolla Imbue Creative New Jersey, USA *Disclosure forms for GOLD Committees are posted on the GOLD Website, www.goldcopd.org ii GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (2023) 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 Dr Eduardo A. Schiavi Buenos Aires, Argentina BANGLADESH Dr Kazi S. Bennoor Dhaka, Bangladesh Prof Md Mostafizur Rahman Dhaka, Bangladesh BELGIUM Prof Wim Janssens Leuven, Belgium BULGARIA Dr Yavor Ivanov Pleven, Bulgaria CHINA Fu-Qiang Wen, MD, PhD Chengdu, China COLOMBIA Alejandro Casas, MD General Director of the Fundacin Neumolgica Colombiana CROATIA Neven Miculinic, MD Zagreb, Croatia CZECH REPUBLIC Stanislav Kos, MD, PhD., FCCP Mirosov, Czech Republic EGYPT Hisham Tarraf, MD Cairo, Egypt FRANCE Prof Gaetan Desle Reims, France GEORGIA YRIGHT COP Maia Gotua, MD, PhD Tbilisi, Georgia GREECE Prof Konstantinos Kostikas Ioannina, Greece HONG KONG CHINA David S.C. Hui, MD Shatin, N.T. Hong Kong ICELAND Dr Gunnar Gudmundsson Reykjavik, Iceland INDIA Dr R. Narasimhan, MD Chennai, India Dr Kshitij Agarwal, MD New Delhi, India INDONESIA Prof Faisal Yunus Jakarta, Indonesia IRAN Dr Masjedi Mohammad Reza Tehran, Iran Mohammad Ashkan Moslehi, MD Shiraz, Iran IRELAND Timothy J. McDonnell, MD Dublin, Ireland ISRAEL Zvi G. Fridlender, MD, MSc Jerusalem, Israel ITALY Prof Lorenzo Corbetta Florence, Italy JAPAN Takahide Nagase, MD OR Tokyo, Japan KAZAKHSTAN COPY Tair Nurpeissov KOREA NOT YSeeoounl-,MSoouktOhhK,oM-reDDaO KPrUoWfeAssITorIAMLoSusa Khadadah KKuYwRTGaEiYtZRUSnTiAvNersity MTaAlant Sooronbaev, MD Bishkek, Kyrgyzstan LEBANON Mirna Waked, MD, FCCP Balamand University, Lebanon LITHUANIA Prof Kestutis Malakauskas, MD, PhD Kaunas, Lithuania MALTA Prof Joseph M Cacciotolo Pieta, Malta MOLDOVA Alexandru Corlateanu, MD, PhD ERS National Delegate Republic of Moldova NORWAY Rune Nielsen, MD, PhD University of Bergen, Norway PAKISTAN Prof Javaid Khan Karachi, Pakistan Dr Jamil Ur Rehman Tahir Kammanwala, Sialkot Cantt, Pakistan Dr Mohammad Osman Yusuf Islamabad, Pakistan POLAND Pawel Sliwinski, MD, PhD Warsaw, Poland ROMANIA Florin Mihaltan, MD Ruxandra Ulmeanu, MD Bucharest, Romania RUSSIA Prof Zaurbek Aisanov, MD Moscow, Russia PKraozafUnAT,leETxaatnardsrteanViRzeelp, uMbDlic, Russian ISTRFSSeeiIbBdregereriyaantFioeSndtaotseeMnkeod, iMcaDl ,UPnhivDersity, D Tomsk, Russia SINGAPORE Kian-Chung Ong, MD Wan-Cheng Tan, MD, Chair, Asian Pacific COPD Roundtable SLOVAK REPUBLIC Ivan Solovic Propad, Slovakia SOUTH AFRICA Prof Richard van Zyl-Smit SPAIN Dr Patricia Sobradillo SWITZERLAND Daiana Stolz, MD Basel, Switzerland SYRIA Yousser Mohammad, MD Lattakia, Syria TRINIDAD & TOBAGO Dr. Sateesh Madhava Sakhamuri The University of the West Indies, Trinidad and Tobago TURKEY Prof Dr. Hakan Gunen Malatya, Turkey Prof Nurdan Kokturk, MD Ankara, Turkey VIETNAM Hanoi, Vietnam Le Thi Tuyet Lan, MD, PhD Ho Chi Minh City, Vietnam Sy Duong-Quy, MD, PhD, FCCP Lam Dong Medical College, Vietnam Prof Chau Ngo Quy Tam Anh General Hospital, Ha Noi iii GOLD 2023 REPORT HIGHLIGHTS The GOLD report is revised annually and has been used worldwide by healthcare professionals as a tool to implement effective management programs based on local healthcare systems. In the 2023 revision of the GOLD report includes several novel and important recommendations as follows: i. A new definition of COPD has been proposed (Page 5) ii. Chapter 1 has been rewritten to incorporate new background information on COPD and new strategies for terminology and taxonomy iii. A new section on Chronic Bronchitis has been added (Page 13) iv. Additional information on Screening and CaseFinding has been included (Page 36) v. The ABCD Assessment Tool has been revised to the ABE Assessment Tool to recognize the clinical relevance of exacerbations, independent of the level of symptoms (Page 115) vi. New information on Imaging and Computed Tomography (CT) has been included (Page 43) vii. Vaccination Recommendations CDC (Page 54) for people with COPD have been updated in line withTEcurrent guidance from the viii. Further information on Therapeutic Interventions to Reduce COPD Mortality aRnIdBUa new table has been included ix. (Page 67) A new definition of COPD Exacerbation and a new set of parameters to aDssIeSsTs exacerbation severity at the point of care has been included (Page 134) OR x. xi. Issues Related to Inhaled Delivery have been addressed Information on the topic of Adherence to Inhaled COPD M(PeagdeicO6at9Pi)oYns has been included (Page 71) xii. A section on Telerehabilitation has been added (Page 76) T C xiii. The section on Interventional & Surgical Therapies for CNOOPD has been expanded (Page 82) xiv. xv. TNheewininfoformrmaatitoionnaonndtfhigeuCrehsooicuetloinfiInnghIanleitriaDl ePvhiacerm-aaDncdOoalongeicwaltaTbreleathmasenbteeanndadFdoelldow(PaugpeP1h1a2r)macological Treatment have been updated. In particularI,AtLhSe positioning of LABA+LAMA and of LABA+ICS has been changed xvi. (Page 115) Chapter 5 on the topic of ManagementToEfRExacerbations has been expanded to include details of possible alternative causes of symptoms andMaAnew table on Diagnosis and Assessment (Page 136) xvii. The sections on COPD and with the latest evidence. CoIGmHorTbidities (Chapter 6) and COVID19 and COPD (Chapter 7) have been updated PYR GOLD has been fortunate to ChaOve a network of international distinguished health professionals from multiple disciplines. Many of these experts have initiated investigations into 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 burden of COPD and to develop programs for early detection, prevention and approaches to management. Alvar G. Agusti, MD Chair, GOLD Board of Directors Claus Vogelmeier, MD Chair, GOLD Science Committee iv GLOBAL STRATEGY FOR DIAGNOSIS, MANAGEMENT AND PREVENTION OF COPD 2023 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 management and prevention, impact of and to post this research on yearly updates on recommendations the GOLD website. in Its mtheemGbTeOErLsDardeorceucmogenniztes drelelaatdeedrs to in COPD research and clinical practice with the scientific credentials to contribute to RthIeBUtask of the Committee and are invited to serve in a voluntary capacity. DIST Updates of the 2011-revised report were released in January 2013, 2014, 20O1R5, and 2016. Updates of the 2017-revised rinecpoorrptowraetreesmaanduepidna2t0e1o8f, 2in0f1o9rm, 2a0t2io0n, 2t0h2at1 haansdb2e0e2n2.rTehviee2w0e2d3bGyOtOLhDPe RYsecipeonrcte, iscothmem5itthteme afrjoormre2v0is2io1ntoof2G0O22LDa,nadnda reassessment and revision of recommendations for the diagnosisT, C assessment and treatment of COPD. NO Process: Toproduce the GOLD report, a PubMed search-(DNOational Center for Biotechnology Information, U.S. National Library of Medicine, Chronic Obstructive Bethesda MD, USA) Pulmonary Disease (wAallsFcieolmdspI)AleALtNSeDd using search fields 2) Clinical Trials or established by Metaanalysis the (All Committee: 1) COPD Fields) OR 3) articles or in the top 20 medical or respiratory journals (avaTiElaRble on request) or The Cochrane Database of Systematic Reviews. MA Publications in peer Science Committee, prreovvieidwinegdtjhoeufrunIGlallHpsaTnpoetr,cianpctluudreindgbaybstthreacPtu, ibsMsuebdmseitatrecdheins may be submitted to the Chair, (or translated into) English. GOLD PYR Members of the CommitteCeOreceive a summary of citations and all abstracts. Each abstract is assigned to two Committee members, although all members are offered the opportunity to provide input on any abstract. Members 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 2023), the Pocket Guide (updated 2023) and the complete list of references examined by the Committee is available on the GOLD website: www.goldcopd.org. GOLD Science Committee Members (2022-2023): C. Vogelmeier, Chair, A. Agusti, A. Anzueto, P. Barnes, J. Bourbeau, G. Criner, 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. v 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 2023 report is a major revision of the GOLD 2022 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 2021 to July 2022. In total, 387 new references have been added to the GOLD 2023 report. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP vi TABLE OF CONTENTS GOLD 2023 REPORT HIGHLIGHTS......................................................................................................................................................................... IV GLOBAL STRATEGY FOR DIAGNOSIS, MANAGEMENT AND PREVENTION OFCOPD 2023 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 KEY POINTS: ....................................................................................................................................................................................................4 WHAT IS COPD? ....................................................................................................................................................................................................5 E Definition ......................................................................................................................................................................................................... 5 UT Causes and risk factors....................................................................................................................................................................................5 IB Diagnostic criteria ...........................................................................................................................................................................................5 TR Clinical presentation........................................................................................................................................................................................5 IS New opportunities...........................................................................................................................................................................................5 R D BURDEN OF COPD.................................................................................................................................................................................................6 O Prevalence ....................................................................................................................................................................................................... 6 PY Morbidity ........................................................................................................................................................................................................6 O Mortality .........................................................................................................................................................................................................7 T C Economic burden.............................................................................................................................................................................................7 O Social burden...................................................................................................................................................................................................8 O N PATHOGENESIS.....................................................................................................................................................................................................8 D Environmental risk factors ..............................................................................................................................................................................8 S - Genetic factors ..............................................................................................................................................................................................10 IAL Trajectories of lung function: development and aging..................................................................................................................................10 R Asthma and airway hyperreactivity .............................................................................................................................................................13 TE Chronic bronchitis .........................................................................................................................................................................................13 MA Infections ....................................................................................................................................................................................................... 14 T Sex .................................................................................................................................................................................................................15 IGH Socioeconomic status....................................................................................................................................................................................15 R PATHOBIOLOGY .................................................................................................................................................................................................. 15 PY Inflammatory changes ..................................................................................................................................................................................15 CO Structural changes ........................................................................................................................................................................................16 PATHOPHYSIOLOGY ............................................................................................................................................................................................ 16 Airflow obstruction and gas trapping............................................................................................................................................................16 Pulmonary gas exchange abnormalities .......................................................................................................................................................17 Pulmonary hypertension ...............................................................................................................................................................................17 Exacerbations ................................................................................................................................................................................................ 17 Multimorbidity ..............................................................................................................................................................................................17 TAXONOMY ........................................................................................................................................................................................................17 REFERENCES .......................................................................................................................................................................................................19 CHAPTER 2: DIAGNOSIS AND ASSESSMENT ...................................................................................................................................................28 KEY POINTS: ..................................................................................................................................................................................................28 DIAGNOSIS .........................................................................................................................................................................................................28 CLINICAL PRESENTATION....................................................................................................................................................................................28 Symptoms...................................................................................................................................................................................................... 28 Dyspnea......................................................................................................................................................................................................... 29 Chronic cough................................................................................................................................................................................................30 Sputum production........................................................................................................................................................................................30 vii Wheezing and chest tightness.......................................................................................................................................................................30 Fatigue ..........................................................................................................................................................................................................31 Additional clinical features in severe disease ................................................................................................................................................31 DIFFERENTIAL DIAGNOSIS OF COPD ...................................................................................................................................................................31 MEDICAL HISTORY ..............................................................................................................................................................................................31 PHYSICAL EXAMINATION ....................................................................................................................................................................................32 SPIROMETRY ....................................................................................................................................................................................................... 33 SCREENING AND CASE-FINDING .........................................................................................................................................................................36 INITIAL ASSESSMENT ..........................................................................................................................................................................................37 Severity of airflow obstruction ......................................................................................................................................................................37 Symptoms...................................................................................................................................................................................................... 38 Exacerbation risk...........................................................................................................................................................................................39 Multimorbidity ..............................................................................................................................................................................................40 Combined initial COPD assessment ...............................................................................................................................................................40 ADDITIONAL INVESTIGATIONS............................................................................................................................................................................41 Physiological tests .........................................................................................................................................................................................41 Imaging .........................................................................................................................................................................................................42 Alpha1 antitrypsin deficiency (AATD)...........................................................................................................................................................43 Composite scores ..........................................................................................................................................................................................44 Biomarkers ....................................................................................................................................................................................................44 TE Treatable traits .............................................................................................................................................................................................45 IBU REFERENCES .......................................................................................................................................................................................................45 TR CHAPTER 3: EVIDENCE SUPPORTING PREVENTION AND MAINTENANCE THERAPY.........................................................................................51 DIS KEY POINTS: ..................................................................................................................................................................................................51 OR SMOKING CESSATION.........................................................................................................................................................................................52 Y Pharmacotherapies for smoking cessation ...................................................................................................................................................52 OP VACCINATIONS ...................................................................................................................................................................................................54 C Influenza vaccine...........................................................................................................................................................................................54 OT Pneumococcal vaccine ..................................................................................................................................................................................54 N Other vaccines...............................................................................................................................................................................................55 DO PHARMACOLOGICAL THERAPY FOR STABLE COPD .............................................................................................................................................55 - Overview of the medications.........................................................................................................................................................................55 LS Bronchodilators .............................................................................................................................................................................................56 RIA Antimuscarinic drugs.....................................................................................................................................................................................56 TE Methylxanthines ...........................................................................................................................................................................................59 A Combination bronchodilator therapy............................................................................................................................................................59 T M Antiinflammatory agents.............................................................................................................................................................................60 H Inhaled corticosteroids (ICS)..........................................................................................................................................................................62 RIG Triple therapy (LABA+LAMA+ICS) ..................................................................................................................................................................65 PY Oral glucocorticoids ......................................................................................................................................................................................65 O Phosphodiesterase4 (PDE4) inhibitors .........................................................................................................................................................65 C Antibiotics .....................................................................................................................................................................................................66 Mucolytic (mucokinetics, mucoregulators) and antioxidant agents (Nacetylcysteine, carbocysteine, erdosteine) ....................................66 Other drugs with potential to reduce exacerbations.....................................................................................................................................66 Therapeutic interventions to reduce COPD mortality....................................................................................................................................67 Issues related to inhaled delivery ..................................................................................................................................................................69 Adherence to inhaled COPD medications ......................................................................................................................................................71 Other pharmacological treatments...............................................................................................................................................................72 Management of mucus hypersecretion.........................................................................................................................................................73 REHABILITATION, EDUCATION & SELF-MANAGEMENT ......................................................................................................................................74 Pulmonary rehabilitation ..............................................................................................................................................................................74 Telerehabilitation ......................................................................................................................................................................................... 76 Education, selfmanagement and integrative care .......................................................................................................................................77 SUPPORTIVE, PALLIATIVE, END-OF-LIFE & HOSPICE CARE ..................................................................................................................................78 Symptom control and palliative care ............................................................................................................................................................78 Therapy relevant to all people with COPD.....................................................................................................................................................78 Endoflife and hospice care ..........................................................................................................................................................................79 OTHER TREATMENTS..........................................................................................................................................................................................80 Oxygen therapy and ventilatory support.......................................................................................................................................................80 viii Ventilatory Support .......................................................................................................................................................................................81 INTERVENTIONAL & SURGICAL THERAPIES FOR COPD........................................................................................................................................82 Lung surgical treatments for patients with emphysema...............................................................................................................................83 Bronchoscopic interventions in COPD ...........................................................................................................................................................84 REFERENCES .......................................................................................................................................................................................................88 CHAPTER 4: MANAGEMENT OF STABLE COPD .............................................................................................................................................108 KEY POINTS: ................................................................................................................................................................................................108 INTRODUCTION ................................................................................................................................................................................................108 IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS .......................................................................................................................................110 Tobacco smoke............................................................................................................................................................................................110 Household and outdoor air pollution ..........................................................................................................................................................110 Occupational exposures ..............................................................................................................................................................................111 PHARMACOLOGICAL TREATMENT OF STABLE COPD ........................................................................................................................................112 Managing inhaled therapy..........................................................................................................................................................................112 Algorithms for the assessment, initiation and followup management of pharmacological treatment .....................................................115 NON-PHARMACOLOGICAL TREATMENT OF STABLE COPD ...............................................................................................................................120 Education and selfmanagement ................................................................................................................................................................120 Physical activity...........................................................................................................................................................................................122 Pulmonary rehabilitation programs ............................................................................................................................................................122 TE Exercise training..........................................................................................................................................................................................122 IBU Endoflife and palliative care .....................................................................................................................................................................123 R Nutritional support......................................................................................................................................................................................124 IST Vaccination .................................................................................................................................................................................................124 D Oxygen therapy...........................................................................................................................................................................................124 OR Ventilatory support .....................................................................................................................................................................................125 Y Interventional bronchoscopy and surgery ...................................................................................................................................................125 OP MONITORING AND FOLLOW-UP.......................................................................................................................................................................128 C Telehealth and remote monitoring .............................................................................................................................................................129 OT Surgery in the COPD patient........................................................................................................................................................................129 N REFERENCES .....................................................................................................................................................................................................130 - DO CHAPTER 5: MANAGEMENT OF EXACERBATIONS ........................................................................................................................................134 LS KEY POINTS: ................................................................................................................................................................................................134 RIA DEFINITION ....................................................................................................................................................................................................... 134 TE Considerations............................................................................................................................................................................................. 135 A TREATMENT OPTIONS ......................................................................................................................................................................................139 T M Treatment setting .......................................................................................................................................................................................139 H Pharmacological treatment ........................................................................................................................................................................141 RIG Respiratory support.....................................................................................................................................................................................143 Y Hospital discharge and followup................................................................................................................................................................146 OP Prevention of exacerbations........................................................................................................................................................................146 C REFERENCES .....................................................................................................................................................................................................148 CHAPTER 6: COPD AND COMORBIDITIES .....................................................................................................................................................155 KEY POINTS: ................................................................................................................................................................................................155 INTRODUCTION ................................................................................................................................................................................................155 Cardiovascular diseases (CVD) ....................................................................................................................................................................156 Heart failure ................................................................................................................................................................................................156 Ischaemic heart disease (IHD) .....................................................................................................................................................................156 Arrhythmias ................................................................................................................................................................................................156 Peripheral vascular disease.........................................................................................................................................................................157 Hypertension ...............................................................................................................................................................................................157 Lung cancer .................................................................................................................................................................................................157 Bronchiectasis .............................................................................................................................................................................................159 Obstructive sleep apnea..............................................................................................................................................................................159 Periodontitis & dental hygiene....................................................................................................................................................................160 Metabolic syndrome and diabetes ..............................................................................................................................................................160 Gastroesophageal reflux (GERD).................................................................................................................................................................160 Osteoporosis ...............................................................................................................................................................................................160 ix Anemia ........................................................................................................................................................................................................161 Polycythemia ............................................................................................................................................................................................... 161 Anxiety and depression................................................................................................................................................................................162 Cognitive impairment..................................................................................................................................................................................162 Frailty ..........................................................................................................................................................................................................162 COPD as part of multimorbidity ..................................................................................................................................................................162 Other considerations...................................................................................................................................................................................163 REFERENCES .....................................................................................................................................................................................................163 CHAPTER 7: COVID19 AND COPD................................................................................................................................................................170 KEY POINTS: ................................................................................................................................................................................................170 INTRODUCTION ................................................................................................................................................................................................170 RISK OF INFECTION WITH SARS-COV-2 ..............................................................................................................................................................170 INVESTIGATIONS ..............................................................................................................................................................................................172 Testing for SARSCoV2 infection.................................................................................................................................................................172 Spirometry & pulmonary function testing...................................................................................................................................................172 Bronchoscopy ..............................................................................................................................................................................................172 Radiology ....................................................................................................................................................................................................172 PROTECTIVE STRATEGIES FOR PATIENTS WITH COPD.......................................................................................................................................174 Vaccination .................................................................................................................................................................................................174 TE DIFFERENTIATING COVID-19 INFECTION FROM DAILY SYMPTOMS OF COPD ...................................................................................................175 IBU MAINTENANCE PHARMACOLOGICAL TREATMENT FOR COPD DURING THE COVID-19 PANDEMIC..................................................................175 R Use of nebulizers .........................................................................................................................................................................................176 IST NON-PHARMACOLOGICAL TREATMENT FOR COPD DURING THE COVID-19 PANDEMIC ..................................................................................177 D REVIEW OF COPD PATIENTS DURING THE COVID-19 PANDEMIC ......................................................................................................................177 OR TREATMENT OF COVID-19 IN PATIENTS WITH COPD ........................................................................................................................................177 Y EXACERBATIONS OF COPD................................................................................................................................................................................178 OP Systemic corticosteroids..............................................................................................................................................................................179 C Antibiotics ...................................................................................................................................................................................................179 OT PULMONARY AND EXTRA-PULMONARY COMPLICATIONS ...............................................................................................................................180 N Anticoagulation ........................................................................................................................................................................................... 180 DO VENTILATORY SUPPORT FOR COPD PATIENTS WITH COVID-19 PNEUMONIA...................................................................................................181 - REHABILITATION...............................................................................................................................................................................................182 LS FOLLOW-UP OF COPD PATIENTS WHO DEVELOPED COVID-19 .........................................................................................................................182 RIA REMOTE COPD PATIENT FOLLOW-UP DURING COVID-19 PANDEMIC RESTRICTIONS.......................................................................................183 TE Introduction ................................................................................................................................................................................................183 A Triage and prioritizing process ....................................................................................................................................................................183 T M Consideration and instruction for remote COPD followup .........................................................................................................................184 H COPD FOLLOW-UP CHECKLIST ..........................................................................................................................................................................185 COPYRIG REFERENCES .....................................................................................................................................................................................................187 x 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 people with COPD. One of the strengths of GOLD reports is the treatment objectives. These have stood the test of time, and 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 BACKGROUND on FEV1 and was called a staging system because it was believed, at path of disease progression in which the severity of COPD tracked the the tsiemveer,itthyaotfthaeirfmUloaTwjEooribtystoruf cptaiotine.nMtsufochlloiws neodwa known about the characteristics of patients in the different GOLD stages - for exTaRmIBple, their risk of exacerbations, hospitalization, breathlessness, eaxnedrcdieseatlhim. iHtaotwioenv,ehre, aaltthanstaintudsiviimdupaalirpmateinetn,talnedverli,skFEoVf 1exiascaeDnrIbSuantiroenli.able marker of the severity of OR At the time of the original report, improvement in both symptoms anOdPhYealth status was a GOLD treatment objective, but symptoms assessment did not have a direct relation to the choTicCe of management, and health status measurement was a complex process largely confined to clinical studies. NowNO, there are simple and reliable questionnaires designed faosrseussseminenrtousytisnteemdatiolybcelindiecavleplorpaectdicteh.aTthdersaewasretoagveatihlae-brDleaOimn emaasunryelaonf gtuhaegiems.pTahctesoef developments have enabled the patient's symptoms and an an aasnsyecslsimniceanltsoeftttihneg apnaytiwenhte'rseriisnktohfehwaovrinldgaansdemrioouvIseAsaLCdSOvePrDsetrheeaatlmtheenvtetonwt.aTrhdiss imndainvaidgueamlizeendt ampepdriocainceh -camnabtcehuinsgedthine patient's therapy more closely to his or her neTeEdRs. MA IGHT PYR Chronic Obstructive PulmonCaOry Disease (COPD) is now one of the top three causes of death worldwide and 90% of these deaths occur in low- and middle-income countries (LMICs).(1,2) More than 3 million people died of COPD in 2012 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.(3) 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 1 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 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 LEVELS OF EVIDENCE o o f f affordable developing tobacco products COPD; diagnostic as well as other exposures spirometry services are not (e.g., household widely available aanirdptohlelurteioanre)TtmEhaojuogrhptrtooblienmcrseawsieththaeccreissks to affordable quality-assured pharmacological and non-pharmacological therapies.RGIOBLUD is therefore concerned that COPD is not being taken seriously and international agencies.(4) It is etinmoeugfhoratthaisnytolecvheal,nfgreomanidndtihveiduGaOlsLDanBdoDcaorISdmTmofuDniitrieecst,otros national governments challenge all relevant stakeholders to work together in coalition with GOLD to address the avoiOdaRble burden of COPD worldwide. GOLD is committed to wishes to do improving its bit to the health of help achieve people at risk of and the United Nations wSuitshtaCinOaPbODle,PwYDheevreeloveprmtehnety happen to have been born, and Goal 3.4 to reduce premature mortality from non-communicable diseases - including COPD - byToCne third by 2030.(5) NO - DO IALS Levels of evidence have been assigned to eviTdEenRce-based recommendations where appropriate (Table A). Evidence levels are indicated in boldface type encMloAsed in parentheses after the relevant statement e.g., (Evidence A). The mtreeathtmodeonltoegficfeacl tis(osur eesffeccotnsciezren)inwgaIsGthcHoenTusissetenotf evidence from one from study meta-analyses were carefully to the next, and we needed to considered identify the when i) common effect; ii) the effect varied frCoOmPoYnRe study to the next, and there was a need to identify the reason for the variation. 2 REFERENCES IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 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. Meghji J, Mortimer K, Agusti A, et al. Improving lung health in low-income and middle-income countries: from challenges to solutions. Lancet 2021; 397(10277): 928-40. 3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442. 4. 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. 5. United Nations. Sustainable Development Goals, online information available here: https://www.un.org/sustainabledevelopment/sustainable-development-goals/ [accessed Aug 2022]. 3 CHAPTER 1: DEFINITION AND OVERVIEW KEY POINTS: Definition Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction. Causes and Risk Factors COPD results from gene(G)-environment(E) interactions occurring over the lifetime(T) of the individual (GETomics) that can damage the lungs and/or alter their normal development/aging processes. The main environmental toxic particles and gases exposures leading to COPD are from household and outdoor air ptoobllauctcioons, mbuotkiontgheaUrnTdeEntvhieroinnmhaelnattaiol nanodf host factors (including abnormal lung development and accelerated lungTaRgiInBg) can also contribute. The most relevant (albeit rare) genetic risk factor for COPD identifieDdItSo date are mutations in the SbEeRePnIaNsAso1cgieatneedtwhaitthleraeddutoced-1luanngtfiturnycptsiionndaenfdicireisnkcoy.f ACOnPuDm,bbeurtOotRfhoetirhienrdgiveindeutaicl evfafericatnstiszehaisvsemaalslol. Diagnostic Criteria OPY In the appropriate clinical context (see `Definition' & `CaTuCses and Risk Factors' above), the presence of non-fully reversible airflow limitation (i.e., FEV1N/FOVC < 0.7 post-bronchodilation) measured by sSpoimroeminedtriyvicdounaflisrmcasnthhaevdeiargenspoisriastoofryCOsyPmDp. to-mDsOand/or structural lung lesions (e.g., emphysema) and/or physiological abnormalities (inIcAluLdSing low-normal FEV1, gas trapping, hyperinflation, re0d.u7cepdosltu-nbgrodnicffhuosdinilgatciaopna).ciTthyeasnedTs/uEobrRjreacptsidaFreEVla1bdeellceldine`P)rwe-iCthOoPuDt'.aiTrhfleowteormbst`PruRcIStimon' ((PFrEeVs1e/rFvVedC Ratio Impaired Spirometry) hasMbAeen proposed to identify those with normal ratio but abnormal spirometry. Subjects withIGPHreT-COPD or PRISm are at risk of developing airflow obstruction over time, but not all of Clinical Presentation thPeYmRdo . Patients with COPCDOtypically complain of dyspnea, activity limitation and/or cough with or without sputum production and may experience acute respiratory events characterized by increased respiratory symptoms called exacerbations that require specific preventive and therapeutic measures. Patients with COPD frequently harbor other comorbid diseases that influence their clinical condition and prognosis and require specific treatment as well. These comorbid conditions can mimic and/or aggravate an acute exacerbation. New Opportunities COPD is a common, preventable, and treatable disease, but extensive under-diagnosis and misdiagnosis leads to patients receiving no treatment or incorrect treatment. Appropriate and earlier diagnosis of COPD can have a very significant public-health impact. The realization that environmental factors other than tobacco smoking can contribute to COPD, that it can start early in life and affect young individuals, and that there are precursor conditions (Pre-COPD, PRISm), opens new windows of opportunity for its prevention, early diagnosis, and prompt and appropriate therapeutic intervention. 4 WHAT IS COPD? Definition Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.(1) Causes and risk factors COPD results from gene(G)-environment(E) interactions occurring over the lifetime(T) of the individual (GETomics) that can damage the lungs and/or alter their normal development/aging processes.(2) The main environmental exposures leading to COPD are tobacco smoking and the inhalation of toxic particles and gases from household and outdoor air pollution, but other environmental(3) and host factors (including abnormal lung development and accelerated lung aging) can also contribute.(2) UTE The most relevant (albeit epidemiologically rare) genetic risk factor for COPD idenTtRifIiBed to date are mutations in the SERPINA1 gene, leading associated with reduced to 1-antitrypsin deficiency, but other lung function and risk of COPD too.(4) genetic varianDtsI,Swith a low individual effect size, are OR Diagnostic criteria OPY In the appropriate clinical context (See `Definition' and `CausesTaCnd Risk Factors' above), the presence of non-fully reversible airflow limitation (FEV1/FVC < 0.7 post-bronchodilaNtOion) measured by spirometry confirms the diagnosis of COPD. - DO Yet, some individuals may present with structuralIAluLnSg lesions (e.g., emphysema) and/or physiological abnormalities (winitchluoduitnagirloflwow-noobrmstarul cFtEioVn1,(FgEasV1tr/aFpVpCing0, .h7AyppToeEsrRitn-bflraotniocnh,ordeidlautcioend).luTnhgesdeifsfuusbijnegctcsaapraeciltaybaenlledd/o`rPrreapCidOPFDEV'.1Thdeectleinrme) `sPpRirIoSmm'et(Pryr.esSeurbvjeedctRs awtiiothImPrpea-iCreOdPDSpoiHrroTPmRMeIStrmy)ahraesabtereisnkporfodpeovseeldoptoinigdeanirtfilfoywthoobssetrwuictthionnoormvearl triamtieo, bbuutt anbontoarlml oafl them do.(5,6) Research is neededYRtoIGdetermine what is the best treatment for these individuals (beyond smoking cessation). COP Clinical presentation Patients with COPD typically complain of dyspnea, wheezing, chest tightness, fatigue, activity limitation, and/or cough with or without sputum production, and may experience acute events characterized by increased respiratory symptoms called exacerbations that influence their health status and prognosis, and require specific preventive and therapeutic measures. Patients with COPD frequently harbor other comorbid diseases that also influence their clinical condition and prognosis and require specific treatment as well. These comorbid conditions can mimic and/or aggravate an acute exacerbation. New opportunities COPD is a common, preventable, and treatable disease, but extensive under and misdiagnosis leads to patients receiving no treatment or incorrect treatment. The realization that environmental factors other than tobacco smoking 5 can contribute to COPD, that it can start early in life and affect young individuals, and that there are precursor conditions (Pre-COPD, PRISm), opens new windows of opportunity for its prevention, early diagnosis, and prompt and appropriate therapeutic intervention.(7) BURDEN OF COPD COPD is a leading cause of morbidity and mortality worldwide with an economic and social burden that is both substantial and increasing.(8,9) COPD prevalence, morbidity and mortality vary across countries.(10,11) The prevalence of COPD is often directly related to the prevalence of tobacco smoking, but in many countries outdoor, occupational and household air pollution (resulting from the burning of wood and other biomass fuels) are important COPD risk factors.(12,13) The prevalence and burden of COPD are projected to increase over the coming decades due to a combination of continued exposure to COPD risk factors and aging of the world's population.(14) Information on the burden of COPD cGalonbbael BfouurdnednoonfiDnitseeransaetiSotnuadlyw.(1e6b) sites, such as the World Health Organization (WHIOB)U(1T5)Eand the World Bank/WHO Prevalence DISTR Existing COPD approaches.(14) prev Of alence note, data all of vary widely due these epidemio to difference logic studies s in surv defined eCyOmOPReDt hods, diagnostic by spirometry criteria, and analytical alone and not by the combination of symptoms and spirometry. The lowest estimates of pOrPevYalence are those based on self-reporting of a doctor's diagnosis of COPD, or equivalent condition. For exampTleC, most national data show that < 6% of the adult population have been told that they have COPD.(17) This is likeNlyOto be a reflection of the widespread under-recognition and under-diagnosis of COPD.(18) - DO Data are emerging that enable more accurate esItAimLaStes of COPD prevalence. A number of systematic reviews and meta-analyses provide evidence compared to non-smokers, in tho that se 4 0thyeeaprTrseEovRaf laegnececoomf COPD pared t is appreciably higher o those < 40, and in m in en smokers and ex-smokers compared to women.(19-21) The Latin American Project for the InvestigMatAion of Obstructive Lung Disease (PLATINO)(22) examined the prevalence of post-bronchodilator airflow obstrucItGioHnTamong persons 40 years in one major city from each of five Latin American countries - the highest Bprreazvial,leCnhcielea, mMoenxigcPoth,YoURsreug>u6a0y,yaenadrsV. Penreevzauleelnac.eThinetphreevtoatleanl cpeopouflCatOioPnD increased steeply ranged from 7.8% with age, with in Mexico City to 19.7% in Montevideo, UrCugOuay. The prevalence was appreciably higher in men than in women,(22) which contrasts with findings from European cities such as Salzburg, Austria.(23) The Burden of Obstructive Lung Diseases (BOLD) program used standardized methodology comprising questionnaires and pre- and post-bronchodilator spirometry to assess prevalence and risks for COPD globally in people aged 40 years.(23-25) BOLD reported an overall prevalence of COPD of 11.8% (SE 7.9) for men and 8.5% (SE 5.8) for women(26) and a substantial prevalence of COPD of 3%-11% among never-smokers.(26) BOLD examined the prevalence of COPD in north and sub-Saharan Africa and Saudi Arabia and found similar results.(27-30) Based on BOLD and other large scale epidemiological studies, it is estimated that the global prevalence of COPD is 10.3% (95% confidence interval (CI) 8.2%,12.8%).(19,31) With the increasing prevalence of smoking in LMICs, and aging populations in high-income countries, the prevalence of COPD is expected to rise. Morbidity Morbidity measures traditionally include physician visits, emergency department visits, and hospitalizations. To date studies indicate that morbidity due to COPD increases with age,(17,18,22) and in patients with COPD the development of comorbidities are seen at an earlier age.(32,33) Morbidity in COPD may also be influenced by concomitant chronic conditions (e.g., cardiovascular disease, musculoskeletal impairment, diabetes mellitus)(34) that are related to smoking, 6 aging and/or COPD.(35) Mortality The World Health Organization (WHO) publishes mortality statistics for selected causes of death annually for all WHO regions.(36) 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 airways obstruction are included in the broad category of "COPD and allied conditions" (ICD-10 codes J42-46). Under-recognition and under-diagnosis of COPD reduces the accuracy of mortality data.(37,38) Furthermore, the accuracy of COPD diagnosis codes recorded in administrative health databases is also uncertain.(39,40) In some jurisdictions, reliance on administrative health data, particularly those that only record hospitalizations, may underestimate the burden of COPD.(41) The reliability of recording of COPD-related deaths in mortality data is also problematic. Although COPD is often a primary cause of death, it is more likely to be listed as a contributory cause of death or omitted from the death certificate entirely.(42) However, it is clear that COPD is one of the most important causes of States.(43) death in most countries. For instance, in 2011, COPD was the third This increase in COPD-related mortality has mainly been driven by ltehaedienxgpUacTnaEudsinegoefpdideaetmhicinotfhsemUonkiitnegd; reduced mortality from other common causes of death (e.g., ischemic heart diseasTeR, IinBfectious diseases); the aging of the world's population, particularly in high-income countries; and scarcity ofDeIfSfective disease modifying therapies. Data from the Global Burden of all-cause deaths)(14,44) of Disease Study 2017 estimated a COPD -attrOibRutable death rate was 42/100,000 (4.72% OPY With these caveats in mind, it can be estimated that globally theTreCare around three million deaths annually due to COPD.(45) It is estimated that the increased prevalence of smNoOking in LMICs coupled with aging populations in high- income countries will result in over 5.4 million annual de- aDtOhs from COPD and related conditions by 2060.(46,47) Economic burden IALS COPD is associated with significant economiTcEbRurden. In the European Union, the total direct costs of respiratory disease are estimated to be about 6% ofMthAe total annual healthcare budget, with COPD accounting for 56% (38.6 binicllrioenasEeuoroves)rothf ethneecxot s2t0oyferaerssp,iwraittohIGrpyHrdoTijseecatseed.(c48o)sItnstohfe$U8n00it.e9d0Sbtialltieosntohre$c4o0stbsilalitotnribpuetraybeleart.o(49C,5O0)PDDynaaremeicxpmeocdteedlintog also predicts that women are PeYxpRected to incur higher direct costs than men and lose more quality-adjusted life yNeoatrssu.(5r0p)rCisOinPgDlye,xtahceerrebiastaiosnCtsrOiakicncgoudnirtefcotrrtehlaetigornesahteipstbpertowpeoerntiothneosfetvheerittoytoalf CCOOPPDDbaunrddtehneocnostht eofhceaarleth, caanrdetshyestceomst. 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 LMICs both direct and indirect medical costs may be substantial. Recent work from the WHO and other organizations suggest that inhaled medicines for COPD are poorly available and largely unaffordable in LMICs.(51) Most inhaled medications are still branded and there are few options currently available for generic inhalers. The situation is similar for access to diagnostic spirometry. 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.(52) Since human capital is often the most important national asset for LMICs, the indirect costs of COPD may represent a serious threat to their economy. 7 Social burden Since mortality offers only a limited perspective on the human burden of a disease, it is desirable to find other measures of disease burden that are consistent and measurable within and between nations. 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).(53) 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.(44,54) In the United States, COPD is the second leading cause of reduced DALYs, trailing only ischemic heart disease.(55) Data from the Global Burden of Disease Study 2017 estimated that the DALYs rate was 1068.02/100,000 for COPD.(44) PATHOGENESIS COPD is the end-result of complex, cumulative and dynamic gene-environment interactUioTnEs over the lifetime that can damage the interactions lungs and/or between the gaeltneerttihce(Gir)nboarcmkgarloduenvdeloofptmheenhtoasltoarnadgvinagriperdoecnevssireosn.(m2) eUTnnRtdaIelBr(Est)arnisdkinfagctthoersroevlaetriothneshliifpestaimnde (T) requires further investigation. The term GETomics has been recently prDoIpSosed to illustrate the complex and dynamic series of interactions between Genetics and Environment over TiOmRe.(2) According to this GETomics proposal, the end result of a given GxE interaction depends not only on G and E,PbYut also on T, as determined by both the age of ent vs aging) and the previous history of GxE the individual at which that particular interaction occurs (develoCpOm interactions that the individual has encountered earlier in her/hiTs life (biological memory).(2) NO Environmental risk factors - DO Cigarette smoking IALS Cigarette smoking is respiratory symptoms aankdeylunegnvfiurnocntmioennatablnorTirsEmkRaflaitciteosr, for COPD. Cigarette a greater annual rate smokers have a higher of decline in FEV1, and a prevalence of greater COPD mortality rate than non-smokers.(56) Yet feMwAer than 50% of heavy smokers develop COPD(57) and it is estimated that half of all COPD cases worldwide aIGreHdTue to risk factors other than tobacco so other pathogenic factors beyond smoking need to be consideredP.(Y3)R Genetics modify the risk of CCOOPD in smokers, but there may also be other risk factors involved. For example, gender and social pressure may influence whether a person takes up smoking or experiences certain occupational or environmental exposures; socioeconomic status may be linked to birthweight (which may impact lung growth and development, and in turn susceptibility to developing COPD)(58); and longer life expectancy will allow greater lifetime exposure to risk factors. Other types of tobacco (e.g., pipe, cigar, water pipe)(59-61) and marijuana(62) 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 COPD.(63) Smoking during pregnancy poses a risk for the fetus, by altering lung growth and development in utero, and possibly priming the immune system by inducing specific epigenetic changes.(64) This is a good example of the GETomics approach discussed above. The fetus exposed to `passive smoking' is likely to respond differently to a second GxE hit later in life.(2) Biomass exposure Tobacco smoking has been recognized as a major risk factor associated with COPD for over five decades, but this was 8 largely because most research was conducted in high income countries. As more studies from LMICs were conducted,(13) it became apparent that non-smoking risk factors were more important in these parts of the world. Whilst tobacco smoking remains the leading risk factor for COPD in high income countries, accounting for over 70% of the cases, in LMICs tobacco smoking contributes to around 30% to 40% of the total burden.(3) Because the LMICs together contribute to over 85% of the total burden of COPD globally, non-smoking risk factors now contribute to over 50% of the global burden of COPD.(3) Wood, animal dung, crop residues, and coal, typically burned in open fires or poorly functioning stoves, may lead to very high levels of household air pollution.(65) Household air pollution exposure is associated with an increased risk of developing COPD in LMICs(66) although the extent to which household air pollution versus other poverty-related exposures explain the association is unclear.(67-70) 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.(71,72) There is limited research about household air pollution related COPD or the interventions that could reduce the risk of developing it.(73) Mnuatnriytioonf ,thaemepnlivfiyrotnhme erinstkaol ef xapirowsuaryeasnindLlMunIgCspaarreenccuhrryemnatllyduanmreagguel.aAteddvoacnadc,yinecffoomrtbsintToaEtmioinniwmitizhepeoxvpeortsyuraendtoproioskr factors must continue, based on robust evidence from epidemiological, translatioRnIBalU, clinical and implementation research.(3) There are no randomized controlled trials of non-smoking COPD. There is therefore an urgent (RCTs) that have need to conduct ardodbruessDtsIeRSdCTTtshetoapbpertoteprriautnedpehrsatramndactohtehemraopsyt effective treatment that can be offered to non-smoking COPD. PhenotypOicRdifferences between smoking and non- smoking COPD have is more common in been reported in only a females, in younger age fgerwousptsu,deiexsh.ibInitsbrsiiemf,ilcaorOm(oPprYamreidldteor)CrOePspDiriantsomryoskyemrsp, tnoomns-samnodkqinugalCitOyPoDf life, a lesser rate of decline in lung function over time, lower TneCutrophils and a trend towards higher eosinophil numbers in the airway sputum, similar spirometric indices, greNaOter small airways obstruction (respiratory oscillometry and radiology), less emphysema and a similar defec-t DinOmacrophage phagocytosis of pathogenic bacteria.(74-76) Pote lung ntial mo aging.(3) lecular mechanisms However, there are fsotirllnsoenv-esrmalokkninogwCIlAeOdLPSgDe include inflammation, oxidative stress, airway remodeling and gaps that exist. Research is urgently needed to fill these gaps, as COPD related to biomass exposure, tobacTcoERsmoking or various other causes (see below) might exhibit different clinical features and trajectories, and MbeAnefit from different approaches to both pharmacological and non- pharmacological treatments.(3) IGHT Occupational exposures PYR Occupational exposures, incCluOding organic and inorganic dusts, chemical agents and fumes, are an under-appreciated environmental risk factor for COPD.(12,77) Individuals with exposure to inhalation of high doses of pesticides have a higher incidence of respiratory symptoms, airways obstruction and COPD.(78,79) 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 without asthma.(80) A cross-sectional observational study demonstrated that self-reported exposure to workplace dust and fumes is associated with not only increased airflow obstruction and respiratory symptoms, but also more emphysema and gas trapping, as assessed by computed tomography scan, in both men and women.(81) An analysis of the large U.S. population-based National Health and Nutrition Examination Survey III survey of almost 10,000 adults aged 30-75 years estimated the fraction of COPD attributable to workplace exposures was 19.2% overall, and 31.1% among never-smokers.(82) 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.(83) 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. 9 Air pollution Air pollution typically consists of particulate matter (PM), ozone, oxides of nitrogen or sulfur, heavy metals, and other greenhouse gases, is a major worldwide cause of COPD, responsible for ~50% of the attributable risk for COPD in low and middle income countries (LMICs).(84) In never smokers, air pollution is the leading known risk factor for COPD(85). The respiratory risk of air pollution to individuals is dose-dependent with no apparent "safe" thresholds. Even in countries with low ambient air pollution levels, chronic exposure to PM2.5 and nitrogen dioxides significantly impairs lung growth in children(86), accelerates lung function decline in adults and increases the risk for COPD, especially among those with additional risk factors for COPD.(87) Poor air quality from air pollution also increases the risk of COPD exacerbations, hospitalizations and mortality(88). Thus, reduction in both indoor and outdoor air pollution is a key goal in the prevention and management of COPD. Genetic factors A significant familial risk of airflow obstruction has been observed in people who smoke and are siblings of patients with severe COPD,(89) suggesting that genetics (in combination with environmental risk factors) could influence this susceptibility. The best documented genetic risk factor for COPD are mutations in the SERPINA1 gene that leads to the hereditary deficiency deficiency is relevant of to -1 only antitrypsin (AATD),(90) a major circulating a small part of the world's population, it iilnluhsibtriatotersotfhseeIBirniUnteTerEpacrotitoenasbeest.wAelethnoguegnheAs AaTnDd environmental exposures populations found AATD P that predispose an individual iZZ genotypes in 0.12% of COPD tpoatCieOnPtDs (.raAnsgyes0te.0m8a-0tIiS.c2T4rR%ev)i,eawndoaf 20 studies prevalence in European ranging from 1 in 408 in Northern Europe to 1 in 1,274 in Eastern Europe.(91) R D PY O There has been COPD. This has a long-standing controversy concerning largely reflected acquisition bias but itsheofricsrkitoTicfaChleOitmerpoozrytgaontcees (MZ due and SZ) to the for the development of large numbers of such individuals worldwide(92) who may potentially benefit from auNgOmentation therapy. Recent careful sibling studies (93,94) indicated no increased risk smokers compared to MM in these siblings. heterozygotes in This likely reflects tthh-eeDapObresesennceceoof fsmlowokcinogncaeltnhtorautgihonlusnogf function was reduced in the Z AAT protein rather than an absolute lack of it(95) and is not an indicatIiAoLnSfor augmentation therapy (discussed in more detail in Chapter 3). TER To date, hundreds of genetic variants assMocAiated with reduced lung function and risk of COPD have been identified, including genes encoding matrix mIGeHtaTlloproteinase 12 (MMP-12), glutathione S-transferase, the alpha-nicotinic aitcreetmylcahinoslinuencreercteapintowr,haentdhethretPhhYeeRsdegegheongesinatreeradcitriencgtlpyroretespino(nHsHibIlPe) .(96,97) Yet, for COPD their individual or are merely effect size is small(4) and markers of other causal genes.(98-102) CO Trajectories of lung function: development and aging At birth, the lung is not fully developed. It grows and matures until about 20-25 years of age (earlier in females), when lung function reaches its peak (Figure 1.1).(56) This is followed by a not very well defined but relatively short plateau and a final phase of mild lung function decline due to physiological lung aging. This constitutes the normal lung function trajectories labelled TR1 in Figure 1.1.(103) This normal lung function trajectory can be altered by processes occurring during gestation, birth, childhood, and adolescence that affect lung growth (hence, peak lung function) and/or processes shortening the plateau phase and/or accelerating the aging phase (hence accelerating the normal rate of lung function decline with age).(104) Spirometrically measured reduced maximal attained lung function can identify individuals who are at increased risk for the development of COPD.(10,105) A large study and meta-analysis confirmed a positive association between birthweight and FEV1 in adulthood . (106) Factors in early life termed "childhood disadvantage factors" are key determinants of lung function in adult life.(106-113) One study in three independent longitudinal cohorts (Framingham, 10 Copenhagen and Lovelace) found that approximately 50% of patients developed COPD due to accelerated decline in FEV1 over time (the traditional Fletcher and Peto model),(114) while the other 50% developed COPD due to abnormal lung growth and development (with normal lung function decline over time; Figure 1.1).(103) Age is often listed as a risk factor for COPD because there is a physiologic decline in lung function with age. Yet, it is unclear if healthy aging as such leads to COPD or if age reflects the sum of cumulative exposures throughout life.(115) However, aging of the airways and parenchyma mimic some of the structural changes associated with COPD(115) and there is evidence of accelerated aging in patients with COPD.(108) A prospective study showed an association between accelerated telomere shortening (a marker of accelerated aging) and progressive worsening of pulmonary gas exchange, lung hyperinflation and extrapulmonary affection in COPD patients followed over 10 years. (116) Further, persistently shorter telomeres over this observation time increase the risk for all-cause mortality.(116) Age-related epigenetic changes in DNA in immune cells are also associated with increased risk of exacerbations and mortality in COPD patients.(117,118) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP The term dysanapsis refers to an anthropometric mismatch of airway tree calibre relative to lung volume.(119,120). It was first proposed by Green and colleagues almost fifty years ago from maximal expiratory airflow variation among healthy adults.(107) There are still major gaps in our understanding of the origins and clinical implications of dysanapsis, but recent research using computed tomography (CT) has shown that: (1) it is common in the general population(107,111,121); (2) it is associated with FEV1/FVC from early adulthood(122); (3) in explanted lungs from adult 11 healthy donors, central airway dysanapsis (detectable by CT) extended to peripheral airways (non-visible on CT)(122); (4) dysanapsis is associated with baseline airflow obstruction and risk of incident COPD independently of age, sex, height and race-ethnicity, but not with lung function decline over time.(111) This observation is consistent with the trajectory of low peak lung function in early adulthood followed by normal lung function decline that accounts for 50% of COPD in older adults(103); (5) a computational study of airway tree fluid dynamics and an in vivo study of regional lung ventilation suggest that dysanapsis may contribute to obstructive lung disease pathophysiology and deposition of aerosolized drugs(123-125); and, (6) the mechanisms contributing to the development of dysanapsis are not well understood. It is not clear whether it is due to genetic predisposition, in utero exposures to noxious particulates or pathogens, premature birth, low birth weight, neonatal lung injury, repeated respiratory infections in early life or a combination of them, but factors affecting airway tree growth early in life(107,109,111) and factors affecting airway tree homeostasis later in life have been implicated.(108,110) Of note, investigating the aetiology of dysanapsis earlier in life will require radiation-free (or lower dose radiation) methods in order to quantify lung structure in children. The fact that COPD can result from reduced peak lung function in early adulthood and/or accelerated lung function decline later in life(104,126) opens novel opportunities for prevention, and earlier diagnosis and treatment of the dcoisnefausseio(7n) bauntd, faatcitlihteatesafmuteurteimrees,ehaarschg:e(1n27e) rated several nosological terms that reqBuiUreTEproper definition to avoid Early COPD ISTRI The word "early" means "near the beginning of a process". Because COPD canDstart early in life and take a long time to manifest clinically, identifying "early" COPD is difficult. Further, a biologiOcaRl "early" related to the initial mechanisms that eventually lead to COPD should be differentiated from a clinicaOl P"eYarly", which reflects the initial perception of soynmlypttoomdissc, ufusnsctthioen"abliolimloigtiactaiol"nfiarnstds/toerpsstroufctthueradl iasbenaoserminaalintiNeesOxnpToetrCeimd.eTnhtaulss, ewtetinpgro. pose to use the term "early COPD" Mild COPD - DO Some studies have used "mild" airflow obstructionIAaLsSa surrogate for "early" disease.(128) This assumption is incorrect because not all patients started their journey fErvoRemritay"noorfmaiarlflpoewakoblusntrgucfutinocnt.i(o10n4)inFuerathrleyra, d"mulitlhdo"oddis,esaosseocmane of them occur at may never suffer any age and may "pmroilgdr"edssisoerasneoitnotveerrmtsimoMefA."(T1s2e6) Accordingly, we propose that "mild" should not be used to identify "early" COPD and used only to dYesRcIrGibHeTthe severity of airflow obstruction measured spirometrically. YThoeutnegrmC"OyoPuDng COPD" is seCeOmPingly straightforward because it directly relates to the chronological age of the patient. Given that lung function peaks at around 20-25 years,(56) we propose to operationally consider "young COPD" in patients aged 20-50 years.(129) Of note, this can include patients who had never achieved normal peak lung function in early adulthood and/or those with shorter plateau and/or early lung function decline.(130,131) Young COPD may be associated with significant structural and functional lung abnormalities (i.e., young COPD is not necessarily synonymous with "mild" COPD) that can have a substantial impact on health and, importantly, is frequently not diagnosed and thus not treated. A family history of respiratory diseases and/or early-life events (including hospitalizations before the age of 5 years) is reported by a significant proportion of young patients with COPD, further supporting the possibility of early-life origins of COPD.(127,131) PreCOPD This term has been recently proposed to identify individuals (importantly, of any age) who have respiratory symptoms and/or other detectable structural and/or functional abnormalities, in the absence of airflow obstruction on forced spirometry. These patients may (or not) develop persistent airflow obstruction (i.e., COPD) over time.(132) A very recent publication highlights the need for RCTs, both in patients with `Pre-COPD', and in young people with COPD.(133) 12 PRISm This term describes individuals with preserved ratio (FEV1/FVC 0.7 after bronchodilation) but impaired spirometry (FEV1 < 80% of reference, after bronchodilation).(6,134) The prevalence of PRISm in population-based studies ranges from 7.1% to 20.3%,(134) and is particularly high in current and former smokers, and associated with both high and low body mass index values.(134) PRISm is associated with increased all-cause mortality. PRISm is not always a stable phenotype and can transition to both normal and obstructed spirometry over time.(134) Despite an increasing body of literature on PRISm, significant knowledge gaps remain in relation to its pathogenesis and treatment.(134) Not all individuals with pre-COPD or PRISm will eventually develop fixed airflow obstruction over time (and hence COPD) but they should be considered "patients" (because they already suffer symptoms and/or have functional and/or structural abnormalities) and, as such, they deserve care and treatment. The challenge is that there is no evidence on what the best treatment is for these patients yet.(135) This is an important gap that deserves research. Asthma and airway hyperreactivity AlosntghimtuadimnaalycaolhsoorbteofatrhisekTfuaccstoonr fEopridtheemdioelovegliocaplmSetundtyoof fchAriorwniacyaOirbflsotwrucotbivsetruDcistieoaInBseUa,nTadEduClOtsPDdi.aIgnnaosreedpoorftafsrtohmmaa were found to have a 12-fold higher risk of acquiring adjusting for smoking.(136) Another longitudinal study oCfOpPeDopolveerwtiitmh easctohmmpaIaSrfTeodRuntdo those without asthma, after that around 20% developed irreversible airflow limitation and reduced diffusing lung capacity.(137) A thRirdDlongitudinal study observed that self- reported asthma was associated with excess loss of FEV1 in the generaPl YpoOpulation.(138) A study examining the pattern of lung-growth decline in children spirometric classification of COPD winitehaarlsythamdualtfhoouondd.(t1h39a) tIn11t%hTemCEeuOtrolupneganfuCnocmtiomnuinmitpyaRiremsepnirtatcoornysiHsteeanltthwSituhrvtehye, airway hyper-responsiveness was second only to cigarette smNokOing as the leading risk factor for COPD, responsible for 15% of chronic the population attributable risk airflow obstruction in asthmatic (smoking had non-smokers a-anDdpOonpounl-aatsiothnmaatttricibsumtaobkleersrisisk of 39%).(140) The pathology of markedly different, suggesting that the two disease entities may remain IdAifLfeSrent even when presenting with similarly reduced lung function.(136,141,142) However, abnormal lung development sinepcahrialdthinogodasathnTmdEaaRdforolemsceCnOcPeDcainn adults cause may be clinically difficult at times. Further, asthma-like symptoms. Given that poor lung development is associated with COPD inMAadulthood (Figure 1.1), these infants and adolescents may have been mislabeled as asthma. IGHT On the other hand, airway hypePrY-rResponsiveness can exist without a clinical diagnosis of asthma and has been shown to be an independent prediCctOor of COPD and respiratory mortality in population studies(143,144) as well as an indicator of risk of excess decline in lung function in patients with mild COPD.(145) Chronic bronchitis Chronic bronchitis (CB) is a common, but variable condition in patients with COPD. CB is defined by the presence of cough with expectorated sputum on a regular basis over a defined period. Variability in the prevalence of CB depends upon the definition used which differs in the regularity or duration of CB symptoms.(146) The classic description defines CB as chronic cough and sputum production for at least 3 months per year for two consecutive years, in the absence of other conditions that can explain these symptoms (an important caveat that is often ignored). Using this definition, the prevalence of CB ranges from 27-35% in large observational studies in patients with COPD.(147-149) Other factors associated with increased prevalence of CB in COPD includes male sex, younger age, greater pack-years of smoking, more severe airflow obstruction, rural location and increased occupational exposures.(146-152) Although the primary risk for CB is smoking, 4-22% of CB is found in never smokers suggesting other factors are involved.(153,154) Inhalational exposures to dusts, biomass fuels, chemical fumes or domestic heating and cooking fuels may be important.(151,152,155) Gastroesophageal reflux is also associated with an increased incidence of CB.(156,157) 13 Normal airway mucus is a gel comprised of 97% water and 3% solids (mucins, non-mucin proteins, cellular debris, salts and lipids ) that traps inhaled toxins which are subsequentially expectorated via the processes of ciliary beating and cough.(158) Mucins are large glycoproteins, two of the secreted mucin polymers, MUC5AC and MUC5B, line the human airways.(159,160) In healthy normal individuals, MUC5AC is produced by proximal airway surface goblet cells while MUC5B is produced by surface secretory cells found throughout the airways and submucosal glands. (159-163) In COPD, MUC5B levels markedly increase due to submucosal gland hyperplasia and airway occlusion can occur.(164-166) Viruses, acrolein and many cytokines (IL-4, IL-13, IL-17, IL-23 and IL-25) can also increase MUC5AC production.(167-172) Lung health depends upon effective mucus clearance. In disease states, thick and viscoid mucus can lead to airway inflammation and infection. Cough and dyspnea are the principal symptoms of impaired mucous clearance.(173,174) Cough and sputum production are predominately associated with mucus production in the large airways. However, increased mucus production also occurs in the smaller conducting airways and is associated with luminal occlusion, hallmarked by dyspnea but less cough and sputum production.(175,176) Radiographic manifestations of mucous plugging may be present and persist in patients with COPD despite a lack of CB symptoms and is associated with greater airflow obstruction, lo hypersecretion wer oxygen should be m saturatio aintained n in and worsened quality all patients with COPD of due ltiofet.h(1e77p,1r78o)teAanhicglihnicinadlTepExroobflemsusspthicaito n for mucus accompanies its presence.(179) How patients who have mucus hypersecretion evident on CT butRdIoBUnot manifest symptoms differ phenotypically and vice versa is not fully understood. DIST The relationship between chronic mucus production and lung function, OeRxacerbations and mortality has been the subject of multiple investigations. In young of chronic cough with sputum identified adults witho a subgroup ut at ahhigihstorirsykoOof fPasYdtehvmealoapnindgnoCrOmPaDl lung function, the independently of presence smoking habits.(180) In adults less than 50 years of age, CB without airflow liTmCitation represents an early marker for susceptibility to the long-term risk of COPD and all-cause mortality.(181) In sNmOokers between the ages of 36 to 43 years of age with chronic mucus production, there was a significant hi-ghDeOr risk of airflow limitation, however, following smoking cmeusscautsiohny,pmerusceucrseptrioonduiscptiroenserenttu, trhneedgrteoalteevretlhseobcIosAenLrcvSuerdreanmt doencgrsetanseevienrFsEmVo1k. eWrsh.(1il8e2)bImotphoMrtUanCt5lyA,CthaendloMngUeCr5cBhrhoanviec been associated with CB symptoms, among TcuErRrent smokers, it is sputum MUC5AC that has been associated more specifically with increased exacerbation MfreAquency, increased symptoms and greater lung function decline.(183,184) LpahrlgeegmepainddemwioomloegnicwsittuhdcioesughhavsheoswIhGoaHwccTnelaefrtaetreaddlojussstomf ent for height, age and lung function.(185) Other smoking history, men studies have suggested with cough or an association between chronic sputum prCoOduPcYtiRon and lower lung function, or greater FEV1 decline in patients with COPD.(185-189) The association of chronic mucus hypersecretion and mortality is unclear. Several studies report no predictive value of mucus production on mortality when controlling for respiratory impairment and smoking(190-192); other studies state sputum production has an independent role in predicting both overall and COPD-specific mortality.(150,193-195) In the Copenhagen city heart study, chronic mucus hypersecretion was associated with pulmonary infection that was implicated in 54% of the deaths.(196) Moreover, chronic mucus hypersecretion was associated with excessive FEV1 decline and increased COPD hospitalizations.(188) In patients with advanced emphysema, chronic bronchitis has been associated with increased hospitalizations and mortality.(197) In patients with non-obstructive chronic bronchitis, increased all-cause and respiratory disease related mortality has been reported.(198,199) Infections A history of severe childhood respiratory infections has been associated with reduced lung function and increased respiratory symptoms in adulthood.(140) The Medical Research Council National Survey of Health and Development documented a synergistic interaction between smoking and infant respiratory infections as well as early life home overcrowding with lung function at age 43.(200) Chronic bronchial infection, particularly with Pseudomonas aeruginosa, 14 has been associated with accelerated FEV1 decline.(201) Tuberculosis (TB) is a risk factor for COPD (23 studies; pooled odds ratio 2.59 (95% CI 2.12,3.15); pooled prevalence of COPD in patients with prior pulmonary TB was 21% (95% CI: 16-25%)).(202,203) Tuberculosis is both a differential diagnosis for COPD and a potential comorbidity.(204,205) Finally, 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))(206) probably due to methylation disruptions in airway epithelium.(207) IgG subclass deficiency has also been observed in hospitalized patients with COPD and this was associated with a significantly increased risk of mortality.(208) Sex Sex related differences in immune pathways and pattern of airway damage might be clinically important although 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 shown that the prevalence of COPD is almost equal in males and females, probably reflecting the changing patterns of tobacco smoking.(209) Although controversial, some studies have suggested that women may be more susceptible to the harmful effects of smoking than men,(20,210-212) leading to more severe disease for the equivalent quantity of cigarettes consumed.(213) This notion PATHOBIOLOGY has been validated in small airway disease animal studies and human pathology in females compared with males specimens, with COPD wdehsicphitheavaesdimemilUaorTnEshtirsattoerdy a greater burden of of tobacco smoke exposure.(214,215) A systematic review and meta-analysis of the global prevaleTnRceIBof COPD reported sex-based prevalence differences across WHO Global Burden of Disease sub-regions. In fDemISales the highest prevalence of COPD winacos mobescearvteegdoirnieNs oprrtehvaAlmenecreicwa a(8s.0h7ig%hevsst 7in.3u0p%p)earn-md iidndulerbinacnosmeetticnogusn(Ot1r3Rie.0s3fo%r vms a8l.e3s4(%9).0. 0U%si)nagntdheinWhoigrhld-inBcaonmk'es countries for females. COPY Socioeconomic status NOT Poverty is consistently associated with airflow obstruct-ioDnO(216) and lower socioeconomic status is associated with an ianncdreoausteddoroisrkaoirfpdoelvluetloanptins,gcCrOowPDdi.n(2g17,,2p1o8)oItr insuntorittcioIlAenaL,rSi,nhfeocwtieovnesr,,owrhoetthheerrftahcitsoprastrteelranterdeftleocltoswexspoocsiouerecosntoomhoicussteahtoulsd. MATER IGHT In patients with COPD pathoPloYgRical changes can be found in the airways, lung parenchyma, and pulmonary vasculature.(219) These incluCdOe inflammatory and structural changes which increase with the severity of airflow obstruction and can persist on smoking cessation (Figure 1.1). Inflammatory changes The inflammation observed in the lungs of COPD patients appears to be a modification of the normal inflammatory response to chronic irritants such as cigarette smoke. The mechanisms for this amplified inflammation are not yet fully understood but may, at least in part, be genetically determined. COPD is characterized by increased numbers of macrophages in peripheral airways, lung parenchyma and pulmonary vessels, together with increased activated neutrophils and increased lymphocytes. These inflammatory cells, together with epithelial cells and other structural cells release multiple inflammatory mediators(220) which attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (via proinflammatory cytokines), and induce structural changes (via growth factors).(221) Lung inflammation can persist after smoking cessation through as yet unclear mechanisms, although autoantigens and perturbations in the lung microbiome may play a role.(222,223) Systemic inflammation may also be present and could play a role in the comorbid conditions frequently found in 15 patients with COPD.(220) The nature of the inflammatory response in non-smoking related COPD is much less well characterized. Although both COPD and asthma are associated with chronic inflammation of the respiratory tract, there are differences in the inflammatory cells and mediators involved in the two diseases.(224) albeit some patients with COPD have an inflammatory pattern with increased eosinophils and ILC2 cells, similar to that of asthma.(225) Oxidative stress can also contribute to COPD.(220,226) 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.(204,227) Structural changes There is compelling evidence for an imbalance in the lungs of COPD patients between proteases derived from inflammatory and epithelial cells that break down connective tissue components and antiproteases that PATHOPHYSIOLOGY cluonugntpearrbeanlachnycemtah,isisaactnioinm.(p22o8r)tPanrottfeeaasteu-rmeeodfiaetmedpdheyssetrmucatibountoiftselraoslteinm, aamy bajeormcoornenedUciTftfiEivceulttistsoueecstoamblpisohneinntaoirfwthaey changes.(229) TRIB DIS Peribronchiolar fibrosis and interstitial opacities have been reported smokers.(222,230-232) An excessive production of growth factors may be fionuOpnadRtiiennstms owkiethrsCaOnPdDpaatniednitns asymptomatic with COPD.(233) Inflammation may precede the development of fibrosis or repeatOedPYinjury of the airway wall itself may lead to eaixrcweassyisveobpsrtorudcutcitoino.n(23o5f) muscle and fibrous tissue.(234) This mNayObTeCa contributing factor to the development of small The lung vasculature can also be altered in patients with- DCOOPD, even those with mild disease.(236) ERIALS MAT Airflow obstruction and gasIGtrHaTpping Airflow obstruction is usually mPeYasRured by spirometry as this is the most widely available and reproducible test of lung function. In COPD, airflowCoObstruction is caused by a mixture of small airways disease (which increases airway resistance) and parenchymal destruction (emphysema, that reduces the normal elastic recoil of the lung parenchyma), the relative contributions of which vary from person to person. Further, these changes do not always occur together and may evolve at different rates over time. Chronic inflammation causes structural changes, narrowing of the small airways, luminal exudates in 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 obstruction and mucociliary dysfunction(237). The reduced number of small airways identified in patients with COPD(237) may be due to an enhanced loss of airways and/or to deficient lung development (see dysanapsis above; Figure 1.1).(126) Collectively, all these changes limit emptying of the lungs during forced expiration, decrease FEV1 and the FEV1/FVC ratio, and contribute to gas trapping and lung hyperinflation.(238) Static lung hyperinflation related to the loss of elastic recoil reduces inspiratory capacity and is commonly associated with further (dynamic) hyperinflation during exercise related to airflow limitation, causing exertional dyspnea and limiting exercise capacity. This can happen even in patients with mild airflow obstruction.(239-241) Lung hyperinflation 16 contributes to impaired contractile properties of respiratory muscles, mostly the diaphragm. Bronchodilators act on these peripheral airways, reduce gas trapping and improve breathlessness and exercise capacity.(242) Pulmonary gas exchange abnormalities Structural abnormalities in the airways, alveoli and pulmonary circulation in patients with COPD alter the normal ventilation-perfusion (VA/Q) distributions. This is the main mechanism of abnormal pulmonary gas exchange resulting in different degrees of arterial hypoxemia, without or with hypercapnia .(243) Rarely, reduced ventilation may also be due to reduced ventilatory drive (e.g., sedatives and hypnotic drugs), causing hypercapnic respiratory failure and acidosis.(240) Parenchymal destruction due to emphysema also leads to decreased lung diffusing capacity (DLco). In general, pulmonary gas exchange worsens as the disease progresses. Pulmonary hypertension In smokers with normal spirometry and in COPD patients with mild airflow obstruction there may be abnormalities in the pulmonary circulation that include intimal hyperplasia and smooth muscle hypertrophy/hyperplasia.(244-247) Moreover, individuals aanloningflwamithmaetvoidryenrceespoofnseendinothveeslisaellsc,elslimdyilsafruntoctitohna.t Yseete,nseinvetrheepauilrmwoanyasT,ryEcahnypbeerteonbssieornveidn in these COPD is rare.(248,249) It may develop late in the course of COPD and it can be due to a combinaRtiIoBnUof loss of pulmonary capillary bheypdedrtueenstioonemmpahyyleseamd atoarnigdh/ot rvehnytproicxuiclarvahsyopceorntrsotrpichtyioanndofevtheentsumalalylltpourlimghDotnI-SsaiTrdyedarhteerairets.faPilruorgere(`scsoivrepuplumlmonoanlaer')y. Severe pulmonary hypertension worsens survival.(250) Interestingly, the diaOmReter of pulmonary artery as measured on cporemvpiouutsedhitsotomryogorfaepxhayce(CrbTa)tsiocanns.s(2h51a) s been shown to relate to thCeOrPisYk of suffering exacerbations, independent of Exacerbations NOT Exacerbations of respiratory symptoms in patients with -CDOOPD can be triggered by a number of different factors (alone or in combination), including respiratory infectioIAnLsSwith bacteria or viruses (which may coexist), environmental pollutants, or increased gas unknown trapping faancdtohrys.pDeurirninflgateioxancweriTbthaEtRrioednus cthedereexispiervaitdoernycfeloowf,intchruesasaecdcoauirnwtianygafnodr systemic increase inflammation, d dyspnea(252), and worsening of VA/Q abnormalities thaMtAcan result in arterial hypoxemia with or without hypercapnia.(253) Other ceoxancdeitriboantsi,onsuocfhCOaPsDp, naenudmneoendiat,opIbGuelHmcToonnsairdye,readndin/othrehcelianritcaflamiluarnea,geammeonntgoof tthheersse, may mimic episodes.(254) or See aggravate Chapter 5 an for an extended discussion on exacPeYrbRations. CO Multimorbidity Most patients with COPD suffer concomitant chronic comorbid diseases linked to the same risk factors i.e., smoking, aging, and inactivity, which may have a major impact on health status and survival.(255) Airflow obstruction and particularly hyperinflation affect cardiac function.(252) 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 (see Chapter 6). TAXONOMY COPD has been traditionally understood as a single "disease" caused by tobacco smoking.(114) Accordingly, most efforts have been devoted to the study of the pathogenetic mechanisms of only one major cause of COPD (cigarette smoking), failing to expand the horizon about the heterogeneity of processes that we know can contribute to its final clinical presentation.(2) It is therefore important to expand the taxonomy (classification) of COPD to include non-smoking 17 related COPD types, so specific studies can be designed and conducted for these different types of COPD or etiotypes.(256) Table 1.1 combines two recent taxonomic proposals developed independently.(1,257) This proposal has relatively little impact on current clinical practice, other than illuminating this so-far ignored aspect of COPD, but it is of the outmost importance to highlight the need to explore current and future therapies in these other etiotypes of COPD. 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Dharmage S, Agusti A. Personal communication. 2022. T C 257. Stolz D, Mkorombindo T, Schumann DM, et al. Towards theNeOlimination of chronic obstructive pulmonary disease: a Lancet Commission. Lancet 2022; 400(10356): 921-7-2.DO ERIALS MAT YRIGHT COP 27 CHAPTER 2: DIAGNOSIS AND ASSESSMENT KEY POINTS: A diagnosis of 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, but forced spirometry showing the presence of a post- bronchodilator FEV1/FVC < 0.7 is mandatory to establish the diagnosis of COPD. The goals of the initial COPD assessment are to determine the severity of airflow obstruction, the impact of disease on the patient's health status, and the risk of future events (such as exacerbations, hospital admissions, or death), to guide therapy. DIAGNOSIS Additional clinical assessment, including the measurement of lung volumUeTs,Ediffusion capacity, exercise testing and/or lung imaging symptoms after initial treatment. may be considered in COPTDRpIBatients with persistent DIS Ccaorndcioomvaistcaunltarchdroisneiacsed,isesakseelset(aml umltiumsoclrebiddityys)fuonccctuiornf,remquOeetRanbtloylicin COPD patients, including syndrome, osteoporosis, depression, anxiety, and lung cancer. These comorbiditiOesPsYhould be actively sought, and treated appropriately when present, because they influenceThCealth status, hospitalizations and mortality independently of the severity of airflow obstructNioOn due to COPD. - DO ERIALS MAT A diagnosis of COPD should be conIGsidHeTred in any patient who has dyspnea, chronic cough or sputum production, and/or a presence hoifstaopryosotf-berxopnocshuordeiltaoPtoYrirsRkFEfVac1t/oFrVsCfo<r0t.h7eisdmiseaansdeat(oTaryblteo 2.1) but forced spirometry that demonstrates establish the diagnosis of COPD.(1). the CO CLINICAL PRESENTATION Symptoms Chronic 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-day(2) and may precede the development of airflow obstruction by many years. Individuals, particularly those with COPD risk factors, presenting with these symptoms should be examined to search for the underlying cause(s). Airflow obstruction may also be present without chronic dyspnea and/or cough and sputum production and vice versa.(3) Although COPD is defined on the basis of airflow obstruction, 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. 28 IBUTE DISTR Y OR COP T NO - DO Dyspnea IALS TER Dyspnea is a cardinal symptom of COPD anMdAa major cause of the disability and anxiety associated with the disease.(4) Dyspnea comprises a sensory and anIGafHfeTctive component.(5) Typically COPD patients describe their dyspnea as a sense of increased may vary bo tehffionrdtivtoidburaellaythaned, cPchuYelRstut rhaellayv.(i6n)ess, air hunger, o r gasping. (6) Ho wev er, the te rm s used to descr ibe dy spnea CO Dyspnea is highly prevalent across all stages of airflow obstruction.(7) It occurs particularly during exertion or physical activity. Moderate-to-severe dyspnea has been reported by > 40% of patients diagnosed with COPD in primary care.(8) Dyspnea is complex and multiple mechanisms can be involved in its pathogenesis, including impaired respiratory mechanics as a consequence of airflow obstruction and lung hyperinflation, gas exchange abnormalities, peripheral muscle dysfunction related to deconditioning (and systemic inflammation in some patients), psychological distress, dysfunctional breathing, cardiovascular or other comorbid diseases.(9,10) Dyspnea measured by the 5-level modified Medical Research Council scale is integrated in the GOLD clinical classification scheme (see below) because patients with high dyspnea scores incur higher healthcare resource utilization and costs.(11) Dyspnea in daily life can be measured by a number of detailed questionnaires that are more discriminant and sensitive to change.(12,13) 29 Chronic 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 it may be present every day, often throughout the day. Chronic cough in COPD may be productive or unproductive.(14) In some cases, significant airflow obstruction may develop without the presence of a cough. Other causes of chronic cough are listed in Table 2.2. Syncope during cough in patients with severe COPD can occur due to rapid increases in intrathoracic pressure during prolonged attacks of coughing. Coughing spells may also cause rib fractures, which are sometimes asymptomatic. 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,(15) but this is a somewhat arbitrary definition that does not reflect the entire range of sputum production that occurs in COPD (see detailed discussion in Chapter 1). Sputum production is often dsiigffnicifuicltantto ceuvltauluraalteanbdecseaux svearpiaattiioenn.tsFumrtahyesrmwaolrleo,wspsuptuutmumprroadthuecrtiothnacnanexbpeecintoterramteiUtitTte,Enat habit that is with periods subject to of flare-up interspersed with periods of remission.(16) Patients producing large volumesToRfIBsputum may have underlying bronchiectasis.(17,18) The presence of purulent sputum reflects an increase development may identify the onset of a bacterial exacerbation, though the ainsDsIioSncfilaatmiomn aistorreylamtiveedlyiawtoeras,k(1.(92,200,2)1)and its Y OR COP T NO - DO ERIALS MAT YRIGHT COP Wheezing and chest tightness Inspiratory and/or expiratory wheezes and chest tightness are symptoms that may vary between days, and over the course of a single day. 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. 30 Fatigue Fatigue is the subjective feeling of tiredness or exhaustion and is one of the most common and distressing symptoms experienced by people with COPD.(22) People with COPD describe their fatigue as a feeling of "general tiredness" or as a feeling of being "drained of energy".(23,24) Fatigue impacts a patient's ability to perform activities of daily living and their quality of life. Additional clinical features in severe disease Weight loss, muscle mass loss, and anorexia are common problems in patients with severe and very severe COPD.(2527) They have prognostic importance(28,29) and can also be a sign of other diseases, such as tuberculosis or lung cancer, and therefore should always be investigated. Ankle swelling may indicate the presence of cor pulmonale. Symptoms of depression and/or anxiety merit specific enquiry when obtaining the medical history because they are common in COPD,(30) are associated with poorer health status, increased risk of exacerbations, and emergency hospital admission, and are treatable.(31) DIFFERENTIAL DIAGNOSIS OF COPD UTE In some patients with COPD, a clear distinction from asthma is difficult using curreTntRiImBaging and physiological testing techniques, since the two conditions share common diagnoses are easier to distinguish from COPD (Tabl traits and e 2.3). clinical ex pressioDnISs. ( 32) M o st o ther po te ntial differential Y OR MEDICAL HISTORY COP T NO A detailed medical history of a new patient who is know-nD, Oor suspected, to have COPD should include: Patient's exposure to risk factors, suchIAaLsSsmoking and environmental exposures (household/outdoor). Past medical history, including eaTrlEyRlife events (prematurity, low birthweight, maternal smoking during pregnancy, respiratory ipnafsescitvieonsms ionkcinhgilTdehMxopAoodsu; HreIVd;utruinbgerincufalonsciys)., asthma, allergy, sinusitis, or nasal polyps; Family history of COPD oIGr Hother chronic respiratory disease. Pattern of symptomPYdeRvelopment: COPD typically develops in adult life and most patients are conscious of increased breCaOthlessness, more frequent or prolonged "winter colds," and some social restriction for a number of years before seeking medical help. History of exacerbations or previous hospitalizations for respiratory disorder. Patients may be aware of periodic worsening of symptoms even if these episodes have not been identified as exacerbations of COPD. Presence of comorbidities, such as heart disease, osteoporosis, musculoskeletal disorders, anxiety and depression, and malignancies that may also contribute to restriction of activity. Impact of disease on patient's life, including limitation of activity, missed work and economic impact, effect on family routines, feelings of depression or anxiety, wellbeing, and sexual activity. Social and family support available to the patient. Possibilities for reducing risk factors, especially smoking cessation. 31 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP PHYSICAL EXAMINATION Although an important part of patient care, a physical examination is rarely (if ever) diagnostic in COPD. Physical signs of airflow obstruction are usually not present until significant impairment of lung function has occurred,(33,34) and detection based on physical examination has relatively low sensitivity and specificity. A number of physical signs (e.g., lung hyperinflation, cyanosis) may be present in COPD, but their absence does not exclude the diagnosis. 32 SPIROMETRY Forced spirometry is the most reproducible and objective measurement of airflow obstruction. It is a noninvasive, reproducible, cheap, and readily available test. Good quality spirometric measurement is possible in any healthcare setting and all healthcare workers who care for people with COPD should have access to spirometry. Some of the factors needed to achieve accurate test results are summarized in Table 2.4.(35,36) Despite its good sensitivity, peak expiratory flow measurement alone cannot be reliably used as the only diagnostic test because of its weak specificity.(37,38) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP As shown in Figure 2.1, forced spirometry measures: (1) the volume of air forcibly exhaled from the point of maximal inspiration (forced vital capacity, FVC); (2) the volume of air exhaled during the first second of this maneuver (forced 33 expiratory volume in one second, FEV1); and (3) the ratio of these two measurements (FEV1/FVC). Spirometry measurements are evaluated by comparison with reference values(36,39) based on age, height, sex, and race. Figure 2.1A shows a normal spirometry tracing and Figure 2.1B shows a tracing obtained in a person with COPD. Patients with COPD typically show a decrease in both FEV1 (due to airflow obstruction) and (to a lesser degree) FVC (due to gas trapping). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT The spirometric criterion foCr aOirPflow obstruction selected by GOLD remains a post-bronchodilator ratio of FEV1/FVC < 0.7. This criterion is simple and independent of reference values because it relates to variables measured in the same individual, and has been used in all the clinical trials that form the evidence base from which treatment recommendations are drawn. It should be noted that the use of a fixed FEV1/FVC ratio (< 0.7) to define airflow obstruction may result in over-diagnosis of COPD in the elderly,(40,41) and under-diagnosis in young adults,(41) 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.(42) It is important to emphasize that airflow obstruction that is not fully reversible is not specific for COPD; the clinical 34 context and risk factors should also be considered. Airflow obstruction that is not fully reversible may also be found in patients with asthma and other diseases. Normal spirometry may be defined by a new approach from the Global Lung Initiative (GLI).(43,44) Using GLI equations, z scores (the number of standard deviations by which the value of a raw score (i.e., an observed value or data point) is above or below the mean value of what is being measured) were calculated for FEV1, FVC, and FEV1/FVC. 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. Importantly, 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 biologic measurement to establish the clinical diagnosis of COPD in the appropriate clinical context (symptoms and 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 bronchodilator the presence or absence FEV1/FVC ratio should be of airflow confirmed obstruction based on a by repeat spirometry on asisnegplearTmaEteeaosuccreamsioenntifotfhethvealpuoestis- between 0.60 and 0.80, as in some cases the ratio may change as a result of biologRicIaBl Uvariation when measured at a later interval.(45,46) If spontaneously above the initial 0.7.(45) Of pnoostte-,brinonpcahtoiednilatstofrroFmEVt1h/eFVSCPIrRaOtiMo ICisS lecsoshDotIShrtaT,nin0.w60hicith is very unlikely to rise the pre-bronchodilator FEV1/FVC ratio was < 0.7 but increased to 0.7 following inhaled bronchoOdRilators, had 6.2 times the hazard of future development of COPD compared to a reference group without obstrOucPtYion.(47) While post-bronchodilator spirometry is required for the diagnoTsisCand assessment of COPD, assessing the degree of reversibility of airflow obstruction (e.g., measuring FEV1 befoNreOand after bronchodilator or corticosteroids) to inform therapeutic decisions is no longer recommended.(48) The- dDeOgree of reversibility in a single patient varies over time and has not been shown with bronchodilators to or cdoifrfteicroesntteiaroteidtsh.(e49)dAiacgcnoordsiiIsnAgfLrlySo,mit asthma, or to predict is not necessary to sto the response to long p inhaled medication -term treatment before obtaining nCeOwPDs.pirometry measurements during folMloAwT-uEpRof patients. Table 2.5 shows the role of spirometry in patients with YRIGHT COP 35 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.(50) 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.(50) Unless relevant predicted values are used the severity of airflow obstruction will be overestimated. Even in high income countries, lung reference values change over time and require periodic revision.(51) SCREENING AND CASEFINDING The role of screening spirometry for the diagnosis of COPD in the general population is controversial.(52,53) In asymptomatic individuals without any significant exposures to tobacco or other risk factors, screening spirometry is pchroebstaibnlfyenctoiot ninsd, eicaartleydli;fewehveerneatss),inthtehodisaegwnoitshticsyymiepldtofomrsCoOrPrDisiks fraeclatotirvse(lye.hgi.g, h>a2n0dpsapciUrkoT-ymEeeatrrsyosfhsomulodkbinegc,ornesciudrerreendt as a method for early case finding.(54,55) TRIB Both FEV1 and FVC predict all-cause mortality independent of tobacco smokingD,IaSnd abnormal lung function identifies a subgroup of smokers at increased risk for lung cancer. This has been the bOaRsis of an argument that spirometry should be employed as a global health assessment tool.(56-58) A risk score basOedPoYn routine data from electronic health records in primary screening scpairreommeatyryfaicsileitfafetectcivaesein-fidnidreincgtinagndmbaencaogsetm-eefnfetcdtievceOi.s(i5To9,n6C0s) However, data to support that population-based or in improving COPD outcomes in patients who are identified before the development of significant symptoOmNs is weak.(53) This may reflect the design and application of current case finding instruments that have not been-uDtilized to identify patients with undiagnosed COPD who are most likely incorporate to benefit exposures, from existing symptoms and thheearlatphiecsa.r(Ie6A1,u6L2tS)iliNzaotvioenl approaches and simple to screening have been developed that peak flow measurement; one of these has been developed for low- and middle-income cToEunRtries and has shown discriminatory properties. (63,64) GOLD advocates active case finding(54,65,66) i.e., performing sMpAirometry in patients with symptoms and/or risk factors, but not screening spirometry. found to be Systematic active an effective way tcoasidee-fIniGntidHfyiTnugnindiaagpnroimseadryCcOaPreDspeatttiinegntvsi.a(67m).aTilh-eouptootef natsiacrleuesneinogf questionnaire spirometry in was also children, adolescents and young adults tPoYiRdentify individuals with poor lung development at risk of COPD and other chronic conditions later in life meritCs Ofuture investigation.(68) COPD case-finding tools have been created based on existing epidemiologic literature or expert opinion (62,69,70) or with a multimodality approach.(63,64) Increasingly, it appears that the combination of questionnaires with simple physiological measurements enhances the operating characteristics and performance of these approaches.(69,71,72) In a variety of settings case-finding has been able to identify previously undiagnosed COPD.(67,71,73,74) In general, these tools identify a high proportion of patients with mild or minimally symptomatic disease, exhibiting modest sensitivity and specificity.(75) COPD screening/case-finding in primary care has been demonstrated to have a small but significant impact on increasing rates of diagnoses and physician's clinical actions but with limited data suggesting a significant impact on patient outcomes.(67,76-78) It remains vital to critically assess how the introduction of case finding approaches can optimally improve clinician behavior, enhance health care utilization, and improve patient outcomes while ensuring that patients identified with these techniques have access to affordable and clinically and cost-effective interventions.(79-81) 36 INITIAL ASSESSMENT Once the diagnosis of COPD has been confirmed by spirometry, in order to guide therapy COPD assessment must focus on determining the following four fundamental aspects: Severity of airflow limitation Nature and magnitude of current symptoms Previous history of moderate and severe exacerbations Presence and type of other diseases (multimorbidity) Severity of airflow obstruction In the presence of FEV1/FVC ratio < 0.7 the assessment of airflow limitation severity in COPD (note that this may be different from severity of the disease) is based on the post-bronchodilator value of FEV1 (% reference). The specific spirometric cut points are proposed for purposes of simplicity (Table 2.6). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 37 IBUTE DISTR Y OR COP T NO Symptoms - DO BexepceauriseenctehderebyistohnelypaatwieenatkocrotrhreelaimtiopnaibrmetewneteonIAftLthhSeesirevheeraitltyhosftaaitruflso,(w82,o83b) sftorrumctaiol nas(sTeasbslmee2n.6t )oafnsdymthpetosymmsputosimngs validated questionnaires is required. TER MA DThyespmnMeRaCqsucaelestwioansnthaeirfeir:stthqeuemstIioGodnHinTfaieirde Medical Research Council (mMRC) dyspnea scale developed to measure breathlessness, which is a key symptom in many patients with COPD, althoughPoYftRen unrecognized.(84) (Table 2.7) Of note, the mMRC score relates well to other multidimensional health staCtuOs measures(85) and predicts future mortality risk.(86,87) Multidimensional questionnaires It is now recognized that COPD impacts patients beyond dyspnea.(88) For this reason, multidimensional questionnaires are recommended. The most comprehensive disease-specific health status questionnaires such as the Chronic Respiratory Questionnaire (CRQ)(89) and St. George's Respiratory Questionnaire (SGRQ)(90) are important research tools but they are too complex to use in routine practice. Shorter comprehensive measures, such as the COPD Assessment Test (CATTM) and The COPD Control Questionnaire (CCQ) have been developed and are suitable for use in the clinic. Below we discuss the CATTM and the SGRQ. The CATTM* is an 8-item questionnaire that assesses health status in patients with COPD (Figure 2.2).(91) It was developed to be applicable worldwide and validated translations are available in a wide range of languages. The score * The COPD Assessment Test was developed by a multi-disciplinary group of international experts in COPD supported by GSK. COPD Assessment Test and the CATTM logo is a trademark of the GlaxoSmithKline group of companies. 2009 GlaxoSmithKline. All rights reserved. GSK activities with respect to the COPD Assessment TestTM are overseen by a governance board that includes independent external experts, one of whom chairs the board. 38 ranges from 0 to 40, correlates very closely with the SGRQ, and has been extensively documented in numerous publications.(92) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT The SGRQ is the most wideClyOdPocumented comprehensive measure; scores < 25 are uncommon in diagnosed COPD patients(93) and scores 25 are very uncommon in healthy persons.(94,95) 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 CATTM is 10.(96) An equivalent mMRC score cannot be calculated because a simple breathlessness cut-point cannot equate to a 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.(97) 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.(97) Exacerbation risk Exacerbations of COPD (ECOPD) are episodes of acute respiratory symptom worsening often associated with incresaed 39 local and systemic inflammation (see Chapter 5).(98-101) ECOPD are key events in the natural history of the disease because they impact significantly on the health status of the patient (often for a prolonged period of time), enhance the rate of lung function decline, worsen the prognosis of the patient and are associated with most of the healthcare costs of COPD.(102) ECOPD rates vary greatly between patients(103) and during follow-up.(104) The best predictor of having frequent exacerbations (defined as two or more exacerbations per year) is the previous history of exacerbations.(103) Worsening of airflow obstruction is associated with an increasing prevalence of exacerbations, hospitalization(66,105) and risk of death.(93,106) The association between blood eosinophil count and risk of exacerbations is discussed in Chapter 3. Multimorbidity People with COPD often suffer other concomitant chronic diseases (multimorbidity). This can occur in patients with mild, moderate or severe airflow obstruction.(93) Multimorbidity influences mortality and hospitalizations independently of the severity of airflow obstruction,(107) and deserves specific treatment. Therefore, comorbid conditions should be looked for routinely, and treated appropriately if present, in any patient with COPD. Recommendations for the diagnosis, assessment of severity, and management of individual comorbid diseases are the same as for patients without COPD. UTE Frequent multimorbid diseases in COPD include cardiovascular disease,(108), mTeRtIaBbolic syndrome, osteoporosis, depression and anxiety, likely in relation to shared risk factors (e.g., aging, smoDkiInSg, alcohol, diet and inactivity).(102,109- 111) Besides, COPD itself may increase the risk lung cancer).(112,113) Whether the association for other between cCoOmPoDrbaindddliusenagsecsOan(Rec.egr.,isCOdPuDe (particularly to common emphysema) and risk factors (e.g., smoking), involvement of shared susceptibility genes and/or impaireOdPcYlearance of carcinogens is unclear. COPD can also have significant extrapulmonary (systemic) effects includingTwCeight loss, nutritional abnormalities, and skeletal muscle dysfunction. The latter is characterized by both sarcopNeOnia (loss of muscle cells) and abnormal function of the remaining cells.(114) Its causes are likely can contribute to exercise intolerance manudltpifoacotrohrieaal l(teh-.gDs.t,Oaintuasctiinvitpya,tpieonotrs diet, with inflammation and/or hypoxia) and it COPD. Importantly, skeletal muscle dysfunction is a modifiable source of exercise intIAolLeSrance by rehabilitation.(115) A more detailed description of the mCoanmagbeimneendt oinf iCtOiaPlDCaOndPcDomaosrsbeidsistimeseiMsnpAtrToEviRded in Chapter 6. In 2011, GOLD proposed to move fIrGoHmTthe simple spirometric grading system for disease severity assessment and treatment to a combined assessPmYeRnt strategy based on the level of symptoms (mMRC or CATTM), the severity of airflow liinmitiitaaltpiohnar(GmOaLcDologgraicdaelst1re-4aCt),mOaenndt.thTehefremqauiennsctyeopf fporrewvaiordusaecxhaieceverbdatbiyontsh.isThciosmclbaisnseifdicaatsisoensswmaesnptrostproasteedgytowgausidtoe incorporate patient-reported outcomes and highlight the importance of exacerbation prevention in the management of COPD. The initial version of the combined assessment relied on both the severity of airflow obstruction (GOLD grades 1-4) and the frequency of previous exacerbations to assess exacerbation risk. The severity of airflow obstruction was subsequently removed from this combined assessment scheme considering its lower precision at the individual level (versus that at a population level) to predict outcomes and drive treatment decisions, while complexifying the use of the classification by clinicians.(83,106,116,117) Now, in this 2023 document, GOLD proposes a further evolution of the ABCD combined assessment tool that recognizes the clinical relevance of exacerbations, independently of the level of symptoms of the patient. Figure 2.3 presents this new proposal. The A and B groups are unchanged, but the C and D groups are now merged into a single group termed "E" to highlight the clinical relevance of exacerbations. We acknowledge, that this proposal will have to be validated by appropriate clinical research. 40 ADDITIONAL INVESTIGATIONS IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP In cases where there is a marked discordance between the level of airflow obstruction and the perceived symptoms, a more detailed evaluation should be carried out to better understand lung mechanics (e.g., full lung function tests and exercise testing), lung structure (e.g., computed tomography) and/or comorbidities (e.g., ischemic heart disease) that might impact patient symptoms. Physiological tests Lung volumes COPD patients exhibit gas trapping (a rise in residual volume) from the early stages of the disease, and as airflow obstruction worsens, static hyperinflation (an increase in total lung capacity) occurs, particularly during exercise (dynamic hyperinflation). These changes can be documented by body plethysmography, or less accurately by helium dilution lung volume measurement. These measurements help characterize the severity of COPD but are not essential to patient management. 41 Carbon monoxide diffusing capacity of the lungs (DLco) The single breath DLco measurement (118) evaluates the gas transfer properties of the respiratory system. DLco is well- standardized and with valid predicted values of practical utility.(39,119-121). The advent of reliable portable systems capable of providing accurate determinations in the field, expands its potential use as a complement to the information provided by spirometry.(122) DLco should be measured in any person with symptoms (dyspnea) disproportionate to the degree of airflow obstruction since reduced DLco values < 60% predicted are associated with increased symptoms, decreased exercise capacity, worse health status(123-125), and increased risk of death, independently of the severity of airflow obstruction and other clinical variables.(126-128) Additionally, in COPD patients, low DLco values help preclude surgical lung resection in patients with lung cancer(129) while in smokers without airflow obstruction, values < 80% predicted (as a marker of emphysema) signal an increased risk for developing COPD over time.(130) Over time people with COPD have an accelerated decline in DLco compared to smokers without the disease, and this decline is significantly greater in women than men.(131,132) However, DLco decline is slow, and years of follow up are often needed before a meaningful change in DLco is detected. Oximetry and arterial blood gas measurement UTE Pulse oximetry can be used to evaluate a patient's arterial oxygen saturation aTnRdIBneed for supplemental oxygen therapy at the point-of-care and should be used to assess all patients with clinicDaIlSsigns suggestive of respiratory failure othrerigimhtpheerfaercttfaciolurrreel.aItfipoenribpehtewraeleanrtoexryiagleonxysgaetunrsaattiounratdieotneicsted92v%ia, parutlesOeriaRol xbilmooedtrygaassescsohmopualdrebde tmoeaarstuerreiadl dbuloeotdo gas.(133) Further, pulse oximetry does not provide information on PaCOOP2Yor pH, which may have potential therapeutic implications (e.g., non-invasive ventilation). T C NO Exercise testing and In some cases, patients assessment may complain of of mphinyimsiaclaslyamcpt-tioDvmiOtsydespite severe airflow obstruction. This may be due to reduced dyspnea perception(134) and/or life-style IaAdLaSptations (sedentarism) to reduce dyspnea generation. In these cdaosnese,eedxmerocirseeintetestnssseutcrheaatsmthenet6(-em.gin.,urteehwabaiTllkitEianRtgiodnis)ttahnacnetmheayinrietivael aelvtahluatattihoen patients are would have severely constrained suggested. and MA Further, objectively measured exercIGiseHTimpairment, assessed by a reduction in self-paced walking distance (135,136) or dpurerdinicgtoinrcorfepmreongtnaolsiesx.(e13r8c)isLeabtoePrsaYttiRnogryitnesatinlagbuosriantgorcyy,c(1le37)oristraeapdomwiellrefurgloimndeitcraytocar noafshsiesat litnhidsetanttuifsyiinmgpcaoi-remxeisntitnganodr alternative conditions e.g.C, Ocardiac diagnoses. Walking tests can be useful for assessing disability and risk of mortality(139) and are used to assess the effectiveness of pulmonary rehabilitation. Both the paced shuttle walk test(140) and the self-paced 6-minute walk test can be used.(141,142) 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.(143) Monitoring of physical activity may be more relevant regarding prognosis than evaluating only exercise capacity.(144) This can be conducted using accelerometers or multi-sensor instruments. Imaging Chest Xray 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 42 changes associated with COPD may 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) In recent years computed tomography (CT) has become increasingly available, both as a research tool and in clinical practice, providing additional insights into the structural and pathophysiologic abnormalities present in COPD. This has led to enhanced understanding of disease phenotypes, severity, and outcomes. From a clinical perspective, emphysema distribution and severity can be readily discerned and can assist with decision making for lung volume reduction surgery (LVRS) or endobronchial valve placement. While historically this has been performed based on expert radiologist visual analysis, particularly for LVRS, increasingly quantitative analysis for emphysema extent, location and fissure integrity is also being performed to assist with endobronchial valve therapy decision making. The presence of emphysema is also associated with more rapid progression of FEV1 decline and mortality and increased likelihood of development of lung cancer.(128) Further, about 30% of COPD patients have bronchiectasis visible on CT, which is now the radiological examination of choice when this is suspected. Bronchiectasis is associated according to with increased bronchiectasis exacerbation frequency and mortality,(145) altho guidelines influences these clinical outcomes. ugh it is no t UyeTtEkno wn whether treatm ent TRIB HdoistuonrdicearlglyocChTesatsCpTarhtaosfneovtablueaetniocnoonfsipduelrmedonaarreyqnuoirdeumleesndtefotercCteOdPDondciahgensotsXDis-rI,Sabyuot rinacsrseeasssimngelnytmfoorrecoCnOcPuDrrepnattielunntgs disease. Recently, the number of patients who would potentially benefit fOroRm chest CT has also expanded. First, this is due to the recent lowering of the age for lung cancer screening to 5O0PyeYars old. Second, the advent of endobronchial vpaaltvieentthserawpiythforpeomstpbhryosnecmhoadhialastaolrso FeExVp1andbeedtwtheeepnoo1l o5%f p-4at5Oi%eTntCsawndhereevCidTeenvcaeluaotifonmmaarykebde hhelyppfeurl,ininflaptaiortniculoanr plethysmography.(146) In such instances, quantification oOf eNmphysema on chest CT by lobe and ensuring fissure integrity of the target lobe is required as part of the eva-luDation process. More detailed computer assisted CT analysis enaIAblLeSs quantification of airway abnormality as well, although these methods are less well standardized than the mTEeRthods used for emphysema quantification. Hence, historically airway measures have been used more in the reseMarAch setting. While segmental and subsegmental measures of wall thickness can and beexpmiraadtoeryditroecidtleyn, tmifyeaasrueraesmoef nnItoGsnHo-efTmsmphayllsaeimrwaatoysus(<ga2smtrmapdpiianmg.eVtearl)idmatuesdt be inferred by algorithms are comparing inspiratory becoming increasingly available, even in the clinical sPeYttRing, that can identify small airway abnormality through this method.(147,148) Small airway abnormality may alCsoObe present even among individuals without detectable spirometric obstruction and identify individuals at increased risk for lung function decline.(149) It should also be noted that CT imaging of the chest can also provide a wealth of information about COPD comorbidities including coronary artery calcium, pulmonary artery enlargement, bone density and muscle mass. Such CT extracted features have been shown to be independently associated with all-cause mortality.(150) As technology advances, such information is likely to become increasingly available to clinicians to enhance patient management. In summary, for COPD patients with persistent exacerbations, symptoms out of proportion to disease severity on lung function testing, FEV1 less than 45% predicted with significant hyperinflation and gas trapping, or for those who meet criteria for lung cancer screening, chest CT imaging should be considered (Table 2.8). Alpha1 antitrypsin deficiency (AATD) The World Health Organization recommends that all patients with a diagnosis of COPD should be screened once for AATD, especially in areas with high AATD prevalence.(151,152) 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 43 patients when they are older and have a more typical distribution of emphysema (centrilobular apical).(153) 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). IBUTE DISTR Y OR COP T NO - DO ERIALS Composite scores MAT SdeisvtearnaclevoarriapbelaeksoidxeyngetinfycpoantsiuemntpstaiotIGnin,HcwrTeeaigshetdlroisssk,faonrdmroerdtuaclittiyoinncolfuadritnegriFaElVo1x,yegxeenractiisoent.oTlhereaBnOceDaEs(sBeosdseydmbaysws ianldkienxg, Obstruction, Dyspnea, and ExerPcYisRe) method gives a composite score that is a better predictor of subsequent survival than need avnaylidsiantgiolencaocmropsosnaenwtiC.d(1Oe54,r1a55n) gSeimopfledrisaelatesernsaetviveersititehsatanddo not include an exercise test have been suggested clinical settings to confirm that they are suitable but for routine clinical use.(156,157) Biomarkers There is rapidly increasing interest in the use of biomarkers in COPD. Biomarkers are `characteristics (either clinical, functional, biologic and/or imaging) 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 cohorts.(158) At present blood eosinophil counts ( 300 cells/L) provide guidance to identify COPD patients at higher risk of exacerbations and more likely to benefit from preventive treatment with inhaled corticosteroids (see Chapter 3).(158) 44 Treatable traits To address the heterogeneity and complexity of COPD in clinical practice, a strategy based on so-called `Treatable Traits' (TTs) has been proposed.(159) TTs can be identified based on phenotypic recognition and/or on deep understanding of critical causal pathways (endotypes) through validated biomarkers (e.g., high circulating eosinophil levels (a biomarker) identify COPD patients at risk of exacerbations (a TT) in whom treatment with inhaled corticosteroid is most effective).(160) TTs can co-exist in the same patient(32) and change with time (spontaneously or because of treatment). 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Lancet Respir Med 2015; 3(6): 443-50. 107. 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. 108. 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. 109. Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest 2005; 128(4): 2099-107. 110. National Institute for Health and Care Excellence. Multimorbidity: clinical assessment and management; NICE guideline [NG56]Published date: 21 September 2016 [accessed Oct 2022]. 2016. https://www.nice.org.uk/guidance/ng56. 111. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187(7): 728-35. 112. 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. 48 113. 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. 114. Wagner PD. Possible mechanisms underlying the development of cachexia in COPD. Eur Respir J 2008; 31(3): 492-501. 115. 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. 116. 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Eur Respir J 2005; 26(4): 720-35. 121. Stanojevic S, Graham BL, Cooper BG, et al. Official ERS technical standards: Global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians. Eur Respir J 2017; 50(3). 122. Gochicoa-Rangel L, Perez-Padilla R, Vazquez-Garcia JC, et al. Long-Term Breath Diffusing Capacity Instrument. Respir Care 2017; 62(2): 231-5. Stability of a PortTaEble Carbon Monoxide Single- 123. Balasubramanian A, MacIntyre Chest 2019; 156(6): 1111-9. NR, Henderson RJ, et al. Diffusing Capacity of CarboRn IMBUonoxide in Assessment of COPD. 124. cEhlbreohnaiciroybAsFtr,uOc'tDivoenpnuelllmCoDn,aArbyddiEslehaasme.eJeAdpAp,lePthayls.iLool w(19re8s5t)in2g01d9if;fu1s2io7(n4c):a1p1aD0ciI7tS-y1T,6d.yspnea, and exercise intolerance in 125. Farkhooy A, Janson C, Arnardottir capacity is the strongest predictor RoHf ,eMxearlciinsoevisncthoileAr,aEnmcetninerCMOP, DH.eCdOenPsDtOr2oR0m13H;.1Im0(p2a):ir1e8d0c-5a.rbon monoxide diffusing 126. Boutou AK, Shrikrishna D, Tanner RJ, et al. Lung function indices foOr pPrYedicting mortality in COPD. Eur Respir J 2013; 127. 42(3): 616-25. de-Torres JP, O'Donnell DE, Marin JM, et al. Clinical and PrognoTstCic Impact of Low Diffusing Capacity for Carbon Monoxide Values in Patients With Global Initiative for ObsNtruOctive Lung Disease I COPD. Chest 2021; 160(3): 872-8. 128. Haruna 40. A, Muro S, Nakano Y, et al. CT scan findings o-fDemOphysema predict mortality in COPD. Chest 2010; 138(3): 635- 129. Ferguson MK, Gaissert obstructive pulmonary HA, Grab JD, disease: the pSrheednicgtSiv.ePIruAolmLleSoonfadriyffcuosminpgliccaaptaiocnitsy.afJtTehr olurancg resection in the Cardiovasc Surg absence of chronic 2009; 138(6): 1297- 130. 302. Harvey BG, Strulovici-Barel Y, Kaner RJ, etTaEl.RRisk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity. Eur RMesApir J 2015; 46(6): 1589-97. 131. 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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. 137. 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. 138. 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. 139. Celli B, Tetzlaff K, Criner G, et al. The 6-Minute-Walk Distance Test as a Chronic Obstructive Pulmonary Disease Stratification Tool. Insights from the COPD Biomarker Qualification Consortium. Am J Respir Crit Care Med 2016; 194(12): 1483-93. 140. Revill SM, Morgan MD, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: a new field test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax 1999; 54(3): 213-22. 141. Casanova C, Cote CG, Marin JM, et al. The 6-min walking distance: long-term follow up in patients with COPD. Eur Respir J 2007; 29(3): 535-40. 49 142. Puente-Maestu L, Palange P, Casaburi R, et al. Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur Respir J 2016; 47(2): 429-60. 143. Beekman E, Mesters I, Hendriks EJ, et al. Course length of 30 metres versus 10 metres has a significant influence on six- minute walk distance in patients with COPD: an experimental crossover study. J Physiother 2013; 59(3): 169-76. 144. Waschki B, Kirsten A, Holz O, et al. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 2011; 140(2): 331-42. 145. Martinez-Garcia MA, de la Rosa-Carrillo D, Soler-Cataluna JJ, et al. Bronchial Infection and Temporal Evolution of Bronchiectasis in Patients With Chronic Obstructive Pulmonary Disease. Clin Infect Dis 2021; 72(3): 403-10. 146. 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. 147. Galban CJ, Han MK, Boes JL, et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012; 18(11): 1711-5. 148. Vasilescu DM, Martinez FJ, Marchetti N, et al. Noninvasive Imaging Biomarker Identifies Small Airway Damage in Severe Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2019; 200(5): 575-81. 149. Bhatt SP, Soler X, Wang X, et al. Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2016; 194(2): 178-84. 150. Ezponda A, Casanova C, Divo M, et al. Chest CT-assessed comorbidities and all-cause mortality risk in COPD patients in the BODE cohort. Respirology 2022; 27(4): 286-93. 151. WHO meeting participants. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health 152. Organ 1997; 75(5): 397-415. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnToEsis and treatment of 153. pulmonary disease in alpha1-antitrypsin deficiency. Eur Respir Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema J 2017; 50(5). distribution in alpha1R-IaBnUtitrypsin deficiency influences 154. lung function impairment. Am Guerra B, Haile SR, Lamprecht J Respir B, et al. Crit Care Med 2004; Large-scale external v1a7l0id(1a1ti)o:n11a7n2d-c8o. mDpISarTison of prognostic models: an 155. application to chronic obstructive Celli BR, Cote CG, Marin JM, et al. Tphuelmboondayr-ymdaissseainsdee. xB,MaiCrfMlowedo2b0s1tr8u;c1t6Oio(1Rn),:d3y3s.pnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350(10O):P10Y05-12. 156. oJobnsetrsuRcCti,vDeopnualmldosonnarGyCd,isCehaasvea:ntnheesDNOHS,EeItnadle. xD.eArmivaJtiRoenspainrdCvrTiatlCCidaarteioMneodf a composite index of severity 2009; 180(12): 1189-95. in chronic 157. Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of tNheOprognostic assessment of patients with chronic 158. oStbosctkrulecytiRveA,pHualmlpoinnaDrMy dGi,seCaesllei :BtRh,eSuinpgdhaDte.dCBhrOoDnEicinO-dbDesxOtrauncdtivtehePuAlDmOoninadreyxD. iLsaenacseetB2io0m09a;r3k7e4rs(9a6n9d1T):h7e0ir4-11. 159. Interpretation. Agusti A, Bel E, Am J Respir Thomas M, eCtriatlC. TarreeaMtaebdle2t0r1a9iItA;s1:L9tSo9w(1a0r)d: 1195-204. precision medicine of chronic airway diseases. Eur Respir J 160. 2016; 47(2): 410-9. Agusti A, Fabbri LM, Singh D, et al. InhaleTd EcoRrticosteroids in COPD: friend or foe? Eur Respir J 2018; 52(6): 1801219. MA YRIGHT COP 50 CHAPTER 3: EVIDENCE SUPPORTING PREVENTION AND MAINTENANCE THERAPY KEY POINTS: Smoking cessation is key. Nicotine replacement and pharmacotherapy reliably increase long-term smoking abstinence rates. Legislative smoking bans and counseling, delivered by healthcare professionals, improve quit rates. There is no evidence to support the effectiveness and safety of e-cigarettes as a smoking cessation aid at present. Pharmacological therapy can reduce COPD symptoms, reduce the frequency and severity of eraxtaecseorbfalutinognsfu, annctdioimn pdreocvlieneheaanldthmstoarttuaslitayn.d exercise tolerance. Data suggUeTstEbeneficial effects on Each pharmacological treatment regimen should be individualized aTnRdIBguided by the severity of symptoms, risk of exacerbations, side-effects, comorbidities, drDugISavailability and cost, and the patient's response, preference, and ability to use various drugOdRelivery devices. Inhaler technique needs to be assessed regularly. OPY COVID-19 vaccines are highly effective against SARST-CCoV-2 infection and people with COPD should have the COVID-19 vaccination in line with natioNnaOl recommendations. Influenza vaccination decreases the inciden-cDeOof lower respiratory tract infections. Pneumococcal vaccination decreasesItAhLeSincidence of lower respiratory tract infections. TER CpaDtCiernetcsowmhmoewnedrsetnhoetTvdaacpcinMvaaAtcecdiniantiaodno(ledsTcaePn/cdeT,Paas; wpeerlltuasssriso,utteintaenuusseaonfdshdiinpgtlheesrviaa)ccfoinreCiOnPaDll COPD patients. IGHT Pulmonary rehabiPlitYaRtion with its core components, including exercise training combined with dgrisaedaesseo-sfpCeOciPfiDcCsOeedvuecraittyio. n, improves exercise capacity, symptoms, and quality of life across all In patients with severe resting chronic hypoxemia (PaO2 55 mmHg or < 60 mmHg if there is cor pulmonale or secondary polycythemia), long-term oxygen therapy improves survival. In patients with stable COPD and resting or exercise-induced moderate desaturation, long-term oxygen treatment should not be prescribed routinely. However, individual patient factors must be considered when evaluating the patient's need for supplemental oxygen. In patients with severe chronic hypercapnia and a history of hospitalization for acute respiratory 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. 51 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 A significant proportion of people with COPD continue to smoke despite knowing they have the disease (approximately 40% of those with COPD are current smokers), and this behavior has a negative impact on prognosis and progression of the disease.(1) 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.(2) Besides individual approaches to smoking cessation, legislative smoking bans are effective in increasing quit rates and reducing harm from second-hand smoke exposure.(3) Pharmacotherapies for smoking cessation Nicotine replacement products UTE Nicotine replacement therapy (nicotine gum, inhaler, nasal spray, transderm reliably increases long-term smoking abstinence rates(4-6) and is significantly aml poTareRtcIehBf,fesucbtilvinegtuhaalntapblalecte,boor. lozenge) Medical contraindications to nicotine replacement therapy include recent myoDcaISrdial infarction or stroke.(7,8) The contraindication to nicotine replacement therapy after acute coronary syOnRdrome remains unclear and the evidence soufgngiceosttsintehgaut mthipsrtordeuatcmesesnetccraentioannsdtshhaotualrdebsewsatlalortweedd>r2atwheeretkhsaanftOaebPrsaYorcbaerddiothvraosucuglhartheevebnutc.c(9a) lCmonutcionsuaouresscuhlteinwgining little absorption and potentially causing nausea. NOT C The efficacy o f elect ro nic cigarett es (e -cigarette s, v aping) - DwOith regard to smo king cessatio n rem ains co ntro versial.(10,11) E-cigarettes provide cigarettes for those a vaporized and doseable wishing to quit but also as naicIrAoisLtiinSngetirnehnadlaftoior nyoaunndgehravpereivnicoruesasneedveinr usage as smokers. an alternative to E-cigarettes may contain not only nicotine but also other cheTmERicals, such as vegetable glycine, propylene glycol, various flavoring agents, volatile carbonyls, are largely unknown. diacetyl, reactTivMe Aoxygen species, furones and metals, the long-term health effects of which IGH Winchluatdiinsgknvoawpinngh-aasssboeceianteredplourPntegYdRinmjuariyn.lySaesveinredivaicduutael or series of case reports lung injury, eosinophilic of the acute pneumonia, effects of alveolar e-cigarettes, hemorrhage, respiratory bronchiolitis anCd Oother forms of lung abnormalities have been reportedly linked to e-cigarette use, and occasionally death.(12-15) The U.S. Centers for Disease Control (CDC), the U.S. Food and Drug Administration (FDA), state and other clinical and public health partners investigated an outbreak of e-cigarette, or vaping, product use- associated lung injury (EVALI). As of February 18, 2020, a total of 2,807 cases of lung illness and 68 deaths had been associated with using e-cigarette products (devices, liquids, refill pods, and/or cartridges).(15) Patients were reported to have had clinical improvement with systemic glucocorticoid therapy and the majority received prolonged courses.(14) Laboratory data have shown that vitamin E acetate, an additive in some THC-containing e-cigarettes, was strongly linked to the EVALI outbreak.(16) Following the identification of vitamin E acetate as a primary cause of EVALI there has been a decline in new cases since September 2019. Neutrophilic inflammation of the airways, airways irritability, ciliary paresis and increased mucus hypersecretion are seen in animal models and in vitro human airway studies similar to changes induced by cigarette smoke and recognised features of COPD. These data are summarized in a review by Gotts and colleagues,(17) although it is likely to be many years before the long-term risks of vaping, including risks of cancer, are clarified, particularly in people with COPD or whether this is an independent risk factor for developing COPD.(12-15) In a large prospective cohort study an increased 52 risk of respiratory disease among former and current e-cigarette users was observed even when adjusted for cigarette and other combustible tobacco product use, demographic characteristics, and chronic health conditions.(18) Pharmacological products Bupropion(20) and nortriptyline(21) have been shown to increase long-term quit rates,(21) 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.(21) Recommendations for treating tobacco use and dependence are summarized in Chapter 4. A five-step program for intervention (Table 3.1)(4,6,22) provides a helpful strategic framework to guide healthcare providers interested in helping their patients stop smoking.(4,6,23) Because tobacco dependence is a chronic disease,(4,6) 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. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Counseling delivered by physicians and other health professionals significantly increases quit rates over self-initiated strategies.(24) Even brief (3-minute) periods of counseling urging a smoker to quit improve smoking cessation rates.(24) There is a relationship between counseling intensity and cessation success.(25) 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.(26) Financial incentive models for smoking cessation have also 53 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.(27) The combination of pharmacotherapy and behavioral support increases smoking cessation rates.(28) VACCINATIONS People with COPD should receive all recommended vaccinations in line with the relevant local guidelines (Table 3.2). Influenza vaccine Influenza vaccination can reduce serious illness (such as lower respiratory tract infections requiring hospitalization)(29) and death in people with COPD.(30-33) 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.(30) Vaccines containing either killed or live inactivated viruses are recommended(34) as they are more effective in elderly people with COPD.(35) Findings from a population-based study suggested that people with COPD, particularly the elderly, had decreased risk of ischemic heart disease when they were vaccinated withUiTnEfluenza vaccine over many years.(36) Occurrence of adverse reactions is generally mild and transient. RIB DIST Y OR COP T NO - DO ERIALS MAT YRIGHT COP Pneumococcal vaccine Pneumococcal vaccinations, pneumococcal conjugated vaccine (PCV20 or PCV15) and pneumococcal polysaccharide vaccine (PPSV23), are approved for adults aged 65 years. They are also approved for adults aged 19-64 years if they have an underlying medical condition such as chronic lung disease (including COPD, emphysema, and asthma), cigarette smoking, solid organ transplant etc. Pneumococcal vaccination is universally recommended for adults in these age groups, if they have never received a pneumococcal conjugate vaccine previously, or if their previous pneumococcal vaccination history is unknown. The current recommendation is PCV15 followed by PPSV23 OR one dose PCV20.(37) Adults who have only received PPSV23 may receive a PCV (either PCV20 or PCV15) 1 year after their last PPSV23 dose (Table 3.2). 54 Specific data on the effects of PPSV and PCV in people with COPD are limited.(38) 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.(39) 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).(40) 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.(41) 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.(42) A 2021 study compared the effectiveness of PPSV23 and PCV13 in COPD patients over a 5-year follow-up cohort study. Although both vaccines have comparable clinical effects during the first year after vaccination, PCV13 showed PHARMACOLOGICAL THERAPY FOR STABLE COPD persistent registered clinical in 47% effectiveness of patients in during the 5-year the PPSV23 group, fvoellroswus-u3p.3p%eroifodp.atPiennetusminontihae bPyCVy1eT3aErg5rouafpte(rp<va0c.c0i0n1a)t.ioSnimwilaasr effect were shown in the reduction of COPD exacerbations.(43) RIBU PCV15, PCV20, or PPSV23 can be co-administered with influenza vaccine iDnISanT adult immunization program, as concomitant administration (PCV15 or PPSV23 and QIV [Fluarix], PCV2O0Rand adjuvanted QIV [Fluad]) has been demonstrated to be immunogenic and safe.(44) COPY Other vaccines NOT In adults with dTaP/dTPa) to COPD protect the US against Centers pertussis f(owrhoDoispeiansgecoCuogn-htD)r,oOtle(tCanDuCs) recommends the and diphtheria, in Tdap those vaccination (also called who were not vaccinated in adolescence and also the routine use of shinIAglLeSs vaccine.(45,46) People with COPD should have the COVID-19 vaccination in line with national recommeMndAaTtiEoRns.(47) IGHT PYR Overview of the medCicOations Pharmacological therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. Individual clinical trials have not been sufficiently conclusive to show that pharmacotherapy can reduce the rate of FEV1 decline.(48-52) However, a systematic review combining data from 9 studies demonstrated a reduction in the rate of FEV1 decline of 5.0 mL/year in active treatment arms compared with placebo arms.(53) The difference between long-acting bronchodilator containing treatment arms and placebo arms was 4.9 mL/year. The difference between inhaled corticosteroid containing treatment arms and placebo arms was 7.3 mL/year. Although we need to be aware of the potential benefit of pharmacotherapy in reducing the rate of lung function decline, further research is needed to know which patients are likely to benefit. 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 the clinical response balanced against side effects. Each treatment regimen needs to be individualized as the relationship between severity of symptoms, airflow obstruction, and severity of exacerbations can differ between patients. The WHO has defined a minimum set of interventions for the management of stable COPD in primary care.(54) 55 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,(55,56) 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.(57,58) Bronchodilator dose-response (FEV1 change) curves are relatively flat with all classes of bronchodilators.(59-65) 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 episodes(66) but is not necessarily helpful in stable disease.(67) 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. Beta2agonists The principal action of beta2-agonists is to relax airway smooth muscle by stimulating beta2-adrenergic receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstrictionU. TThEere are short-acting (SABA) and long-acting (LABA) beta2-agonists. The effect of SABAs usually needed use of SABAs improve FEV1 and symptoms.(68) LABAs show wears off duration owf iathctiTnioR4nIBtoof 6 hours.(61,62) Regular and 12 or more hours and do as- not preclude additional benefit from as-needed SABA therapy.(69) DIS OR Fstoartmuso,teexroacl earnbdatsiaolnmreatteeroalnadrenutmwibceer-doafilhyoLsApBitAalsiztahtaiotnssig,(n70if) ibcaunt thlyavimOe PnporYoevfefeFcEtVo1namndorltuanligtyvoorlurmateeso, fdydsepcnlienae,ohfelaulnthg function. Indacaterol is a once daily LABA that improves breathlesTsnCess,(71,72) health status(72) and exacerbation rate.(72) Some patients experience cough following the inhalation of inNdOacaterol. Oladaterol and vilanterol are additional once daily LABAs that improve lung function and symptoms.(7-3D,74O) Adverse effects IALS Stimulation of beta2-adrenergic receptors canTEprRoduce resting sinus tachycardia and has the potential to precipitate cardiac rhythm disturbances in susceptibMleA patients. Exaggerated somatic tremor is troublesome in some older patients treated occur, especially with higher doses when treatment iosIfGcboHemTtab2i-naegdo nists, with regardless of route o thiazide diuretics,(75) f administration. Although and oxygen consumption hypokalemia can can be increased under resting conditions in patiePnYtRs with chronic heart failure,(76) these metabolic effects decrease over time (i.e., show tachyphylaxis). Mild falls inCOpartial pressure of oxygen (PaO2) can occur after administration of both SABAs and LABAs(77) 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.(70,78,79) Antimuscarinic drugs Antimuscarinic drugs block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors expressed in airway smooth muscle.(80) Short-acting antimuscarinics (SAMAs), namely ipratropium and oxitropium, also block the inhibitory neuronal receptor M2, which potentially can cause vagally induced bronchoconstriction.(81) 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.(80) 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 56 for oral steroids.(82) 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 (glycopyrrolate).(80,83) LAMA treatments improve symptoms, including cough and sputum and health status.(80,84,85) They also improve the effectiveness of pulmonary rehabilitation(86,87) and reduce exacerbations and related hospitalizations.(84) Clinical trials have shown a greater effect on exacerbation rates for LAMA treatment (tiotropium) versus LABA treatment.(88,89) Adverse effects Inhaled anticholinergic drugs are poorly absorbed which limits the troublesome systemic effects observed with atropine.(80,90) Extensive use of this class of agents in a wide range of doses and clinical settings has shown them to be very safe. The main side effect is dryness of mouth.(81,91) Although occasional urinary symptoms have been reported, there are no data to prove a true causal relationship.(92) Some patients using ipratropium report a bitter, metallic taste. An unexpected small increase in cardiovascular events in COPD patients regularly treated with ipratropium bromide has been reported.(93,94) In a large, long-term clinical trial in COPD patients, tiotropium added to other standard therapies had no effect on cardiovascular risk.(52) Although there were some initial concerns regarding the safety of teixoatcroeprbiuamtiodnerlaivteersywvhiaenthceomRepsapriimngattio(9t5r)oinphiuamleri,ntahedrfyin-pdoinwgds eorfinahlaarlegreatnridalthoebsReersvpeidmUnaTotEdiinffhearleenr.c(9e6)inThmeroertaarleityleossr safety data available for the other LAMAs, but the rate of anti-cholinergic side effeTcRtsIBfor drugs in this class appears to be low and generally similar. Use result of the contact between the of solutions with a facemask solution and the eye.(97-99) can precipitatDe IaScute glaucoma, probably as a direct Y OR COP T NO - DO ERIALS MAT YRIGHT COP 57 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 58 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.(100-102) 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,(100) 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.(103) Addition of theophylline to salmeterol produces a greater improvement in FEV1 and breathlessness than salmeterol alone.(104,105) Earlier studies reported contradictory evidence regarding the effect of low-dose theophylline on exacerbation rates.(106,107) A study that investigated the effectiveness of adding low-dose theophylliUnTeEto ICS in COPD patients at increased risk of over a one-year exacerbatio period.(108) n showe A large d no difference placebo-contro com lled ptrairael dshwoitwhepdlancoebeoffiencttThReoIfBnourmabl etrheoof COPD exacerbatio phylline alone or ns in combination with prednisolone 5 mg daily on exacerbations of severe COPD.(1D09I)S OR Adverse Toxicity is effects dose-relate d, which is a particular pro blem with xanthine dOerPivYativ es because their therapeutic ratio is sm all and most of the benefit occurs only when near-toxic doses are T C given.(101,103) Methylxanthines are non-specific inhibitors of all phosphodiesterase enzyme subsets, which explains theiNr wOide range of toxic effects. Problems include atrial and ventricular arrhythmias (which can prove fatal) and g-raDnOd mal convulsions (which can occur irrespective of prior ethpeilethpetircahpiesutotircyr).aOngtheeorfssiedreuemffelecvteslisnoclfutdheeohpehaydlalIicAnheLe.SsT,hinessoemmneiad,icnaatuiosnesa,haanvde heartburn, and these may o significant interactions with ccur within commonly used medications such as erythromycin (but TnEoRt azithromycin), certain quinolone antibiotics (ciprofloxacin, but not ofloxacin), allopurinol, cimetidine (but MnoAt ranitidine), serotonin uptake inhibitors (fluvoxamine) and the 5- lipoxygenase inhibitor zileuton. IGHT CCoommbibniinngatbiroonncbhroodinlactohrosCdOwiPliatYhtRodriftfehreenrat pmyechanisms 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.(110,111) Combinations of SABAs and SAMAs are superior compared to either medication alone in improving FEV1 and symptoms. (112) Treatment with formoterol and tiotropium in separate inhalers has a bigger impact on FEV1 than either component alone.(113) There are numerous combinations of a LABA and LAMA in a single inhaler available (Table 3.3). These combinations improve lung function compared to placebo(110); 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.(114) 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.(115-118) 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 burden.(119) 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.(120) The LABA+LAMA combination demonstrated favorable improvements compared with the monotherapies for the majority of outcomes irrespective of baseline HRQoL.(121) These clinical trials deal with group 59 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 patients(122) (Table 3.4). These findings have been shown in people across different ethnic groups (Asian as well as European).(123) 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.(124) 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.(125) Another study in patients with a history of exacerbations showed that a combination LABA+LAMA decreased exacerbations to a greater extent than an LABA+ICS combination.(126) 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 3).(127) A large observational pharmaco-epidemiological study found similar effectiveness of LABA+LAMA and LABA+ICS but a significantly higher risk of pneumonia in those treated with LABA+ICS.(128) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Antiinflammatory agents To date, exacerbations (e.g., exacerbation rate, patients with at least one exacerbation, time-to-first exacerbation) represent the main clinically relevant end-point used for efficacy assessment of drugs with anti-inflammatory effects (Table 3.5). 60 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 61 Inhaled corticosteroids (ICS) Preliminary general considerations In vitro evidence suggests that COPD-associated inflammation has limited responsiveness to corticosteroids. Moreover, some drugs including beta2-agonists, theophylline or macrolides may partially facilitate corticosteroid sensitivity in COPD.(129,130) The clinical relevance of this effect has not yet been fully established. In vivo data suggest that the dose-response relationships and long-term (> 3 years) safety of ICS in people with COPD are unclear and require further investigation.(126) Because the effects of ICS in COPD can be modulated by the concomitant use of long-acting bronchodilators, these two therapeutic options are discussed separately. 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. (127,131) Efficacy of ICS (alone) Most studies have mortality in people found that regular treatment with ICS alone does not modify with COPD.(132) Studies and meta-analyses assessing the effect otfhreelgUouTnlagEr-tterrematmdeecnlitnwe iothf FEV1 nor ICS alone on mortality in people with COPD have not provided conclusive evidence of benTeRfitIB.(132) In the TORCH trial, a trend troecweaivrdinghipglhaecrebmooortrasliatlymwetaesroolbpselursvefldutfiocar spoanteiepnrtosptiroenaatteedcwomithbifnluattiiocans.o(1n33e)DHpIoSrwopeivoenra, taenailnocnreeacsoeminpamreodrtatolitythwosaes not observed in COPD patients treated with fluticasone furoate in the OSuRrvival in Chronic Obstructive Pulmonary Disease with Heightened Cardiovascular Risk (SUMMIT) trial.(134) In OmPoYderate COPD, fluticasone furoate alone or in combinatio on average n 9 with ml/y vilante ear.(135) rAolnwumasbaesrsoofcsiatuteddiews ihtahvseloinwveersdtiegcaltiendeOwiTnhFCeEtVhe1rctohmerpeairseadrweliathtiopnlascheipbobeotrwveileanntICerSotlrealaotnmeebnyt and risk of lung cancer with conflicting results.(136) - DO N IInCSpaitniecnotsmwbitihnmatoidoenrawteittho vloernygseavcetrienCgObPDroanncdIhAeoLxSdacilearbtoatriotnhse,raanpICyS combined with a LABA is more effective than either component alone in improving lung fTunEcRtion, health status and reducing exacerbations.(137,138) Clinical trials powered on all-cause mortality as the pMrimA ary outcome failed to demonstrate a statistically significant effect of combination therapy on survival.(133I,G134H) T Most studies that found a bePnYefRicial effect of a LABA+ICS fixed dose combination (FDC) over a LABA alone on exacerbation rate, recruitedCpOatients with a history of at least one exacerbation in the previous year.(137) 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 CATTM 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.(139) 62 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.(127,140-144) 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.(145) Data modeling indicates that ICS containing regimens have little or no effect at a blood eosinophil count < 100 cells/L,(140) therefore this threshold can be used to identify patients with a low likelihood of treatment benefit with ICS. In addition, lower blood and sputum eosinophils are associated with greater presence of proteobacteria,(146-148) notably haemophilus, and increased bacterial infections and pneumonia.(149) Lower blood eosinophil counts therefore may identify individuals with microbiome profiles associated with increased risk of clinical worsenings due to pathogenic bacterial species. The threshold of a blood eosinophil count 300 cells/L identifies the top of the continuous relationship between eosinophils and ICS, and can be used to identify patients with the greatest likelihood of treatment benefit with ICS. There is evidence that on average blood eosinophil counts are higher in COPD patients, although there is overlap with controls.(150,151) Higher blood numbers and the presence of eosinophil counts in COPD patients are associated higher levels of markers of type-2 inflammation in the awirUiwthTaEyisn.c(1r5e2a,1s53e)dThluenseg eosinophil differences in airway inflammation may explain the differential response to ICS treatmeTnRt IBaccording to blood eosinophil counts.(145) DIS The thresholds of < 100 cells/L and 300 cells/L should be regarded as eOstRimates, rather than precise cut-off values, that can predict different probabilities of treatment benefit.(145) OPY Sources of evidence include: 1) Posthoc analyses comparing LAOBAT+CICS versus LABA(140,141,143); 2) Pre-specified analyses cLoAmBAp+aLrAinMg Atr(1ip54l)eotrhseturadpyyinvgeIrCsSuswLitAhBdAra+wLAaMl.(1A55o-15r7)LAMA-(1D27O,142N,144) and, 3) other analyses comparing LABA+ICS versus The treatment effect of ICS containing regimens (LIAABLSA+LAMA+ICS and LABA+ICS vs LABA+LAMA) is higher in patients with high exacerbation risk ( 2 exacerbationTs EanRd / or 1 hospitalization in the previous year).(126,127,142) Thus, the use of blood eosinophil counts to predict ICS eMffAects should always be combined with clinical assessment of exacerbation risk (as indicated by the location) could influence pthreevrioeulastihoIGinstsHohTripy of exacerbations). between ICS effect Other factors (smoking status, ethnicity, and blood eosinophil count but remains geographical to be further explored. COPYR The repeatability of blood eosinophil counts in a large primary care population appear reasonable,(158) although greater variability is observed at higher thresholds.(159) Better reproducibility is observed at the lower thresholds (e.g., 100 cells/L).(160) All in all, therefore, blood eosinophil counts can help clinicians estimate the likelihood of a beneficial preventive response to the addition of ICS to regular bronchodilator treatment, and thus can be used as a biomarker in conjunction with clinical assessment when making decisions regarding ICS use. Cohort studies have produced differing results with regard to the ability of blood eosinophils to predict future exacerbation outcomes, with either no relationship(161) or a positive relationship reported.(162,163) 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. Greater FEV1 decline was observed in mild to moderate COPD patients with higher blood eosinophil counts in a population where ICS use was low,(164) highlighting the possible usefulness of blood eosinophil counts as a prognostic biomarker for lung function decline when not confounded by ICS use. In younger individuals without COPD, higher blood eosinophil counts are associated with increased risk of the subsequent development of COPD.(165) 63 Factors to consider when initiating ICS treatment in combination with one or two long-acting bronchodilators are shown in Figure 3.1.(166) Adverse effects There is high quality evidence from randomized controlled trials (RCTs) that ICS use modifies the airway microbiome(167) and is associated with higher prevalence of oral candidiasis, hoarse voice, skin bruising and pneumonia.(132) This excess risk has been confirmed in ICS studies using fluticasone furoate, even at low doses.(168) 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 obstruction.(169,170) Independent of ICS use, there is evidence that a blood eosinophil count < 2% increases the risk of developing pneumonia.(171) In studies of patients with moderate COPD, ICS by itself or in combination with a LABA did not increase the risk of pneumonia.(134,170) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Results from RCTs have yielded varied results regarding the risk of decreased bone density and fractures with ICS treatment, which may be due to differences in study designs and/or differences between ICS compounds.(50,168,172-174) Results of observational studies suggest that ICS treatment could also be associated with increased risk of diabetes/poor control of diabetes,(175) cataracts,(176) and mycobacterial infection.(177) An increased risk of tuberculosis has been found in both observational studies and a meta-analysis of RCTs.(178-180) In the absence of RCT data on these issues, it is not possible to draw firm conclusions.(181) ICS and lung cancer incidence is discussed in Chapter 6. 64 Withdrawal of ICS Results from withdrawal studies provide equivocal results regarding consequences of withdrawal on lung function, symptoms and exacerbations.(182-186) Some studies 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,(186) which could be associated with increased baseline circulating eosinophil numbers.(155) 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/l at baseline.(157) 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. Triple therapy (LABA+LAMA+ICS) The step up in inhaled treatment to LABA plus LAMA plus ICS (triple therapy) can occur by various approaches(187) and has been shown to improve lung function, patient reported outcomes and reduce exacerbations when compared to LAMA alone, LABA+LAMA and LABA+ICS.(127,142,144,188-195) A posthoc pooled analysis of three triple therapy clinical trials in COPD patients withIsBeUveTrEe airflow obstruction and a history inhaled of exace therapy rbations showed a no compared to non-ICS n-significant trend based treatments. for (196) lTowwoelramrgoerotanleit-yy(eaasrsrIeSasnTsedRdo as a safety outcome) with triple mized controlled trials reviewed below (named IMPACT and ETHOS) provide new evidence on mortality RreDduction with fixed-dose inhaled triple cinotmerbviennattiioonnss tcoormedpuacreedCOtoPDdumaol rbtarolitnyc'h. odilation.(197,198) These daCtOa PwYillObe discussed in the section `Therapeutic Oral glucocorticoids NOT Oral glucocorticoids have numerous side effects, inclu-dDinOg steroid myopathy(199) which can contribute to muscle wfoeratkrenaetsisn,gdaeccureteaseexdacfeurnbcatitoionnaslitiny,haonsdpirteaslipzierdatpoarIytAiefLanSitlus,reorindupreionpgleemweitrhgevnecryy dseevpearretmCeOnPtDv.isSiytss,tehmavicegbleuecnocsohrotiwconidtos reduce the rate of treatment failure, the rTaEteRof relapse and to improve lung function and breathlessness.(200) Conversely, prospective studies on the loMnAg-term effects of oral glucocorticoids in stable COPD are limited.(201,202) Tchhreorneifcordea,ilwyhtrileeaotmraelngtluincoCcOoPrtDicobeidcIsGapuHlsaTeyoaf raollaeciknotfhbeeanceuftitebmalaannacgeedmaegnatinosft eaxhaicgehrbraatteioonfs,sythsteeymhiacvceomnoplriocaletiionntsh. e PYR Phosphodiesterase4C(OPDE4) inhibitors The principal action of PDE4 inhibitors is to reduce inflammation by inhibiting the breakdown of intracellular cyclic AMP.(203) 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.(204) The effects on lung function are also seen when roflumilast is added to long-acting bronchodilators,(205) and in patients who are not controlled on fixed-dose LABA+ICS combinations.(206) The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute exacerbation.(207,208) 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.(209) 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 treatment, are reversible, and diminish over time with continued treatment. In controlled studies an average unexplained weight loss of 2 kg has 65 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 COPD(210,211) 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.(212) Later studies have shown that regular use of some antibiotics may reduce exacerbation rate.(213,214) 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.(215-217) Azithromycin use was associated with an increased incidence of bacterial resistance, prolongation of QTc interval, and impaired hearing tests.(217) A posthoc analysis suggests lesser benefit in active smokers.(208) There are no data showing the efficacy or safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one-year of treatment. Pulse therapy with exacerbations had moxifloxacin no beneficial (400 mg/day for effect on the ex 5 days every 8 weeks) in patients acerbation rate overall.(218) with cUhrToEnic bro nchitis and frequent TRIB Mucolytic (mucokinetics, mucoregulators) and antioxidant aDgIeSnts (Nacetylcysteine, carbocysteine, erdosteine) OR In COPD patients not receiving ICS, regular treatment with mucolyOtiPcsYsuch as carbocysteine and N-acetylcysteine (NAC) may erdosteine reduce exacerbations may have a significant and modestly effect on (mild) iemxapcreorvbeathieoanlOsthiTrrsCetsaptuesc.t(i2v1e9-2o22f)coInnccuornretrnatsttr, eitathmaesnbteweinthsIhCoSw. Dnutehtaot the heterogeneity of studied populations, treatment dosinOg aNnd concomitant treatments, currently available data do not allow precise identification of the potential target p-oDpulation for antioxidant agents in COPD.(223) Other drugs with potential to reduce eIxAaLcSerbations Four large phase 3 studies have investigatedTthEeRefficacy of the anti-IL-5 monoclonal antibody mepolizumab(224) and the anti-IL-5 receptor- antibody benraMlizAumab(225) in patients with severe COPD, recurrent exacerbations and peripheral blood evidence of eosinoIGphHilTic inflammation despite high intensity inhaled therapy. The studies showed a 15-20% variable reduction between instuthdeiersataenodfPsdYeoRvseerse. exacerbations but the effect was There was no effect on FEV1 not always or quality statistically significant, of life scores and no and it was consistent relationship between the reCspOonse to treatment and the peripheral blood eosinophil count. A posthoc 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. (226,227) 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.(228) An RCT of the selective 1 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 to the placebo group and hospitalization for exacerbation was more common among the patients treated 66 with metoprolol.(229) There is no evidence that beta-blockers should be used in people with COPD who do not have a cardiovascular indication for their use. Simvastatin did not prevent exacerbations in people with COPD who had no metabolic or cardiovascular indication for statin treatment.(230) An association between statin use and improved outcomes (including decreased exacerbations and mortality) has been reported in observational studies of people with COPD who received them for cardiovascular and metabolic indications.(231) There is no evidence that supplementation with vitamin D has a positive impact on exacerbations in unselected patients.(232) In a meta-analysis vitamin D supplementation reduced exacerbation rates in patients with low baseline vitamin D levels.(233) Therapeutic interventions to reduce COPD mortality COPD is the third leading cause of death worldwide, causing 3.23 million deaths in 2019. We are still learning about the mechanisms that cause death in patients with COPD. Demonstrating benefits of therapeutic modalities on mortality in populations RCTs with has been difficult, requiring a high but preventable risk olafrdgeeapthopduulraitniognfsolalonwd/-ourpl.oInngafdodlliotiwon-u, pthdeUulrToaEwtionnumanbde/roor fheigvhelnytssemleactkeeds the analysis of disease specific mortality (e.g., respiratory or cardio-vascular) in moTsRt tIBrials difficult. Table 3.6 presents a summary of pharmacological and non-pharmacological therapies with evidenDcIeSof efficacy in reducing the mortality of COPD patients. OR Pharmacological therapy OPY Previous studies such as the TORCH clinical trial(133) and the SUMTMCIT trial(234) failed to provide efficacy of a LABA+ICS combination in reducing the mortality (primary outcome) of CNOOPD patients compared to placebo. These trials had no requirement analysis, i.e., for 30 a history of previous ex days after completion acerbations. of the study Tphee-rilDoadOrg, edsitdLnA'tMdAemtroenastmtraetnet trial UPLIFT, a reduction in in the mo intention to treat rtality (secondary outcome) compared to placebo. The majority of pIAatLieSnts included in this study utilized an ICS. Recently, evidence has emerged from two larTgEe Rrandomized clinical trials, IMPACT(127) and ETHOS,(198) that fixed-dose inhaled triple combinations (LABA+LAMAM+AICS), reduce all-cause mortality compared to dual inhaled long-acting bronchodilation therapy. These trialIsGwHeTre enriched for symptomatic patients (CAT 10) with a history of frequent ( 2 moderate exacerbations) andP/oYrRsevere exacerbations ( 1 exacerbation requiring a hospital admission). Nonpharmacological tChOerapy Smoking cessation. From the Lung Health Study, a randomized clinical trial (RCT) that included asymptomatic or mildly symptomatic COPD patients treated with a 10-week smoking cessation intervention program and followed up to 14.5 years, the overall mortality rate was reduced in the smoking cessation intervention group compared to the usual care group.(235) Pulmonary rehabilitation (PR). A systematic review of RCTs reported a reduction in mortality for patients who had PR initiated during hospitalization or 4 weeks after discharge compared to those who didn't have PR.(236) These results have been corroborated by real-world evidence, from a large population-based cohort of 190,000 patients hospitalized for COPD, in whom initiation of PR within 90 days of discharge, while rare, was associated with a statistically significant reduced mortality.(237) 67 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Long term oxygen therapy (LTOT). Survival benefit of LTOT in COPD demonstrated in two studies in the early 1980s laid the foundation for long-term domiciliary management of hypoxemia. The Nocturnal Oxygen Therapy Trial (NOTT)( 19 hours of continuous oxygen compared to 13 hours)(238) and the Medical Research Council (MRC)( 15 hours compared to no oxygen),(239), two RCTs in COPD patients with resting PaO255 mmHg or < 60 mmHg with cor pulmonale or secondary polycythemia showed a survival benefit. No significant benefit of LTOT was found in patients with moderate desaturation.(240) Noninvasive positive pressure ventilation (NPPV). Recent meta-analyses(241,242) have shown positive results of long- term NPPV in patients with stable COPD. Although RCT results have being inconsistent on survival, larger trials with mortality as the primary outcome, enrolling patients with marked hypercapnia and applying higher IPAP levels demonstrated a reduction of mortality.(243,244) 68 Lung transplantation and lung volume reduction surgery (LVRS). Because of the absence of randomized trials, observational data has been used to estimate the survival benefit of lung transplantation, relative to remaining "untransplanted." The survival benefit of transplantation varied by disease group, with a 2-year expected benefit in 2/5 of transplanted COPD patients.(245) LVRS has been shown to prolong survival compared to medical therapy in a very select group of patients with severe COPD, predominantly upper lobe emphysema, and low exercise capacity.(246) Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was higher in the surgery group than in the medical-therapy group. In summary, available data suggest that several pharmacological and non-pharmacological treatments may reduce mortality. Further analyses or studies may help to determine whether specific patient subgroups demonstrate a greater survival benefit. Issues related to inhaled delivery When a treatment is given by the inhaled route, the importance of education and training in inhaler device technique cbaronnncohtobdeilatoovresr(-bemotphhsahsoizret-d.anTdhelorneg-aarcetincgu)rraenndtliynhaatleldeacsotrt3ic3osdteifrfoeirdesn(tICiSn)haalloende tohUreTirnEapcioems bcionnattaioinnisn(gTadbilfefe3re.3n)t. In addition, at least 22 different inhaler devices are available,(247) including nebuliTzeRrIsB, metered-dose inhalers (MDIs) used with or without valved holding chamber (VHC)/spacers, breath-actuatedDMISDIs (BAIs), soft mist inhalers (SMIs) aMnodrderiynfpoorwmdaetiroinnhaabloeurst (iDnhPaIsla)(t2i4o8)nIndemvuiclteis-disosaevaDilPaIbs,lethoenptohwe dAeerroissocol DntrauignOeMRdainnaagreemseernvtoIimr oprroinvienmdievnidtuTaelabmlis(tAeDrsM.(2I4T8)) and the Asthma + Lung UK websites.(249,250) OPY T C Devices differ in their size and portability. They also differ in tNhOe number of steps required to prepare them,(251) in the force needed maintenance, to as load well or as actuate them,(252) in the inspiratory inmathneoetuimvree-tDraekOqeunirteoddteolivuesre the drug, and in the need them effectively.(248) The for cleaning and number of steps reduces the ease of use and likelihood that patienIAtsLuSse the inhaler correctly.(253) There may also be quite significant differences made from, in the carbon how they are fmooatnpurfianct toufreddevaincedsTwrEehRfelethcetirntghweyhectahnebr eo r not they reused or contain a propellant gas, what they are recycled.(254) Smart inhalers incorporate sensors that detect the date and time ofMuAse, and for some inspiratory flow and inspired volume. These allow the identification of problems and feIeGdHbTack in real time(255) and can provide objective data on adherence and technique.(256,257) PYR Particles > 5 microns (m) aCreOmost likely to be deposited in the oropharynx. For drug delivery to the lower respiratory tract and lungs, particle size (mass-median aerodynamic diameter) can be fine (2-5 m) or extra-fine (< 2 m), which influences the total respirable fraction (particles < 5 m) and the amount and site of drug deposition (more peripheral deposition with extra-fine particles).(248) Inspiratory flow, flow acceleration, and inhaled volume are important factors for patients to successfully inhale drug particles from handheld devices into the lower respiratory tract.(248,258) MDIs and SMIs require a slow and deep inspiration while DPIs require forceful inspiration. Each DPI has a unique internal resistance and patients must create turbulent energy within the device during inhalation to disaggregate the powder into fine particles. Prescribers should check visually that the patient can inhale forcefully through the device and, if there is doubt, either check the inspiratory flow objectively(259,260) or switch to an MDI+/-spacer/VHC or SMI depending on drug availability and patient's characteristics. Randomized controlled trials have not identified superiority of one device/formulation and there is no evidence for superiority of nebulized therapy over hand-held devices in patients who are able to use these devices properly.(248) However, patients included in these trials are usually those who master inhalation technique and receive proper education and follow-up regarding this issue, and therefore may not be reflective of normal clinical practice. Fixed- 69 dose triple inhaled combination therapy in one inhaler may help improve health status compared to treatment using multiple inhalers.(261) Ability to use delivery system correctly Specific instructions are available for each type of device.(248-250) On average more than two thirds of patients make at least one error in using an inhalational device.(262-265) Observational studies in these patients show that, although the type and frequency of inhalation errors vary between devices depending on their characteristics, there is no device obviating the need to explain, demonstrate and regularly check inhalation technique.(266-272) The main errors in delivery device use relate to problems with inspiratory flow, inhalation duration, coordination, dose preparation, exhalation maneuver prior to inhalation and breath-holding following dose inhalation.(273) Patients' ability to use inhalers correctly is affected by their cognitive ability, manual dexterity and coordination skills, the inspiratory flow that they can achieve, the use of different types of device, and previous education on inhaler technique.(263,274) Poor inhaler technique and errors using devices are more common with advancing age,(275) but this is likely to be mainly due to cofounders such as cognitive impairment or reduced manual dexterity.(276,277) pMDIs require priming sufficient hand which needs a strength to actuate the degree of strength.(252) iPnahtaielenrt,sawnidthalpthooourgdhexBtAeIrsitayremtaryigsgterruegdgUlbeTytEionhloaaladtiaonDPthI,epyasrttiilcl urelaqrulyirief capsules require extraction from foil, insertion into the device or puncturing priorTtRoIaBdministration.(252) Tremor may result in shaking of the device and loss of the dose.(278) DIS If there is any doubt that the patient will not be able to use a pMDI correctOlyRthey should be prescribed a VHC/spacer; however, these are not a panacea and there is evidence that incorrecOt PuYse of pMDIs is more common in older patients if they 150 to use 250 a VHC.(279) Currently available mL have been shown to be as eVfHfeCcstirvaenagsetihnovsoeluwmiteOh TflarorCgmer<v5o0lutmoe7s5(2081m) aLn(2d80a) rbeumt oVrHeCpworitthabvloel.uAmsews efrlol ams reducing difficulties caused by poor co-ordination and inspOiraNtory maneuvers with pMDIs, VHCs increase pulmonary and reduce oropharyngeal deposition, which is particula-rlDy important to minimise the risk of oropharyngeal candidiasis with corticosteroid containing pMDIs.(248) ALS Leaflets included in device packages are insuffEicRieI nt to provide proper education of patients regarding inhaler use. T Other strategies and tools including physicMaAl training and use of video or web-based education have proven effective tUosiinmgprtohvee"itnehaaclhe-rbtaecckh"niaqpuperoinascohm(IpeGabHtuiTetnntostbaellinpgataiesnktesdotnothsehoswhorhto-twermth,ebudteveifcfeechtsaasptpoeabretousweadn) eaopvpeeratrismteo.(2b53e) particularly effective.(282) PharmPaYciRst-, physician-, physiotherapist- and nurse-led interventions(283) as well as lay health coaching(284) can improve inChOalation technique and adherence in COPD patients. As in asthma, digital inhalers could contribute to improve adherence and inhaler technique in patients with COPD.(285) Selection of delivery system Selecting the optimum delivery system is essential to ensure patients gain maximum benefit from inhaled therapies. The selection process should aim to identify the optimal device for each individual patient. The final choice should be made jointly by the prescriber and the patient, taking into account device attributes and the patient's abilities, goals and preferences. Shared decision making has been shown to improve outcomes for patients with asthma and is likely also to do so for patients with COPD.(286,287) If a patient is currently taking inhaled therapy and able to use their current device correctly, new therapy is best prescribed in the same device. If a new device is required, either because the patient is not using the current device correctly or the drug is not available in the same device, a systematic process should be used to select a delivery system and ensure the patient can use it. A systematic review identified several published algorithms for inhaler choice proposed by experts and consensus-based taskforces, but none was developed using strict item generation/reduction 70 methodology nor including input from patients, and none has yet been prospectively tested.(288) Factors included in the algorithms correspond to three domains: patient factors, device attributes, and health care professional factors. Adherence to inhaled COPD medications Adherence is defined as the process by which a person takes their medication as prescribed by a healthcare provider.(289) Adherence to therapy is a challenging issue in any chronic condition including COPD. Non-adherence to COPD medication has been associated with poor symptom control, increased risk of exacerbation, increased healthcare utilization and costs, decreased health-related quality of life and higher mortality risk.(290-300) Although inhaled therapy is a key component in the management of COPD, the adherence to inhaled medication is generally low, even in very severe disease. One systematic review(301) reported non-adherence rates to COPD medication of 22% to 93%, with over half of the included studies reporting non-adherence in >50% of subjects.(301) Most studies included were conducted in high-income countries and many used pharmacy claims data to assess adherence.(301) Self-reported non-adherence to COPD medication varies between 28% and 74% (mean 50.9) in high income countries(292,301,302) and between 46 However, when compared with data obtained and 93% (mean through electronic 61.7) in low- and monitoring, studies mhaiUdvTdelEeco-innsciosmteentlcyoduenmtroienss.(t3r0a3-t3e0d6) that self-reports are inaccurate as people generally over-report medication TRIB use.(307,308) DIS Adherence treatment is a complex concept, related factors.(309) Sev influenced by multiple eral studies have explo factors red the ivnacrluiadbilnegOs sRaoscsioacl/iaetnevdi ronm with ental, perso medication n related and adherence in people with COPD.(301,303) Factors such as the presence of co-morbOidPitYies, in particular depression, smoking status, schooling level, disease severity, and drug regimen factors such aTsCdosage complexity, polypharmacy and side effects of therapy, are the main factors associated with low NO adherence.(300,301,303,304,310,311) In addition, socioeconomic factors, ibnecelundisnhgouwnnemtpolonymegeanttiv, elolyw-iinnfcloumenecsetaitnuhs,ailmedmimgreadtiioc-anDtsiOotantuas,dlhiveinregnacleoneanadndtpooobremeredliactaetdiontoavatihlaebinlitoyn(3-1u2s) ehavoef medication.(310,313,314) IALS Although patient preferences may vary, preTsEcrRibing strategies that could help improve adherence often include selecting devices with a similar inhalationMteAchnique (in the case of multiple inhalers) and combination therapy. - (315) (261) IGHT Healthcare provider and caregPivYerRfactors can also contribute to perception of disease, healthcare, medication and ultimately adherence. A beCttOer understanding of the disease and drug therapy, as well as greater trust in healthcare professionals and pharmacist-led interventions have been shown to improve COPD medication adherence.(283,301) Self- management education can help a person understand their disease and the benefits of proper use of medication. Prescribing behavioral components that are tailored to the individual barriers of each person (e.g., keeping medications in one place, self-monitoring of symptoms, medication reminders, etc) is more effective in changing behavior than offering general suggestions. A study assessing interventions intended to improve adherence to pharmacological therapy showed that multi-component interventions with education, motivational or behavioral components delivered by health professionals may improve adherence.(316) Involving a person in establishing an individually tailored treatment plan has been shown to improve adherence.(317) Further research on medication adherence in COPD is needed to gain insight into the effectiveness of different self-management education and health behavior change strategies. 71 Other pharmacological treatments Other pharmacological treatments for COPD are summarized in Table 3.7. IBUTE DISTR OR Alpha1 antitrypsin augmentation therapy The logical approach to minimize the development and progressioOnPYof lung disease in AATD patients is alpha-1- antitrypsin augmentation. Such therapy has been available in manTyC, though not all, countries since the 1980s. Because AATD is rare, few clinical trials to assess efficacy with convNeOntional spirometric outcome have been undertaken. However, a wealth of observational studies suggest a-rDedOuction in spirometric progression in treated versus non- treated patients(318) and smokers with an FEV1 that this reduction is of 35-60% predicted mhaovsetIAebLfefSeecnt ive for patients with suggested as those FEV1 35-49% predicted.(319) Never or ex- most suitable for AATD augmentation therapy (Evidence B). MATER TAhAeTDa/vPaiiZlaZb) lgeencolintyicpael. RtriisaklsatnodotrheegriIsGgterHynTodtayptaeshhaavveeanlomtobseteenxecxlupsloivreeldy inbecelinnicfoalctursiaselsdalothnopuagthiepnetospwleitwhitthhteheZZZ/(nZuZl-l ogernnoutlyl/pneusllagreennootytpceosnhsiadveereedveaPntYlroRiwskeorrlelvikeelslyotfopblaesnmeafitAfArTomanaduagrme uensutaatlliyonastsheesrsaepdyf.oRreacuegnmt esntutadtieiosnhtahveeraspuyg.gOesthteedr an increased risk of developCinOg mild COPD in heterozygotes for the Z gene(320,321) although unlike ZZ neither develop COPD in the absence of smoking, so smoking cessation is thought to prevent progression and hence augmentation is not necessary or appropriate. Studies using sensitive parameters of emphysema progression determined by CT scans have provided evidence for an effect on preserving lung tissue compared to placebo.(322-324) 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.(325) 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.(325) 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.(326) Intravenous augmentation therapy has been recommended for individuals with alpha-1 antitrypsin deficiency (AATD) and an FEV1 72  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.(327) The main limitation for this therapy is very high cost and lack of availability in many countries. Antitussives The role of antitussives in people with COPD is inconclusive.(328) Vasodilators Vasodilators have not been properly assessed in COPD patients with severe/disproportionate pulmonary hypertension. Inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation- perfusion balance and is contraindicated in stable COPD.(329) Studies have shown that sildenafil does not improve the results of rehabilitation in people with COPD and moderately increases pulmonary artery pressure.(330) Tadalafil does not appear improve exercise capacity or health status in COPD patients with mild pulmonary hypertension.(331) Management of mucus hypersecretion UTE Treatment goals for patient with chronic bronchitis (CB) include: 1) reducingTtRhIeB overproduction of mucus; 2) decreasing mucus hypersecretion by reducing inflammation; 3) facilitating eliDmIiSnation of mucus by increasing ciliary transport; 4) decreasing mucus viscosity and 5) facilitating cough mechaniOsmRs. Smoking cessation can improve cough by improv injury by ing muco limiting cimiliamryunfuencmtieocnhaanndismdescrtehaastincgaguosbeleptecreslilshteynpteripnlOfalasPimaY.m(33a2t) ioSmn oaknindg cessation abnormal may decrease airway epithelial cell gene expression.(333) NOT C Mucus clearance treatments that promote mechanical - DmOovement through the airway such as oscillating positive expiratory mucus has pressure therapy may improve mucus been used in obstructive lung disease amIAnoLdbScilyizsatitciofnib.(r3o34s)isThweituhsbeeonfenfiecbiaulleizfefedchtsy.pHeortwoenvicers,ailninpeaftoier nctospwioiuths COPD, current studies are limited, and resMulAtsTaErRe inconsistent (335-339) Long-acting decrease co umguhsicnapriantiicenatnstawgiothnimstos,dIGeprHraeTtdeotmo inantly severe tiotropium and aclidinium, COPD.(340-343) Triple therapy can improve sputum with dual long acting production and bronchodilators cliofemrbeignaerddlwesitshoifnthhaelepdrestseernociedsoPmfYmaRyucbuesehffyepcetrivseecinrerteiodnu.cing exacerbations and improving lung function and quality of CO Use of mucolytics was associated with a reduction of 0.03 exacerbations per participant per month compared with placebo, that is, about 0.36 per year, or one exacerbation every three years. Very high heterogeneity was noted for this outcome, so results need to be interpreted with caution.(220) Nevertheless, in participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics may produce a small reduction in acute exacerbations and a small effect on overall quality of life.(220) Recombinant human DNase has similarly shown lack of benefit in mucopurulent patients with COPD.(344,345) New classes of mucolytics agents are being developed.(346) In a small double-blind placebo-controlled study, patients randomized to receive a CFTR potentiator icenticaftor had improvements in FEV1 and sputum bacterial colonization compared to placebo.(347) New bronchoscopic interventions have been proposed to reduce mucus hypersecretion by eliminating airway goblet cell hyperplasia and submucosal glands. Liquid nitrogen metered cryospray, rheoplasty, and targeted lung denervation are currently under evaluation.(348-351) 73 REHABILITATION, EDUCATION & SELFMANAGEMENT Pulmonary rehabilitation Pulmonary rehabilitation is defined as "a comprehensive intervention based on thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, self-management 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."(352) Pulmonary rehabilitation should be considered as part of integrated patient management, and usually includes a range of healthcare professionals to ensure optimum coverage of the many aspects involved.(353) 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.(354,355) 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.(355) Supervised exercise traininUgTEat least twice weekly is recommended, training; upper and this can include any regimen from endurance and lower limbs ideally should be included as well as twraailnkiinngg,eixnetTreRcrivsIBael; training, resistance/strength flexibility, inspiratory muscle training and neuromuscular electrical stimulation can also be incorporated. InDalIlScases the rehabilitation intervention (content, scope, frequency, and intensity) should be individualized to maOxiRmize personal functional gains.(355) When the intervention goal setting) but includes ongoing feedback (telephone the program is not supervised, it is no calls, more beifofefecetOidvPbeYaicnkimprporvoivdiendg via pedometer and progressive physical activity than a walking program with no feedback.(356) The importance of long-term behTaCvior change to improve physical functionality, and reduce the psychological impact of COPD, should be emphasiNzeOd to the patient. - DO TshhoewbnenteofitbsetothCeOmPDosptateieffnetcstifvreomthpeuralmpeountaircysrterhaIAatebLgiSlyitatotioinmaprreovcoensshidoertrnabesles (oTfabblree3a.t8h),, hanedaltrhehsatbaitluitsataionndheaxsebrceiesne tolerance.(357) Pulmonary rehabilitation is apTpErRopriate for most people with COPD; improved functional exercise ceavpidaecnitcyeainsdeshpeeacltihallryelsattreodngquinalpitaytoiefnltiTfsewMhiAathvemboedeenradteemtoonssetrvaetreeddaicsreoassse.alElvgernadpeastioefnCtsOwPDithsecvherroitnyi,cahltyhpoeurgchaptnhiec failure show benefit.(358) IGH Exercise-induced oxygen desatuPrYaRtion can be seen in a significant minority of COPD patients and has been associated with impaired quality of lifeC,Oexacerbation risk, and mortality.(359) A large RCT did not suggest clinical improvement with long term oxygen therapy for patients without resting hypoxemia but exertional desaturation.(360) During 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,(361) but most evidence was limited by low study quality. A large RCT,(362) 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.(363) 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.(364) However, a greater improvement in 6-minute walking distance (6MWD) test was observed with HFNT. A similar small trial suggested an improved walking distance.(365) The proportion of patients 74 reaching the minimal clinically important difference (MCID) in endurance time and 6MWD was also significantly higher with HFNT. Finally, there was no significant difference between the two therapies in patients' satisfaction. Further studies are needed to evaluate the efficacy of this treatment. IBUTE DISTR Y OR COP T NO - DO IALS There are limited data from large RCTs regardTinEgRthe effectiveness of pulmonary rehabilitation after hospitalization for an acute exacerbation of COPD. A systemMatAic review that included 13 RCTs reported reduced mortality, and number of of readmissions discharge.(236) aLmonogn-gteprmatieefnftescwtshoIoGnhHmaTdorptaullimtyownaerrye rehabilitation initiated during hospitalization or within 4 weeks not statistically significant, but improvements in health-related quality of life and exercise capPaYcRity appeared to be maintained for at least 12 months. These results have been corroborated by real world eCvOidence, from a large population-based cohort of more than 190,000 patients hospitalized for COPD in the US, in whom initiation of pulmonary rehabilitation within 90 days of discharge, while rare, was significantly associated with lower risk of mortality(237) and fewer rehospitalizations at one year.(366) One study has reported that initiating pulmonary rehabilitation before the patient's discharge may compromise survival through unknown mechanisms.(367) Pulmonary rehabilitation ranks as one of the most cost-effective treatment strategies.(353) 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.(368) Another challenge is encouraging sustained long-term physical activity. Although the approach may need to be personalized, behavioral lifestyle physical activity intervention has shown promising results i.e., the potential to decrease sedentarity and increase physical activity in patients with moderate to severe COPD.(369) 75 A major barrier to full participation is access, which is particularly limited by geography, culture, finances, transport and other logistics.(352,370-372) Pulmonary rehabilitation can be conducted at a range of sites.(352) Community-based and home-based programs have been shown to be as effective as hospital-based programs in randomized controlled trials,(373,374) as long as the frequency and intensity are equivalent.(375) In countries where there is economic limitation or those with challenges because patients live in rural or remote regions, home-based programs that deliver exercise training using a stationary bicycle(373) or a walking program(374) could be considered as alternative to traditional hospital rehabilitation training programs. There is also evidence that standardized home-based pulmonary rehabilitation programs improve dyspnea in COPD patients.(376) However, in real life, traditional pulmonary rehabilitation with supervision remains the standard of care and first-line option, with home-based exercise likely to be a less effective alternative for people with COPD who are unable to attend pulmonary rehabilitation.(377) Another challenge is that the benefits of rehabilitation tend to wane over time. There is insufficient evidence, with conflicting research findings in the 11 available RCTs, to recommend continuation of lower intensity or lower frequency exercise programs with the aim of maintaining benefit long-term. However, if such programs are available they should target health behavior taking into account the pdaetpireensts'sioonwsynmppretofemres.n(3c7e9)s, needs and personal goals.(355,378) Pulmonary rehabilitatioBnUmTaEy help reduce anxiety and Telerehabilitation TRI DIS In- or out-patient pulmonary outcomes.(357,380) There is clear rehabilitation evidence that (PR) core in co COPD is effectiv mponents of PR eOinRcinludimingpreoxveinrgcisseevtrearianlincglinciocmallbyinreedlewvaitnht disease-specific education and self-management interventions(352,357O) cPaYn benefit almost every COPD patient.(381-383) T C However, there are many challenges encountered in the deNlivOery of PR, which include systemic barriers integral to some health that do exist ctaernedstyostbeemlsocleaatdedingintuorabascnaarcreitayso. fHienn-pceeras-otDtneOnPdRinpgroPgRraims cshaanlldenfagciniligtifeosr. In many regions, the many COPD patients. programs Even for tshtiollsbeepaatciheanltlsenregsei.ding in urban areas, availabiEliRtyIAoLf Sfrequent transportation that is required for out-patient PR may Tele-rehabilitation has been proposed asMaAnTalternative to the traditional approaches. This has become even more relevant in the COVID-19 pandemicIGerHaTwhere in-person PR has not been feasible, and models of delivery had to be aareddvaaippettwee.dd(3.8m4H)oodweelsv.eMr,oitstisoifmthpCeoOratPvaanYitlRatboledeisvtiidnegnucisehrbeegtawrdeienng teevlied-erenhcea-bbilaitsaetdiotnelhea-rsebheaebniliatnatailoynzemdoindealsreacnedntpCaoncdhermanice- Across multiple trials performed in groups and individuals with a large variety of tele-rehabilitation delivery platforms (videoconferencing, telephone only, website with telephone support, mobile application with feedback, centralized "hub" for people to come together), the reported results suggest that telerehabilitation is safe and has similar benefits to those of center-based PR across a range of outcomes. The evidence-based models from the Cochrane review were published before the COVID-19 pandemic, and have all included an in-person exercise test at the center prior to commencement, for the purposes of assessing the full extent of desaturation during exercise training(385) and accurately prescribing exercise capacity.(386) In the field of tele-rehabilitation, the evidence base is still evolving and best practices are not yet established at this time due to a lack of: i) standardization of delivery platform, e.g., no one single best mode of tele-rehabilitation delivery; ii) tests performed remotely allowing for accurate exercise prescription; iii) information on suitable variations in components and timing of interventions (e.g., no data are available regarding post-exacerbation rehabilitation); and iv) evidence about duration of benefit (beyond immediate post PR). Furthermore, it is unclear what types of patients 76 were recruited to these studies or their level of familiarity with the technology used. In order to ensure that PR is accessible to all, we must understand the barriers that might be unique to tele-rehabilitation. Education, selfmanagement and integrative care 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. Selfmanagement A Delphi process has resulted in a conceptual definition for COPD self-managementUiTnEterventions: "A COPD self- management engaging and siunpteprovretnintigotnheispsattriuecnttusrteodpbousittivpeelrysoadnaapliztetdheairnhdeaolftthenbemhauvltioi-rc(osm) aTpnRodnIBdeenvt,elwopithskigllosatlos of motivating, better manage their disease."(387) The process requires iterative interactions between patientDs IaSnd healthcare professionals who are competent in delivering self-management interventions. Behavior chanOgRe techniques are used to elicit patient motivation, confidence and competence. Literacy sensitive approachOePs Yare used to enhance comprehensibility.(387) Systematic reviews have provided evidence that self-managemeTntCinterventions improve outcomes in COPD. A 2022 Cochrane review reported that interventions for people withNOCOPD are associated with improvements in HRQoL, a lower probability of respiratory-related hospital admissi-oDnsO, and no excess respiratory-related and all-cause mortality risks.(388) This strengthens the view previously been concerns that health btehnatefsiteslff-rmomaIAnsaLegSlef-mmeanntaginetmeervnetnptrioongrsamarse unlikely to cause harm. There had in COPD could be counterbalanced by increased mortality.(389,390) However, a previoTuEsRCochrane review and another meta-analysis reported no impact of self-management interventions on overalMl mAortality, and while the Cochrane review did find a small, but statistically sciagrnei,fitchaenta,uhtihgohresrorfetshpeiraretovrieyw-resltaatteIeGddHmtThoertraelistuyltrsatsehoinultdhbeeseinlft-emrparneatgeedmweintht invention group as compared caution as misclassification in to usual cause of death the ov is common, the overall erall analysis. Furtherm oePrfefYe, Rtcwt wo ainsddeopmenindaetnetd, by two studies, and no effect on all-cause mortality was seen in well designed studies, the COMET(391) and the PIC-COPD,(392) have shown the potential for reduCcOtion in mortality from integrated case management with self-management interventions. The program in these two studies may have promoted earlier appropriate treatment for exacerbations, which could have prevented some fatal complications. These data, in conjunction with the most recently published Cochrane review, once again strengthens the view that self-management interventions are unlikely to cause harm.(388) An RCT has shown that implementation of a comprehensive 3-month program to improve long-term self-management of patients recently discharged from hospital with COPD exacerbation resulted in nearly two-fold higher rates of COPD- related hospitalizations and emergency visits over 6 months. These data suggest that self-management strategies in recently hospitalized patients may lead to increased health care service utilization compared with usual care.(393) There remain problems with heterogeneity among interventions, consistency of their application, specifics of the intervention, patient populations, follow-up times and outcome measures that make generalization difficult in real life. It is also challenging to formulate clear recommendations regarding the most effective form and content of a self- management intervention in COPD given the range of heterogeneity across studies, and lack of precise definitions of self-management components (e.g., skills taught) and fidelity measures. The recent conceptual definition should help 77 redress these deficiencies. For example, in the definition it is mentioned that: "The process requires iterative interactions between patients and healthcare professionals who are competent in delivering self-management interventions." Having proper health coaching is important to improve self-management abilities. In people with COPD admitted for an exacerbation, a study has reported the positive effect of health coaching, commencing at the time of hospital discharge, on reducing risk of re-hospitalization and emergency department visits.(394) Furthermore, 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.(395) 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 52 studies shows that integrated disease management probably results in improvement in disease-specific quality of life, exercise capacity, hospital admissions, and hospital days, although not mortality.(396) In contrast, a large multicenter study in primary care within SUPPORTIVE, PALLIATIVE, ENDOFLIFE & HOSPICE CARE an existing well-organized telemedicine did not show system of care did not a significant effect.(398,399) confirm this.(397) Besides, The pragmatic conclusion idsetlhivaetrwineUgllTionErtgeagnraizteedd interventio care is impo ns by rtant, but there may be no advantage in structuring it tightly into a formalized program. FTuRrItBhermore, integrated care needs to be individualized to the stage of the person's illness and health literacy. DIS Y OR COP T Symptom control and palliative care NO Palliative care is a broad term that encompasses approa-cDhOes to symptom control as well as management of terminal patients close to death. The goal of palliative careIiAs LtoSprevent and relieve suffering, and to support the best possible quality of COPD is a hliifgehflyorsypmatpietonmtsaatincddtisheeairsefaamndiliheas,sTrmEeRgaanrydelelesms oefnttshesuscthagaes of disease or the fatigue, dyspnea, need for other therapies.(400) depression, anxiety, insomnia that require symptom-based palliative treMatAments. There is evidence that people with COPD are less likely to receive such services treatment to compared to increase the patients focus on IwtGhiHethTglouanlgs cancer.(401,402) of enhancing Palliative quality of care life, expands traditional disease-model medical optimizing function, helping with decision- making about end-of-life careP, YaRnd providing emotional and spiritual support to patients and their families.(400) Palliative approaches are esCsOential 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.(403) 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 with advanced lung cancer.(402) Therapy relevant to all people with COPD Even when receiving optimal medical therapy many people with COPD continue to experience distressing breathlessness, impaired exercise capacity, fatigue, and suffer panic, anxiety and depression.(372) Some of these symptoms can be improved by wider use of palliative therapies that in the past have often been restricted to end-of- life situations. Palliative treatment of dyspnea Relieving dyspnea during daily life activities to limit disability, improve quality of life, and reduce medical resource use is a major goal of COPD care. Multiple therapeutic approaches can be considered to target the variety of involved 78 mechanisms; they are dominated by inhaled bronchodilators, self-management education (where patients learn breathing techniques) and pulmonary rehabilitation that includes exercise training. The roles of oxygen therapy, high- flow nasal therapy and non-invasive ventilation for palliation of dyspnea are debated.(404) Opiates,(405-407) neuromuscular electrical stimulation (NMES),(407,408) chest wall vibration (CWV)(407) and fans blowing air onto the face(407,409,410) can relieve breathlessness. Morphine improved health status in COPD patients.(411) Immediate- release morphine extended exercise endurance time in over half of patients with advanced COPD, although further research is required to determine what patient characteristics predict response.(412) The optimal formulation and administration route remain under discussion.(407,413) Oxygen may offer some benefit even if the patient is not hypoxemic (Sp02 > 92%).(414) Pulmonary rehabilitation is effective and in severe cases non-invasive ventilation can also reduce daytime breathlessness. Acupuncture and acupressure are other non-pharmacological approaches in patients with advanced COPD that may improve breathlessness and quality of life.(415) Refractory dyspnea may be more effectively managed with a multidisciplinary integrated palliative and respiratory care service.(416) There is no evidence for a beneficial effect of benzodiazepines(417) and there is notUeTnEough data to recommend distractive auditory stimuli or psychotherapy.(418) (music), relaxation, counseling and support, with or wiTthRoIuBt breathing relaxation training, DIS Nutritional support OR Low BMI and particularly low fat free mass is associated with OwPoYrse outcomes in people with COPD.(419) In malnourished peo improvements in prelespwiritahtoCrOyPmD,unsculteritsitorneanlgstuhpapnledmoevnetraatlilohnepaOrlotThmC-roetleastesidgnqifuiacalintyt weight gain and leads to significant of life.(420) Nutritional antioxidant supplementation (vitamin C and E, zinc, and selenium) haOs bNeen shown to improve antioxidant deficits, quadriceps strength, and serum total protein, without further im-prDovement in quadriceps endurance. Only in malnourished patients has nutritio muscle strength and nal supplementatio health status.(421) A n 1 2d-emmoonnthsItArnauLttSerditisoignnailfiincatenrtviemnptiroonveinmmenutssclfeowr 6a-smteidnuptaetiwenatlks test, respiratory had no effect on physical capacity but physical activity was signTiEficRantly higher.(422) MA PThaenciacu, saensxoifedteyp&resdseiopnraensdsiaonnxietIyGsHyTmptoms in people with COPD are multifactorial and include behavioral, social and biological factors.(423) PPulYmRonary rehabilitation may help reduce anxiety symptoms. The efficacy of antidepressants in people CwOith 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.(424) Fatigue Fatigue in people with COPD can be improved by self-management education, pulmonary rehabilitation, nutritional support and mind-body interventions.(425) Endoflife 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.(426) Although mortality rates following hospitalization for an acute exacerbation of COPD are declining,(427) reported rates still vary from 23%(428) to 80%.(429) Progressive respiratory failure, cardiovascular diseases, malignancies and other diseases are the primary cause of death in people with COPD hospitalized for an exacerbation.(429) In qualitative studies, as well as 79 describing the high symptom burden, people with COPD and their families describe a need for a better understanding of their condition and the psychological impact of living and dying with COPD.(430) Palliative care is a broad term that includes approaches to symptom control as well as management of terminal patients close to death. Palliative care, end-of-life care, and hospice care are important components of the care of patients with advanced COPD. End-of-life care should also include discussions with patients and their families about their views on resuscitation, advance directives and place of death preferences.(431) At an individual level, prediction of 6-month survival in people with COPD is unreliable and therefore early discussion of these issues is important together with phased introduction of supportive care.(432) Hospitalization may be a trigger to initiate discussion of advance care planning. Patients and their families live with uncertainty about the timing of death and fear of death will result from worsening dyspnea and suffocation.(433) Good advance care planning can reduce anxiety for patients and their families by talking about death and dying and offering emotional support. It can also ensure that care is consistent with their wishes and avoids unnecessary, unwanted and costly invasive approaches.(434,435) For patients with very advanced or terminal illness, hospice services may provide additional benefit. Hospice services often home focus on patients with severe disability or symptom burden or in hospice beds in dedicated hospice units or other ainndstmituatyiopnrsovsiudcehthaessehTsoEesrpviitcaelss within the patient's or nursing homes. Organizations such as the National Hospice and Palliative Care Organization(436) provRidIeBgUuidance for selecting patients wreistphonnosniv-ecatnocebrrodniscehaosdeislalitkoersCOanPdD pforor garcecsessisotnoohfoasdpvicaensceerdvidceisse(afsoer edxeammopnlsetD,rdaISitseTadblbinygindcyrsepanseinagathroessptittahlaiztaitsiopnosorolyr emergency department visits).(401,402) These guidelines discuss the difficultOieRs in accurately predicting the prognosis of ppaattiieennttss.(w40i0t)hKeaydpvaoninctesdfoCrOpPaDll,iabtiuvte,reecnodg-onfiz-leifethaendaphporsoppicrieatceanreesinsCOoCfOPpPYrDoavrideinsugmhmosapriiczeedseinrvTicaebslefo3r.9s.ome of these NOT - DO ERIALS MAT YRIGHT COP 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.(437) 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.(438) Breathlessness may be 80 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).(438-440) There are contradictory studies although the majority do not demonstrate changes.(362) Although air travel is safe for most patients with chronic respiratory failure who are on long-term oxygen therapy,(441) patients should ideally maintain an in-flight PaO2 of at least 6.7 kPa (50 mmHg). Studies indicate that this can be achieved in those with moderate to severe hypoxemia at sea level by supplementary oxygen at 3 liters/min by nasal cannula or 31% by Venturi facemask.(442) Those with a resting oxygen saturation > 95% and 6-minute walk oxygen saturation > 84% may travel without further assessment,(443) although it is important to emphasize that resting oxygenation at sea level does not exclude the development of severe hypoxemia when travelling by air.(441) Careful consideration should be given to any comorbidity that may impair oxygen delivery to tissues (e.g., cardiac impairment, anemia). Also, walking along the aisle may profoundly aggravate hypoxemia.(444) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Ventilatory Support During exacerbations of COPD Noninvasive ventilation (NIV) in the form of noninvasive positive pressure ventilation (NPPV) is the standard of care for decreasing morbidity and mortality in patients hospitalized with an exacerbation of COPD and acute respiratory failure(241,445-447)(see also Chapter 5). Stable patient 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.(448) 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.(449) A multicenter 81 prospective RCT of COPD patients 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.(449) Results showed that adding home NIV to oxygen therapy significantly prolonged the time to readmission or death within 12 months.(449) 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.(241) Two previous retrospective studies(450,451) and two of three RCTs(243,449,452-454) 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.(243) Several factors may account for discrepancies: differences in patient selection, underpowered studies, NPPV settings incapable of achieving adequate ventilation, and poor adherence with NPPV therapy.(455) NPPV when indicated should be instituted and monitored under the direction of personnel familiar with the process and the devices utilized.(456,457) 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.(448) INTERVENTIONAL & SURGICAL THERAPIES FOR COPD IBUTE ISTR COPD is associated with airway and lung parenchyma structural changeDs that provide potential targets for interventional and surgical treatments to alleviate dyspnea, reduce couOgRh and mucous production, and improve quality of life (Figure 3.2). COPY NOT - DO ERIALS MAT YRIGHT COP 82 Lung structural related therapies for COPD include airway and emphysematous predominant treatments. Phenotyping patients with clinical, physiological, and imaging tests is critical to select appropriate candidates and in assessing the benefits, timing, and type of intervention to be performed. Multidisciplinary collaboration of pulmonology, thoracic surgery and imaging disciplines are necessary to ensure quality outcomes. Airway predominant treatments are currently the subject of Phase III clinical trials; emphysematous based treatments include bullectomy, lung volume reduction surgery, bronchoscopic lung reduction and in select cases, lung transplantation. Each of these therapies are reviewed below. Surgical and interventional treatments for patients with emphysema depends upon the severity of patient symptoms despite optimized medical treatment, the specific structural abnormalities and features of the lung seen on CT imaging, the presence of pulmonary and non-pulmonary comorbid conditions, physiological assessment, and the balance of benefits and risks for the individual patient. Lung surgical treatments for patients with emphysema TE Bullectomy Giant bullectomy is a rare, but effective procedure for surgical resection of bulRlaIBthUat occupies > one-third of a hemithorax and compresses adjacent viable lung tissue. Reductions in dyspneaD, aISnTd improvements in lung, respiratory muscle, and cardiac performance, as well as exercise tolerance have ObeRen reported. (458-460) Blood or thrombin instillation may be effective in those unfit for resection.(461-463) PY Lung volume reduction surgery (LVRS) T CO Lung hyperinflation is a major contributor to impaired rNesOpiratory function and is associated with increased hospitalization and mortality. Hyperinflation increases - tDhOe sensation of breathlessness and causes a reduction in eisxmerocsistepdrouneotuonicnecdreianstehdocsheepsattwieanltl sewlasitthanCcOePaDntdIhAraeLtdShuacveedarnesepmirpahtoyrsyemmautsoculesapnreddcoamrdiinaacnmt pechheannoitcysp. eH.yperinflation TER With LVRS, the most emphysematous poMrtiAons of the lungs are resected to reduce hyperinflation,(464) and increase leuxnpgiraetlaosrtyicflorewcoainl dpcrehsessutrweaalln,dredspeniIrGsaitHtoyT.r(y46m5) uTshcelesatrnudcctuarradliacchmanegcehsanthicast.(4r6e6s,4u67lt) from LVRS that results can significantly in improvements improve in FEV1, walking distance and Emphysema Treatment qTuriaallit(yNPEoTYfTR)li,fae.R(4C68T-4t7h1)atLVinRcSludcaend be performed unilaterally or bilaterally. severe emphysema patients, bilateral LVRS In the National improved survival in patients with upper-lobeCemOphysema and low post-rehabilitation exercise capacity.(246) In similar patients with high post-pulmonary rehabilitation exercise capacity, no difference in survival was noted after LVRS, although health status and exercise capacity improved. A reinterpretation of the NETT data at 5 years post treatment showed sustained improvements in lung function, exercise, shortness of breath and quality of life.(472) LVRS has been demonstrated to result in higher mortality than medical management in severe emphysema patients with FEV1 20% predicted and either homogeneous emphysema on high resolution computed tomography or a DLco 20% of predicted.(473) In addition to a lower DLco, a lower FEV1 and BMI have also been reported to increase mortality.(474) Postoperative BODE (body mass index, degree of airflow obstruction, level of dyspnea and exercise capacity) is a predictor of survival following LVRS.(475) Successful outcomes with LVRS have been reported in select patients with severely impaired DLco when hyperinflation is severe, and associated with approachable emphysematous targets for resection.(476) Identification of target zones using three-dimensional computed tomographic imaging is beneficial in selecting resectable target zones. (477) A prospective economic analysis in NETT indicated that LVRS is costly relative to healthcare programs that do not include surgery.(478) 83 Post NETT, experienced centers have reported substantial physiological and functional improvements with LVRS with reduced morbidity and mortality.(479,480) However, the numbers of patients undergoing LVRS remains low worldwide.(480,481) Several patient factors such as difficulty in obtaining referrals, the perception of increased surgical complications, and limited continuity of care are reasons why the numbers of patients undergoing LVRS remain low despite its reported benefits.(482) Additionally, respiratory physicians are reluctant to refer patients for LVRS because of the uncertainty about the associated complications, or lack of access to a multidisciplinary team to discuss patient candidates.(483) To achieve successful outcomes, a multidisciplinary team is key to select potential LVRS patients and coordinate postoperative care.(484) Lung transplantation Over 1,000 patients with COPD undergo lung transplantation on an annual basis, about 30.6% of all patients that undergo transplantation.(485) Since implementation of the lung allocation severity (LAS) scoring system, the numbers of patients undergoing lung transplantation for COPD is exceeded by the numbers of patients receiving transplantation for interstitial lung diseases. Patients with COPD should be referred for consideration of lung transplantation when they have progressive disease despite maximal medical treatment, are not candidates for lung volume reduction surgery, have a They should be BODE index considered of fo 5 r to 6, a listing PaCO2 > for lung 50 mmHg (6.6 transplantatio kPa) and/or n when the PaO2 < 60 m BODE index misUH>Tg7E(,8FkEPVa1) and is < FEV1 15 to < 25%.(486) 20%, and they have had three or more severe exacerbations during the previous year, one seTveRrIeBexacerbation with hypercapnic respiratory failure, or have moderate to been increasingly performed in patients soefvoelrdeerpualgme,onhiagrhyehryBpMerIt,epnrsiioornc.(h48e6s)DtInsISutrhgeerlays,tpdoeocranduet,rliutinognatrl asntastpulasn, tprhioasr evidence of chronic infection, cardiovascular disease, or extrapulmonary cOomR orbid conditions.(487) OPY LnuontgatnrainncsrpelaansetaitniosnuirnvipvaatlieenxctsepwtitfhorCOCOPDPDhapsabtieeenntspwreidthomseinvOaetrTeelCyAaAsTsDocoiarttehdowseithseavnerimelypriomvpeamireendt winitqhuahliigtyhoBfOliDfeE, scores.(458,488-494) The median survival post lung transplantatOioNn for COPD is 5.9 years.(485) Over 70% of lung transplants conducted in COPD patients are double lung transplant-s;Dthe remainder are single lung transplants.(495) Bilateral lung transplantation leads to longer survival in patientsAwLitSh COPD especially in those < 60 years of age.(496,497) Two unique native lung complications haveERbIeen proposed to account for the superiority of double lung T transplantation in patients with COPD, natMivAe lung hyperinflation and lung cancer occurrence in the native lung.(498,499) Lung cancer has 5.2-6.1%.(498,500) NbeaetinverelupnogrtheydpteorionIcGflcaHutriToinn the native lung following single following single lung lung transplantation transplantation with an incidence of for COPD has been reported to occur 1co5u-3p0le%dowfitthheretdimuece.(d501c,5o0m2) pPCloiOasniPtciYveeRinpraensseudreemvaetnotuilsatailolongirnafat pmaatyiernetswulitthinCnOaPtiDvewluitnhgahnyopveerirnlyflactoimonp.liHaonwt neavetirv,esolumneg studies have shown no impact of single lung transplant on post-transplant morbidity, and even improved survival following single lung transplantation in patients with COPD.(501,503,504) In general, lung transplantation has limited availability due to the shortage of donor organs and cost, thus single vs. double lung transplantation is balanced between individual patient factors vs. societal demands to increase the donor pool for eligible recipients.(505) The complications most seen in COPD patients after lung transplantation are acute rejection, bronchiolitis obliterans, opportunistic infections and lymphoproliferative disease.(506) Bronchoscopic interventions in COPD 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.(507) These include a variety of different bronchoscopic procedures to perform lung volume reduction (i.e., endoscopic lung volume reduction, ELVR) including airway bypass stents, endobronchial one-way valves (EBV) , self-activating coils, sealants and thermal ablative techniques.(507) Bronchoscopic techniques depend 84 upon the presence of an intact fissure between the treated and non-treated lobe for EBV to be successful, but not for the other techniques. 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. Endobronchial oneway valves (EBV) EBV are the most well studied therapy of all the ELVR techniques. RCTs showed significant increases in FEV1 and 6- minute walk distance as well as health status in subjects selected for the absence of interlobar collateral ventilation compared to the control group at 6 and 12 months.(508,509) Adverse effects in the endobronchial valve treatment group in both studies included pneumothorax, valve removal or valve replacement.(508) Pneumothorax was seen in 26.6% of subjects treated with the endobronchial valve usually within the first 72 hours of the procedure (76%).(509-511) But benefits have also been shown in patients with heterogeneous compared to those with homogenous emphysema in one study.(508) Early-onset pneumothorax in the EBV treated group likely results from lung structural 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 collateral ventilation.(512) Pleural oafdshuecscieosnssfulmtaarygeatlsloobebeoccaluscioonntirnibpuatitniegntfsacwtoitrhUitTnoEtactthefissduerveeslooprmaebnsetncoef of a pneumothorax.(513) The occurrence of pneumothorax highlights the need for physTicRiaInBs performing this procedure to have expertise in the management of procedural complications.(512) DIS After the post-procedural period however, patients treated with EBV comOpRared to usual care tend to have a lower number of exacerbations and episodes of respiratory failure. A comOpaPrYison of treatment benefits and complications acossmopcilaictaetdiownist.h(50E9B) VAdcodmitipoanraelldy,toELLVVRRShsahsoswimcoilamrpbaeranbelfeicbiaelneeffOfietTsctwCsitwhheentdhoebr riotnischpiaelrvfoarlvmeetdreiantmtheentubpuptewr iothr fewer lower lobes.(509,512) - DO N Improved survival survival has also bheaesnbereenpoarstseodciaintepdawtiietnhtpsowstitphIrAosLceSevdeureralhaytpeelericntfalasitsioonf the treated lobe post EBV.(514-516) undergoing EBV compared to a Improved matched population not undergoing ELVR.(517) MATER When treatm preferences for ents with EBV ov m er edical LVRS o rtrceoIaGnttmHinTeunetdfmoredpiaatliethnetsrawpyit.(h518s)eEvLeVrRe emphysema are elicited, the m with EBV is clinically available and ajority chose approved for tvreenattimlateinotn.(5in09,51m9,5a2n0)y counCtrOiePsYRin the treatment of patients who have intact fissures or lack collateral The following bronchoscopic lung volume reduction techniques do not depend upon the presence of intact fissures or absence of collateral ventilation. Airway bypass stents Airway bypass stents are transbronchial passages that are created through the walls of the central airways into the emphysematous parenchyma to facilitate the emptying of trapped gas. In a prospective randomized controlled clinical trial, patients had short term improvements, but no durable improvements were found in lung function, 6 MWD or quality of life.(521) Sealants A multicenter study examining the effects of a lung sealant to create lung reduction was discontinued prematurely; while the study reported significant benefits in some physiologic parameters, the intervention was associated with significant morbidity and mortality.(522) 85 Vapor ablation In a prospective RCT, targeted thermal vapour ablation of more diseased emphysematous segments to produce fibrosis and atelectasis 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.(523,524) This therapy has limited clinical availability. Selfactivating coils 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. Studies reported an increase in 6-minute walk distance with coil treatment compared to control and smaller improvements in FEV1, and quality of life measured by St George's Respiratory Questionnaire.(525-527) Patients with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease are more likely to have clinically meaningful improvements in lung function and quality of life.(528) Major complications included pneumonia, pneumothorax, hemoptysis and COPD exacerbations occurring more frequently in the coil group.(526) This therapy has limited clinical availability. UTE Additional data are needed to define the optimal bronchoscopic lung volume teTchRnIBique to produce bronchoscopic lung volume reduction in patients who lack fissure integrity, or exhibit coDllIaSteral ventilation, and to refine the procedure to reduce complications and improve longer term clinical outcoOmRes.(526) Sequential performance of LVRS or ELVR prior to or followOiPnYg lung transplantation Because COPD is a progressive disease, LVRS or ELVR may be foTlloCwed by lung transplantation. Conversely, patients who undergo single lung transplantation may subsequently NunOdergo LVRS or ELVR to treat the hyperinflated native ltuhneg.nIneehdypfeorrinflulantgedtpraantisepnltasnwtaittihoandvoarncoepdtiemmizpehytsheem- acDo,OLnVdRitSioonr EoLfVRpamtiigehnttsbewehffoecmtivaeytreevaetnmteunatllsytoreeqituhierer dleulnagy transplantation.(529-531) In some patients followingIAsLinSgle lung transplantation, the performance of LVRS or ELVR to dpeocsrtoeapseerantiavteivbeleleudnignghryepqeuriinrifnlagtiroen-emxpaloyraimtiTopEnroRavnedlurenngalfudnycstfiuonnctaionnd performance status.(532-537) requiring dialysis or the use The incidence of of extracorporeal membrane oxygenation (ECMO) may be MhiAgher in patients undergoing lung transplantation following LVRS.(538,539) Previous ELVR has been reported toIhGaHveT no impact on morbidity or survival post subsequent lung transplantation but may affect microbial colonizatioPnY.R(539,540) Airway predominant trCeOatments Abnormalities that predominantly involve the airways, such as excessive dynamic collapse of the large airways (tracheobronchomalacia) chronic bronchitis and frequent and severe exacerbations not responsive to optimal medical treatment pose significant clinical challenges. Excessive dynamic airway collapse (EDAC) EDAC or tracheobronchomalacia (TBM) is a disorder of the large airways where abnormal collapsibility occurs with expiration. Commons symptoms are dyspnea, cough and wheezing with inability to expectorate phlegm. In a cross- sectional analysis of smokers the presence of excessive dynamic airway collapse observed on CT imaging was 5% and associated with worsened quality of life and more frequent and severe exacerbations.(541) Airway stenting and tracheoplasty may be beneficial in select patients.(542,543) Chronic bronchitis is a common and significant contributor to a worsening of patient's symptoms of cough and sputum production and cause worsened quality of life and increased mortality. No specific medical intervention significantly and consistently alleviates chronic bronchitis. Newer interventions have been proposed to reduce mucous 86 hypersecretion by eliminating airway goblet cell hyperplasia and submucosal glands. Nitrogen cryospray Liquid nitrogen metered cryospray is delivered to the central airways and ablates the epithelium to a depth of 0.1 to 0.5 mm.(348)After treatment, rapid regeneration of normal epithelium occurs without scarring and may potentially treat chronic bronchitis.(544) Another novel treatment for chronic bronchitis is rheoplasty.(545) Rheoplasty delivers short bursts of high frequency electrical energy to the airway epithelium targeting submucosal tissues and goblet cells to facilitate their replacement with healthier tissue. Ongoing phase III randomized clinical trials are evaluating the efficacy of these therapies.(546,547) Lung denervation Targeted lung denervation is another therapy currently undergoing phase III clinical trial study to determine its impact of frequent moderate or severe exacerbations in patients with COPD already on maximal inhaled respiratory treatment.(548,549) The therapy intends to disrupt the parasympathetic nerve transmission to and from the lungs. In patients with COPD, basal and airway contraction. parasympathetic tone The treatment uses is a ewleavtaetre-cdoaonleddinccartehaesteesracweittyhlchraodliinoeUfrlTeeqEvueelsnacnydemnuercguys parasympathetic nerve transmission while protecting the airway TRIB surface.(350,351,549,550) DIS Key points for interventional therapy in stable COPD are summarized in TaObRle 3.11. COPY NOT - DO ERIALS MAT YRIGHT COP production to disrupt 87 REFERENCES 1. Montes de Oca M. Smoking Cessation/Vaccinations. 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Permutt S. Lung voIluGmHeTreduction surgery and airflow limitation. Am J Respir Crit Care Med 1998; 157(3 Pt 446790.. dWGiesadesadhsekesoeDGx,RaDc,aeFvrabineasVtiMSo,n,RsKCa.oOmAymasPemYJyaRRSHeDs,,peeitrt aCalrl..itETfChfaeerceetfoMfefceltudno2gf0-l0uvo8nl;gu1mv7o7elu(-2rme):de1ur6ce4tdi-ou9nc. tsiounrgseurrygienrypaotniecnhtrsowniitchosbesvterurecteivmepphuylsmeomnaa.rNy Engl J Med 2000; 343(4): 239-45. 471. van Geffen WH, Slebos DJ, Herth FJ, Kemp SV, Weder W, Shah PL. Surgical and endoscopic interventions that reduce lung volume for emphysema: a systemic review and meta-analysis. Lancet Respir Med 2019; 7(4): 313-24. 472. Lim E, Sousa I, Shah PL, Diggle P, Goldstraw P. Lung Volume Reduction Surgery: Reinterpreted With Longitudinal Data Analyses Methodology. Ann Thorac Surg 2020; 109(5): 1496-501. 473. National Emphysema Treatment Trial Research Group, Fishman A, Fessler H, et al. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001; 345(15): 1075-83. 474. Greening NJ, Vaughan P, Oey I, et al. Individualised risk in patients undergoing lung volume reduction surgery: the Glenfield BFG score. Eur Respir J 2017; 49(6). 475. Imfeld S, Bloch KE, Weder W, Russi EW. The BODE index after lung volume reduction surgery correlates with survival. Chest 2006; 129(4): 873-8. 476. Caviezel C, Schaffter N, Schneiter D, et al. Outcome After Lung Volume Reduction Surgery in Patients With Severely Impaired Diffusion Capacity. Ann Thorac Surg 2018; 105(2): 379-85. 477. Caviezel C, Froehlich T, Schneiter D, et al. Identification of target zones for lung volume reduction surgery using three- dimensional computed tomography rendering. ERJ Open Res 2020; 6(3). 478. Ramsey SD, Berry K, Etzioni R, et al. Cost effectiveness of lung-volume-reduction surgery for patients with severe emphysema. N Engl J Med 2003; 348(21): 2092-102. 479. Ginsburg ME, Thomashow BM, Bulman WA, et al. The safety, efficacy, and durability of lung-volume reduction surgery: A 10-year experience. J Thorac Cardiovasc Surg 2016; 151(3): 717-24 e1. 104 480. Abdelsattar ZM, Allen M, Blackmon S, et al. Contemporary Practice Patterns of Lung Volume Reduction Surgery in the United States. Ann Thorac Surg 2021; 112(3): 952-60. 481. Stanifer BP, Ginsburg ME. Lung volume reduction surgery in the post-National Emphysema Treatment Trial era. J Thorac Dis 2018; 10(Suppl 23): S2744-S7. 482. Buttery S, Lewis A, Oey I, et al. Patient experience of lung volume reduction procedures for emphysema: a qualitative service improvement project. ERJ Open Res 2017; 3(3). 483. McNulty W, Jordan S, Hopkinson NS. Attitudes and access to lung volume reduction surgery for COPD: a survey by the British Thoracic Society. BMJ Open Respir Res 2014; 1(1): e000023. 484. Rathinam S, Oey I, Steiner M, Spyt T, Morgan MD, Waller DA. The role of the emphysema multidisciplinary team in a successful lung volume reduction surgery programmedagger. Eur J Cardiothorac Surg 2014; 46(6): 1021-6; discussion 6. 485. Chambers DC, Cherikh WS, Goldfarb SB, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation. J Heart Lung Transplant 2018; 37(10): 1169-83. 486. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2015; 34(1): 1-15. 487. Arjuna A, Olson MT, Walia R. Current trends in candidate selection, contraindications, and indications for lung transplantation. J Thorac Dis 2021; 13(11): 6514-27. 488. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung 489. Transplantation: 29th adult lung and heart-lung Stavem K, Bjortuft O, Borgan O, Geiran O, Boe J. transplant report-2012. Lung transplantation in pJ aHteieanrttsLuwnitghTcrharTnosEnpilcanotb2st0r1u2c;ti3v1e(p1u0l)m: 1o0n7a3r-y86. 490. disease Tanash in a HA, national Riise GC, cohort is Hansson Lw,iNthilosusot nobPvMio,uPsiistuurlaviinvaelnbEe.nSeufritv.ivJaHl ebaernteLfuitnogfTluranngstpRrlaaInBnstUp2la0n0t6a;t2io5n(1in): 75-84. individuals with 491. sTeavnearsehaHlpAh,aR1ii-saenGti-Ct,ryEpksstinrodmefMiciPe,nHcyan(PssiZoZn) La,nPdiietumlapihnyesneEm. aS.uJrvHiveaalrtbeLunnegfitToraDfnlIusSpnTlgatnrta2n0sp1l1a;n3t0a(t1io2n):f1o3r 4c2h-r7o.nic 492. obstructive Eskander A, pulmonary disease in Sweden. Ann Thorac Waddell TK, Faughnan ME, Chowdhury N, SSiunrgge2r 0L1G4. ;B9O8D(6E):inO1d9Re3x0a-5n.d quality of life in advanced chronic obstructive pulmonary disease before and after lung transplantatioOnP. 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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. 509. Criner GJ, Sue R, Wright S, et al. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE). Am J Respir Crit Care Med 2018; 198(9): 1151-64. 105 510. Kemp SV, Slebos DJ, Kirk A, et al. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM). Am J Respir Crit Care Med 2017; 196(12): 1535-43. 511. Valipour A, Slebos DJ, Herth F, et al. Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study. Am J Respir Crit Care Med 2016; 194(9): 1073-82. 512. Criner GJ, Delage A, Voelker K, et al. Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial. Am J Respir Crit Care Med 2019; 200(11): 1354-62. 513. van Geffen WH, Klooster K, Hartman JE, et al. Pleural Adhesion Assessment as a Predictor for Pneumothorax after Endobronchial Valve Treatment. Respiration 2017; 94(2): 224-31. 514. Hopkinson NS, Kemp SV, Toma TP, et al. Atelectasis and survival after bronchoscopic lung volume reduction for COPD. Eur Respir J 2011; 37(6): 1346-51. 515. Garner J, Kemp SV, Toma TP, et al. Survival after Endobronchial Valve Placement for Emphysema: A 10-Year Follow-up Study. Am J Respir Crit Care Med 2016; 194(4): 519-21. 516. Gompelmann D, Benjamin N, Bischoff E, et al. Survival after Endoscopic Valve Therapy in Patients with Severe Emphysema. Respiration 2019; 97(2): 145-52. 517. Hartman JE, Welling JBA, Klooster K, Carpaij OA, Augustijn SWS, Slebos DJ. Survival in COPD patients treated with bronchoscopic lung volume reduction. Respir Med 2022; 196: 106825. 518. 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Y OR COP T NO - DO ERIALS MAT YRIGHT COP 107 CHAPTER 4: MANAGEMENT OF STABLE COPD KEY POINTS: The management strategy of stable COPD should be predominantly based on the assessment of symptoms and the history of exacerbations. All individuals who smoke should be strongly encouraged and supported to quit. The main treatment goals are reduction of symptoms and future risk of exacerbations. Management strategies include pharmacologic and non-pharmacologic interventions. INTRODUCTION IBUTE ISTR COPD patients should have an assessment of the severity of their airfloDw obstruction, symptoms, history of exacerbations, exposure to risk factors and comorbidities (Figure 4.1) OtoRguide management. The assessment is summarized in Chapter 2. OPY We propose a tailored approach to initiate treatment based OonT C the level of symptoms and risk for exacerbations. Treatment can be escalated/de-escalated based on the prOeseNnce of the predominant symptoms (treatable traits) of breathlessness and exercise limitation, and the continue-dDoccurrence of exacerbations whilst on maintenance therapy. Tehviedebnacseisgfeonr ethraetseedrfercoommrmanednodmatiizoends,cwonhtircohllperdotpIrAoiaLsleSs.aHnoowregvaenriz, eads tahpepsreoraecchotmomtreenadtmateionnt,s waraesipnatertnlydeddertiovesudpfproomrt clinician decision-making, they also incorporaTteEeRxpert advice based on clinical experience. MA Itthiastctrhuecyiaal nfodrtpheeoirphleeawltithhcaCrOePwDotrokIeuGrnsHdmTerussttapnldaythine nature o order to f the disease, risk factors for its progression, and the achieve optimal management and health outcomes. ro le PYR Following the assessment, CinOitial management should address reducing exposure to risk factors including smoking cessation. Vaccination should be offered, and patients should receive general advice on healthy living, including diet, and that physical exercise is safe and encouraged for people with COPD. Initial pharmacotherapy should be based on the patient's GOLD group (Figure 4.2). Patients should be offered guidance on self-management of breathlessness, and stress management, and they should be given a written action plan. Comorbidities should also be managed as per specific guidelines, irrespective of the presence of COPD (Figure 4.1). Patients should be reviewed after a suitable interval (shorter in more severe patients and longer in less severe patients) and their current level of symptoms (using either the CAT or mMRC scores) and exacerbation frequency assessed. The effect of treatment and possible adverse effects should be evaluated, and comorbidities reassessed. Inhaler technique, adherence to prescribed therapy (both pharmacological and non-pharmacological), smoking status and continued exposure to risk factors should be checked at each clinical visit. Physical activity should be encouraged and referral for pulmonary rehabilitation considered in severe patients. The need for oxygen therapy, non-invasive ventilatory support, lung volume reduction and palliative approaches should also be considered individually and the action plan should be updated accordingly. Spirometry should be repeated at least annually. If the patient is already 108 receiving bronchodilator treatment, the latter should not be interrupted for performing spirometry. We no longer refer to asthma & COPD overlap (ACO), instead we emphasize that asthma and COPD are different disorders, although they may share some common treatable traits and clinical features (e.g., eosinophilia, some degree of reversibility). Asthma and COPD may coexist in an individual patient. If a concurrent diagnosis of asthma is suspected, pharmacotherapy should primarily follow asthma guidelines, but pharmacological and non- pharmacological approaches may also be needed for their COPD. Pharmacological and non-pharmacological therapy should be adjusted as necessary (see below) and further reviews undertaken (Figure 4.1). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 109 The aim of COPD management is to reduce symptoms and reduce future risk (Table 4.1). IDENTIFY AND REDUCE EXPOSURE TO RISK FACTORS IBUTE DISTR Y OR COP T Identification and reduction of exposure to risk factors is impNoOrtant not only for the prevention of COPD but also as part of the identifiable management risk factor for of a COPD COPD, and patient. smoking Cceigsasraetito-tenDOssmhoouklidngbeisctohnetinmuoasllty commonly encountered and easily encouraged for all individuals who samir opkoell.uRtaendtusc,tsiohnouolfdtaoltsaol bpeerasdodnraelsesxepdo.sure toERocIAcuLpSational dusts, fumes, and gases, and to household and outdoor Tobacco smoke MAT Smoking cessation is a key interventIiGonHfTor all COPD patients who continue to smoke. Healthcare providers are pivotal ianvadielalibvleerionpgpsomrtoukninitgy.cessatCioOnPmYeRssages and interventions to patients and should encourage patients to quit at every Smokers should be provided with counseling when attempting to quit. When possible, the patient should be referred to a comprehensive smoking cessation program that incorporates behavior change techniques that enhance patient motivation and confidence, patient education, and pharmacological and non-pharmacological interventions. Recommendations for treating tobacco use and dependence are summarized in Table 4.2.(1) Household and outdoor air pollution Reducing exposure to household and outdoor air pollution requires a combination of public policy, local and national resources, cultural changes, and protective steps taken by individual patients. Reduction of exposure to smoke from biomass fuel is a crucial goal to reduce the prevalence of COPD worldwide. Efficient ventilation, non-polluting cooking stoves and similar interventions are feasible and should be recommended.(2-4) Measures to reduce risk factor exposure are summarized in Table 4.3. 110 Occupational exposures There are no studies that demonstrate whether interventions that reduce occupational exposures also reduce the burden of COPD, but it seems logical to advise patients to avoid ongoing exposures to potential irritants e.g., dusts, fumes and gases, if possible. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 111 PHARMACOLOGICAL TREATMENT OF STABLE COPD Pharmacological therapies in COPD aim to reduce symptoms, and the risk and severity of exacerbations, improve the health status and exercise tolerance and, in some cases, survival in patients with COPD. The classes of medications commonly used to treat COPD are shown in Table 3.3 and a detailed description of the effects of these medications is given in Chapter 3. The choice within each class depends on the availability of medication and the patient's responses and preferences. Managing inhaled therapy Most of the drugs used to treat COPD are inhaled. Thus, appropriate use of inhaler devices is crucial to optimize the benefit-risk ratio of inhaled therapy. Achieving this goal requires to choose the appropriate device, provide education and follow-up, check inhaler use regularly and whenever necessary adapt education and device (Table 4.4). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT IGHT Choice of inhaler device PYR Table 4.5 summarises the CmOain principles that should be considered to guide the individualized selection of the appropriate device for a given patient. 112 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT IGHT Tagaebnlets4,.a6npdrTeasebnlets4k.8eysupmoimntasrifPzoeYrsRbtrhoenmchaoindiclaotnosriduesrea,tTioanbslefo4r.7thpereusseenotfs pkheayrpmoaincotslofgoircathl etreuastemoefnatnst.i-inflammatory CO 113 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 114 Algorithms for the assessment, initiation and followup management of pharmacological treatment A proposal for the INITIATION of pharmacological management of COPD according to the individualized assessment of symptoms and exacerbation risk following the ABE assessment scheme is shown in Figure 4.2. It is an attempt to provide clinical guidance. There is no high-quality evidence such as randomized controlled trials to support initial pharmacological treatment strategies in newly diagnosed COPD patients. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT Definition of abbreviationsC: OeoPs: blood eosinophil count in cells per microliter; mMRC: modified Medical Research Council dyspnea questionnaire; CATTM: COPD Assessment TestTM. Following implementation of therapy, patients should be reassessed for attainment of treatment goals and identification of any barriers for successful treatment (Figure 4.3). Following review of the patient response to treatment initiation, adjustments in pharmacological treatment may be needed. 115 IBUTE DISTR Y OR COP T NO A separate algorithm is provided for FOLLOWUP treat-mDeOnt, where the management is based on two key treatable traits: persistence of designed to facilitate dyspnea and management occurrence of patients toafkIieAnxgLaSmcearibnatteinoannsc(eFitgrueraetm4.e4n)t.(Ts)h,ewseheftohlleorwe-aurply recommendations are after initial treatment or after years of follow-up. These recommeTnEdRations incorporate the evidence from clinical trials and the use of peripheral blood eosinophil counts as a bMioAmarker to guide the use of ICS therapy for exacerbation prevention (see more detailed information regarYdiRngIGbHloTod eosinophil counts as a predictor of ICS effects in Chapter 3). COP 116 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT Figure 4.4 presents suggestCedOePscalation and de-escalation strategies based on available efficacy and safety data. The response to treatment escalation should always be reviewed. Patients, in whom treatment modification is considered, in particular de-escalation, should be undertaken under close medical supervision. We are fully aware that treatment escalation has not been systematically tested; trials of de-escalation are also limited and only include ICS. Initial pharmacological management Rescue short-acting bronchodilators should be prescribed to all patients for immediate symptom relief. Group A All Group A patients should be offered bronchodilator treatment based on its effect on breathlessness. This can be either a short- or a long-acting bronchodilator. If available and affordable a long-acting bronchodilator is the preferred choice except in patients with very occasional breathlessness. This should be continued if benefit is documented. 117 Group B Treatment should be initiated with a LABA+LAMA combination. It has been shown in a RCT that in patients with 1 moderate exacerbation in the year before the study and a CATTM 10 LABA+LAMA is superior to a LAMA with regard to several endpoints.(5) Therefore, providing there are no issues regarding availability, cost and side-effects LABA+LAMA is the recommended initial pharmacological choice. If a LABA+LAMA combination is not considered appropriate, there is no evidence to recommend one class of long- acting bronchodilators over another (LABA or LAMA) for initial relief of symptoms in this group of patients. In the individual patient, the choice should depend on the patient's perception of symptom relief. Group B patients are likely to have comorbidities that may add to their symptomatology and impact their prognosis, and these possibilities should be investigated and treated, if present, by following national and international guidelines.(6,7) Group E A Cochrane systematic review and network meta-analysis comparing dual combinatiUoTnEtherapy versus mono long- acting bronchodilators showed that the LABA+LAMA combination was the highestTrRaInBked treatment group to reduce COPD is the exacerbations.(8) Therefore, prov preferred choice. LABA+LAMA is ided there are the preferred no issues choice fo rreingiatiradlinthgearvaapiylaDibnIilSgitryo, co up st E and side-effects patients. LABA+LAM A OR Use of LABA+ICS in COPD is not encouraged. If there is an indicaOtPioYn for an ICS, then LABA+LAMA+ICS has been shown to be superior to LABA+ICS and is therefore the preferredTchCoice.(9,10) Consider LABA+LAMA+ICS in group E if eos 300 cells/L (NprOactical recommendation). As outlined in Chapter 3 the effect of ICS on exacerbation prevention is correlated t-oDbOlood eosinophil count. As there are no direct data in the lfioter rraetsuerrevicnogntcheirsntirnegatinmiteianttiofonropfattrieipnltestwheitrhapayhtigrIehAaLetSomseinnotpinhinl ceowulyntd(iag3n0o0secedllps/atiLe)n. ts, we think there is a rationale TER If patients with COPD have concomitaMntAasthma they should be treated like patients with asthma. Under these circumstances the use of an ICS is mIaGnHdTatory. Followup pharmacologicaPlYmRanagement The follow-up pharmacologCicOal treatment algorithm (Figure 4.4) can be applied to any patient who is already taking maintenance treatment(s) irrespective of the GOLD group allocated at treatment initiation. The need to target primarily dyspnea/activity limitation or to prevent further exacerbations should be evaluated in each patient. If a change in treatment is considered necessary, then select the corresponding algorithm for dyspnea (Figure 4.4 left column) or exacerbations (Figure 4.4 right column); the exacerbation algorithm should also be used for patients who require a change in treatment for both dyspnea and exacerbations. Identify which box corresponds to the patient's current treatment and follow the suggested algorithm. Follow up pharmacological management should be guided by the principles of first review and assess, then adjust if needed (Figure 4.3): Review Assess Review symptoms (dyspnea) and exacerbation risk (previous history, blood eosinophils). Assess inhaler technique and adherence, and the role of non-pharmacological approaches (covered later 118  Adjust in this chapter). Adjust pharmacological treatment, including escalation or de-escalation. Switching inhaler device or molecules within the same class (e.g., using a different long acting bronchodilator) may be considered as appropriate. Any change in treatment requires a subsequent review of the clinical response, including side effects. Dyspnea For patients with persistent breathlessness or exercise limitation on bronchodilator monotherapy,(11) the use of two long acting bronchodilators is recommended. If the addition of a second long acting bronchodilator does not improve symptoms, we suggest considering switching inhaler device or molecules. At all stages, dyspnea due to other causes (not COPD) should be investigated and treated appropriately. Inhaler technique and adherence should be considered as causes of inadequate treatment reBspUoTnEse. Exacerbations TRI For patients with persistent exacerbations on bronchodilator monotDheISrapy, escalation to LABA+LAMA is recommended. Y OR Blood eosinophil counts may identify patients with a greater likeCliOhoPod of a beneficial response to ICS. For patients who develop exacerbations under mono long acting bronchodilTator treatment and a blood eosinophil count 300 cells/L escalation to LABA+LAMA+ICS may be considered.(9) NO In patients who develop further exacerbations on LAB-AD+OLAMA therapy we suggest two alternative pathways. Blood eosinophil counts < 100 cells/L can be used to prIeAdLicSt a low likelihood of a beneficial ICS response: Escalation to LABA+LAMA+ICS. A TbEenReficial response after the addition of ICS may be observed at blood eosinophil eosinophil counts counts. 100 cellTs/MLA, with a greater magnitude of response more likely with higher If patients treated with LABA+RLAIGMHA+ICS (or those with eos < 100 cells/L) still have exacerbations the following options may be considered: OPY Add roflumilastC. This may be considered in patients with an FEV1 < 50% predicted and chronic bronchitis,(12) particularly if they have experienced at least one hospitalization for an exacerbation in the previous year.(13,14) Add a macrolide. The best available evidence exists for the use of azithromycin, especially in those who are not current smokers.(15,16) Consideration to the development of resistant organisms should be factored into decision-making. Withdrawing ICS can be considered if pneumonia or other considerable side-effects develop. If blood eosinophils are 300 cells/L de-escalation is more likely to be associated with the development of exacerbations.(17,18) Carefully consider the dose of ICS used to reduce the potential of ICS related side effects that are more frequent at higher doses. Patients under treatment with LABA+ICS If a patient with COPD and no features of asthma has been treated - for whatever reason - with LABA+ICS and is well controlled in terms of symptoms and exacerbations, continuation with LABA+ICS is an option. Yet, if the patient 119 has a) further exacerbations, treatment should be escalated to LABA+LAMA+ICS; b) major symptoms, switching to LABA+LAMA should be considered. NONPHARMACOLOGICAL TREATMENT OF STABLE COPD Non-pharmacological treatment is complementary to pharmacological treatment and should form part of the comprehensive management of COPD. After receiving a diagnosis of COPD a patient should be given further information about the condition. Physicians should emphasize the importance of a smoke free environment, empower adherence to prescribed medication, ensure proper inhaler technique, promote physical activity, prescribe vaccinations, and refer patients to pulmonary rehabilitation. Some relevant non-pharmacological measures based on the GOLD group AT DIAGNOSIS are summarized in Table 4.9. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Recommendations for FOLLOW UP non-pharmacological treatments are based on patient's treatable traits e.g., symptoms and exacerbations (Table 4.10). Education and selfmanagement Self-management education and coaching by healthcare professionals should be a major component of the "Chronic Care Model" within the context of the healthcare delivery system. 120 The aim of self-management interventions is to motivate, engage and coach patients to positively adapt their health behavior(s) and develop skills to better manage their COPD on a day-to-day basis.(19) Physicians and healthcare providers need to go beyond pure education/advice-giving (didactic) approaches to help patients learn and adopt sustainable self-management skills. The basis of enabling patients to become active partners in their ongoing care is to build knowledge and skills. It is important to recognize that patient education alone does not itself change behavior or even motivate patients, and it has had no impact on improving exercise performance or lung function,(20,21) but it can play a role in improving skills, ability to cope with illness, and health status.(22) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Patients may have individual and/or group education sessions. During group sessions, patients engage in active, participatory-based learning of program content. During one-on-one interactions, a motivational communication style should be used, as this approach empowers patients to take greater responsibility for their health and well-being, where physicians and other healthcare professionals only serve as guides in the behavior change process. Topics considered appropriate for an education program include: smoking cessation; basic information about COPD; general approach to therapy and specific aspects of medical treatment (respiratory medications and inhalation devices); strategies to help minimize dyspnea; advice about when to seek help; decision-making during exacerbations; and advance directives and end-of-life issues. The intensity and content of these educational messages will vary depending on the severity of the patient's disease, although the specific contributions of education to the improvements seen after pulmonary rehabilitation remain unclear.(23) Implicit in this description is the provision of "self-management support/coaching", which refers to the strategies, techniques and skills used by healthcare providers to arm patients with the knowledge, confidence and skills required to self-manage their disease effectively. 121 However, the individual patient's evaluation and risk assessment with respect to exacerbations, patient's needs, preferences, and personal goals should inform the personalized design of the self-management education plan. Physical activity Pulmonary rehabilitation, including community and home-based, is an approach with clear evidence of benefits. However, the challenge is promoting physical activity and maintaining it. There is evidence that physical activity is decreased in COPD patients.(24) This leads to a downward spiral of inactivity which predisposes patients to reduced quality of life, increased rates of hospitalization and mortality.(25-27) As such, there has been tremendous interest in implementing behavior-targeted interventions with the aim of improving physical activity(28) and these should be encouraged.(25) Technology-based interventions have the potential to provide convenient and accessible means to enhance exercise self-efficacy, and to educate and motivate people in their efforts to make healthy lifestyle changes.(29) The use of an internet-mediated intervention may benefit people with COPD with low baseline self-efficacy to increase physical activity.(30) However, most published studies to date provide little guidance, being inconsistent in the techniques, and lacking the necessary details (e.g., type, quantity, timing and method of delivery; tools used; quality-assurance methods) to replicate the study or adapt the interventions for clinical care. One RCT that evaluated the long-term effectiveness exacerbation history showed of no abecnoemfitmsuinniatyc-ubtaesceadrepuhsyesicoarlsuacrvtiivviatly.(3c1o) AacnhoitnhgerinpteedrvoUemTneEtitoenr-binaspeedopphleyswicaitlhacCtOivPitDy interventional study (pedometer alone or pedometer plus a website with feedbacTkR) IsBhowed an association between the intervention and reduced risk for acute exacerbations over 12-15 monthDs IoSf follow-up.(32) Non-pharmacological ifnutnecrtvioenntaionndsinsucrcehaassedpuerxseerdcilsipe cbarepaatchitiynginapnadtideinatpshwraitghmCaOtiPcDb.r(e33a) thinPgYhaOvRe also been shown to improve pulmonary Pulmonary rehabilitation programs T CO Patients with high symptom burden and risk of exacerbationsN(OGroups B and E), should be encouraged to take part in a formal rehabilitation program that includes setting -pDatOient goals and is designed and delivered in a structured maraenonldeer,rt,afekmingalien,tmo oacrecoduenptritvheedi,nodrivhiadvueala'scCoOmPoDrbIAcihdLaiStryaoctfedriiasbtiecsteasn, dasctohmmoar,boirdpitaieins.f(u22l,c34o,3n5d) Tithioisninacnluddceusrrpeanttielynatps pwehaor less likely to be referred for pulmonary rehMaAbTiliEtaRtion.(36) Exercise training HT A meta-analysis of RCTs found thatIGexercise training alone, or with the addition of activity counseling, significantly improved physical activity levelPs YinRCOPD patients.(37) A combination of constant load or interval training with strength training provides better outCcoOmes than either method alone.(38) Where possible, endurance exercise training to 60-80% of the symptom-limited maximum work or heart rate is preferred,(39) or to a Borg-rated dyspnea or fatigue score of 4 to 6 (moderate to severe).(40) Endurance training can be accomplished through either continuous or interval exercise programs. The latter involves the patient doing the same total work but divided into briefer periods of high-intensity exercise, a useful strategy when performance is limited by other comorbidities.(41,42) In some cultures, other alternatives such as Tai Chi practice, emphasizing the use of `mind' or concentration for control of breathing and circular body movement, has been shown to improve exercise capacity in comparison to usual care in COPD patients.(43) However from this meta-analysis, the effects of Tai Chi in reducing dyspnea level and improving quality of life remain inconclusive. Future studies addressing these topics and the most beneficial protocols for Tai Chi practice are warranted. Exercise training can be enhanced by optimizing bronchodilators,(44) since both LAMA and LABA have shown reduced 122 resting and dynamic hyperinflation. These changes contribute to better training effects.(45,46) Adding strength training to aerobic training is effective in improving strength, but does not improve health status or exercise tolerance.(47) Upper extremities exercise training improves arm strength and endurance, and results in improved functional capacity for upper extremity activities.(48) Exercise capacity may also be improved by whole-body vibration training.(49) Inspiratory muscle training increases strength of inspiratory muscles,(50) but this not consistently translate to better performance, reduced dyspnea or improved health related quality of life when added to a comprehensive pulmonary rehabilitation program.(51-53) Assessment and followup Baseline and outcome assessments of each participant in a pulmonary rehabilitation program should be made to specify individual maladaptive behaviors (including motivation), physical and mental health impediments to training, goals, barriers and capabilities and to quantify gains and to target areas for improvement. Assessments should include: Detailed history and physical examination. Measurement of post-bronchodilator spirometry. UTE TRIB Assessment of exercise capacity. Measurement of health status and impact of breathlessness. DIS Assessment of inspiratory and expiratory muscle strength andOloRwer limb strength in patients who suffer from muscle wasting. OPY Discussion about individual patient goals and expectaTtiCons The first two assessments are important for establishing enNtOry suitability and baseline status but are not used in outcome assessment. - DO Exercise tolerance can be assessed by cycle ergomIAeLtSry or treadmill exercise with the measurement of a number of physiological variables, including maximumTEoRxygen consumption, maximum heart rate, and maximum work performed. Standardized self-paced, timedMwAalking tests (e.g., 6-minute walking distance) are useful in clinical practice as they require m information than inanimeanl tfiarceillyitiseeslfa-npdaIGcaeHrdeTrteelsetv, ant to routine functioning. Shuttle and are simpler to perform than walking tests provide more complete a treadmill test.(54) Walking tests do require at least one practice sePssYioRn before data can be interpreted. It is important not to limitCaOssessment only to these outcome measures but gather information on each patient's ultimate goal (relevant or valued outcomes), such as their desired achievements in work, home and leisure by the end of the program. Several detailed questionnaires for assessing health status are available, including some specifically designed for patients with respiratory disease. Health status can also be assessed by generic instruments, although these are less sensitive to change than the disease specific questionnaires such as the CATTM, CRQ or SGRQ. The Hospital Anxiety and Depression Scale (HADS)(55) and the Primary Care Evaluation of Mental Disorders (PRIMEMD) Patient Questionnaire(56) have been used to improve identification and treatment of anxious and depressed patients. Endoflife and palliative care Clinicians should develop and implement methods to help patients and their families to make informed choices that are consistent with patients' values. Simple, structured approaches to facilitate these conversations may help to improve the occurrence and quality of communication from the patients' perspective.(57) 123 Nutritional support In people with COPD, weight loss and malnutrition develop as disease severity progresses and indicates a poor prognosis. Malnutrition in COPD is associated with impaired lung function, increased hospitalizations, poor exercise tolerance, worsened quality of life and increased mortality.(58-63) Malnutrition has been reported in 30-60% of patients hospitalized with COPD;(64) up to 50% of people with COPD weigh less than 90% of ideal body weight.(65) Weight loss occurs when energy expenditure exceeds energy supply; in people with COPD decreases in appetite and oral intake often coincide with elevated systemic levels of pro-inflammatory cytokines and the appetite suppressant hormone, leptin.(66,67) The severity of airflow obstruction correlates with the presence of malnutrition(68) since ventilator inefficiency increases daily energy requirements.(69) The imbalance of decreased oral intake and increased energy expenditure can lead to a negative nitrogen balance and decreases in skeletal muscle mass and function.(70-72) Nutritional repletion in people with COPD should be coupled with optimization of lung function, regular exercise, and improvement of tissue oxygenation. Dietary advice and oral supplementation have been reported to improve body weight, quality of life, respiratory muscle strength and 6-minute walk distance.(64,73) However, nutritional support has not been consistently shown to improve lung function.(73-76) Multimodality treatment that incorporates rehabilitation with nutritional support and protein supplementation may improve fat free mass, BMIUaTnEd exercise performance.(77) Aimmporonvgemdahlannodugrirsihpesdtr,ehnogstphi,tabloizdeydwpeeiogphlteawndithnuCtOriPtiDon, aalpbriootmeianrkeenrrsic9h0eddasyuspppolestmThReonIBstpaittiaolndidsecchraeragsee.(d78m) ortality and DIS Vaccination OR People with COPD should receive all recommended vaccinations in lOinPeYwith relevant local guidelines. See Chapter 3 and Table 3.2 for current vaccination recommendations. T C Oxygen therapy NO Long-term oxygen therapy (LTOT) is indicated for stable-pDaOtients who have: PaO2 at or below 55 mmHg (7.3 kPa)IAorLSSaO2 at or below 88%, with or without hypercapnia confirmed tPwaOiceboevtewreaetnh5re5em-wmeHegk (p7e.3riokPda; )oTarEndR60 mmHg (8.0 kPa), or SaO of 88%, if there is evidence of pulmonary 2 hypertension, peripheral edeMmAa suggesting congestive 2 cardiac failure, or polycythemia (hematocrit > 55%). IGHT Once placed on LTOT the patiePnYt Rshould be re-evaluated after 60 to 90 days with repeat arterial blood gas (ABG) or oxygen saturation measureCmOents while inspiring room air and the level of oxygen flow that had been prescribed to determine if oxygen is still indicated and if so, therapeutic. An appropriate algorithm for the prescription of oxygen to COPD patients is shown in Figure 4.5. 124 IBUTE DISTR Y OR COP T NO - DO ERIALS Ventilatory support MAT NIV is occasionally used in patients wIGitHhTstable very severe COPD.(79) NIV may be considered of some use in a selected group of patients, systematic review particularly was unable iPntoYtRhsuopsepowrittho pronounced r refute this. daytime hypercapnia and recent hospitalization, (80) In contrast, in patients with both COPD and although a obstructive sleep apnea there are clearCinOdications for continuous positive airway pressure (CPAP).(81) Interventional bronchoscopy and surgery In selected patients with heterogeneous or homogenous emphysema and significant hyperinflation refractory to optimized medical care, surgical or bronchoscopic modes of lung volume reduction (e.g., endobronchial one-way valves, lung coils or thermal ablation) may be considered.(82) Some of these therapies (vapor ablation and lung coils) are not widely available for clinical care in many countries. In selected patients with a large bulla, surgical bullectomy may be considered. In selected patients with very severe COPD and without relevant contraindications, lung transplantation may be considered. Choosing bronchoscopic lung reduction (endobronchial valve, coil placement or thermal ablation) or surgical resection (lung volume reduction surgery, LVRS) to treat hyperinflation in an emphysematous patient depends on a number of factors. These include: the extent and pattern of emphysema identified on HRCT; the presence of interlobar collateral ventilation measured by fissure integrity on HRCT or physiological assessment (endoscopic balloon occlusion and flow 125 assessment); regional availability of the various therapies for clinical care, local proficiency in the performance of the procedures; and patient and provider preferences. Vapor ablation therapy is the only lung reduction therapy that has been reported to be successfully performed at the segmental rather than lobar level.(83) For further details see Chapter 3. Figure 4.6 provides an overview of the various interventional and surgical options for patients with emphysema. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Key points for the use of non-pharmacological treatments are given in Table 4.11. 126 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 127 MONITORING AND FOLLOWUP Routine follow-up of COPD patients is essential. Lung function may worsen over time, even with the best available care. Symptoms, exacerbations and objective measures of airflow obstruction should be monitored to determine when to modify management and to identify any complications and/or comorbidities that may develop. Symptoms At each visit, information on symptoms since the last visit should be collected, including cough and sputum, breathlessness, fatigue, activity limitation, and sleep disturbances. Questionnaires such as the COPD Assessment Test (CATTM)(84) can be used; trends and changes are more valuable than single measurements. Exacerbations The frequency, severity, type and likely causes of all exacerbations(85) should be monitored. Sputum volume and presence or absence of sputum purulence should be noted. Specific inquiry into response to previous treatment, uimnpscohretadnutl.eHdovsipsiittsalitzoatpiornosvisdheorus,ldtebleepdhoocnuemecanltlesdf,oirncalsusdisintagntchee, faancidlituys, eduorfatuiorgneonftsotUaryTe,Emanedrgaennycuysceaoref cfraitciicliatliecsaries or mechanical ventilatory support. ISTRIB Adherence and appropriate use of prescribed treatments R D This is a key action in the chronic management of COPD patients that shoOuld be mandatory in each clinical visit. The following aspects needs careful and personalized attention: COPY Dosages of prescribed medications Adherence to the regimen NOT O Inhaler technique Effectiveness of the current regime - D IALS Side effects. TER Treatment modifications should be recomMmAended (Figure 4.2). Smoking status IGHT At each visit, the current smokiPnYg Rstatus and smoke exposure should be determined followed by appropriate action. CO Measurements Decline in FEV1 can be tracked by spirometry performed at regular intervals (e.g., yearly) to identify patients who are declining quickly, although other lung function parameters reflecting hyperinflation and gas transfer may also be informative. A timed walking test (6-minute walking distance or shuttle-walking test) provides additional information regarding prognosis.(86,87) Measurement of oxygenation at rest in an arterial blood gas sample may help identify patients who will benefit from supplemental oxygen to improve both symptoms and survival in those with severe resting hypoxemia. Imaging If there is a clear worsening of symptoms, imaging may be indicated. When exacerbations are repeatedly characterized by purulent sputum, patients should be investigated for bronchiectasis. 128 Comorbidities Symptoms that may indicate the development or worsening of a comorbid condition such as lung cancer, obstructive sleep apnea, congestive heart failure, ischemic heart disease, osteoporosis or depression/anxiety etc. should be recorded. If present, an appropriate diagnostic work-up should follow (see also Chapter 6). Telehealth and remote monitoring The COVID-19 pandemic has dramatically changed how outpatient care is delivered in health care practices. Telehealth may offer a bridge to care, and now offers a chance to consider virtual and hybrid virtual/in-person care models, with a goal of improved healthcare access, outcomes, and affordability. However, incorporate virtual care into our ambulatory care should be based on evidence. From a recent Cochrane review(88) on telehealth for remote monitoring and consultations for patients with COPD, different models have been reviewed based on RCTs: Remote monitoring (linked to a healthcare professional) plus usual care versus usual care alone (as reported by trialists). Remote consultation (e.g., real-time contact with a health professioInBaUl)TpElus usual care versus usual care alone (e.g., face-to- reported by trialists). face visit for a check-up in a health seIrSviTcRe with a health professional, or as Remote monitoring or remote consultation versus usual careR(eD.g., where tele healthcare has replaced an element of usual face-to-face care). PY O In most of the studies (24 RCTs) included remote monitorinTgCiOnterventions requiring participants to transfer measurements using a remote device and later health profesNsiOonal review (asynchronous) as opposed to only 5 RCTs that transferred data and allowed review by health prof-eDssOionals in real time (synchronous). The results of this systematic review demonstrateItAhLeSpaucity of evidence of superiority of these models compared to ustsiullaul nccalreea,ri.we.h, iecxhaCceOrPbDatsioenvse,rihtyosspuitbaglrizoautpiosnTw,EhoReualdlthbesntaetfuits and of if mortality. There was no any may be harm from evidence of harm, but it telehealth interventions. is If telehealth interventions may be beneficiaMl aAs an additional health resource depending on individual needs based on professional assessment, the long-teIGrmHTeffects remain unknown. Surgery in the COPD patPieYnRt General surgery CO Postoperative pulmonary complications are as important and common as postoperative cardiac complications and, consequently, are a key component of the increased risk posed by general surgery in COPD patients.(89) The key factors that can contribute to the risk include smoking, poor general health status, age, obesity, and COPD severity. A comprehensive definition of postoperative pulmonary complications should include only major pulmonary respiratory complications, namely lung infections, atelectasis and/or increased airflow obstruction, which all potentially result in acute respiratory failure and aggravation of COPD.(90-92) Increased risk of postoperative pulmonary complications in COPD patients may vary with the severity of COPD, although the surgical site is the most important predictor and risk increases as the incision approaches the diaphragm.(92) Most reports conclude that epidural or spinal anesthesia have a lower risk than general anesthesia, although the results are not totally uniform. Some studies conducted in patients undergoing sham bronchoscopic procedures have reported acute exacerbation rates as high as 8.4%.(93) These data suggest that intubation and/or simple airway manipulation may increase the risk of exacerbation in select COPD patients. 129 To prevent postoperative pulmonary complications, stable COPD patients clinically symptomatic and/or with limited exercise capacity should be treated medically intensively before surgery, with all the measures already well established for stable COPD patients who are not about to have surgery. The presence of comorbid conditions, especially cardiac abnormalities, should be systemically assessed and treated before any major surgical intervention. Lung resection. For lung resection, the individual patient's risk factors should be identified by careful history taking including physical examination, chest radiography, and pulmonary function tests. Although the value of pulmonary function tests remains contentious, there is consensus that all COPD candidates for lung resection should undergo a complete battery of tests, including spirometry with bronchodilator response, static lung volumes, diffusing capacity, and arterial blood gases at rest.(94,95) COPD patients at high risk for surgical complications due to poor lung function should undergo further assessment, for example, tests of regional distribution of perfusion and exercise capacity.(94,95) The risk of postoperative complications from lung resection appears to be increased in patients with decreased predicted postoperative pulmonary function (FEV1 or DLco < 30-40% predicted) or exercise capacity (peak VO2 < 10 REFERENCES ml/kg/min pulmonary or 35% predicted). specialist, primary The final clinician, adnedcistihoenptaotipeunrts.uSeursguergryersyhoshuoldulbdebpeomstapdoeneadftiefUraTdnEisecxuascseiorbnawtiiothn the surgeon, is present. TRIB DIS OR 1. 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N Engl J Med 2018; 378(18): 1671-80. 10. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very- Severe COPD. N Engl J Med 2020; 383(1): 35-48. 11. Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)- agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; (4): CD008989. 12. 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. 13. Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting Beta-2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE2SPOND) A Randomized Clinical Trial. Am J Respir Crit Care Med 2016; 194(5): 559-67. 14. 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Respirology 2014; 19(2): 193-202. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteris tics of phTysEical activities in daily life in 25. cWharotznHic,oPbitsttaruFc,tRivoechpeuslmteornCaLr,yedt iasle.aAsne.oAffmiciJalREeusproirpCeraitnCRaersepMiraetdor2y0S0o5c;i1e7ty1(s9ta):te9m7R2e-In7Bt.Uon physical activity in COPD. Eur 26. Respir J 2014; 44(6): 1521-37. Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM. Regular physical acDtiIvSitTy reduces hospital admission and 27. mYoohratanlniteysiAnMch,rBoanlidcwoibnsRtrCu,cCtiovnenpoulllymMon. aMryordtiaselitaysep:readpioctpourlsaitniodnisbaabsleindgcOcohhRroornticstoubdsyt.ruThctoivraexp2u0lm06o;n6a1r(y9d):is7e7a2s-e8.in old age. Age Ageing 2002; 31(2): 137-40. OPY 28. Mantoani LC, Rubio COPD: a systematic N, McKinstry B, MacNee W, Rabinovich review. Eur Respir J 2016; 48(1): 69-81. RA. T ICnterventions to modify phys ical activity in patients with 29. Spielmanns M, Gloeckl R, Jarosch I, et al. Using a smartphoNneOapplication maintains physical activity following 30. pRuolbminosnoanrySAre, hShabimiliatdataioSnL,inQupiagtlieeynKtsS,wMithoyCMOPLD. A: awrea-bn-DdboOamseisdepdhcyosnictarol allectdivtirtiyali.nTtehrovreanxt2io0n2b2.enefits persons with low 31. self-efficacy Nguyen HQ, in COPD: Moy ML, results Liu IA, from et al. EaffreacntdoofmPihzyeIAsdiLccaSolnAtcrotilvleitdy trial. J Behav Coaching on Med 2019; Acute Care 42(6): 1082-90. and Survival Among Patients With 32. CWharnonEiSc,OKbasnttrourcotwivsekPi uAl,mPoonlaakryMD, iesteaasl.eL:oATnEPgr-RtaegrmmaetifcfeRcatnsdoofmwiezbe-dbCalsiendicapleTdroiaml.eJtAeMr-mA eNdeitawteOdpinetne2rv0e1n9t;io2n(8o):neC1O99P6D57. exacerbations. Respir Med 2020; 162:M1A05878. 33. fYuanncgtiYo,nWaenidLe, WxearcnigseSc, aept aacl.itTyhIiGen HepfaTfteicetnstos fwpiuthrsCeOdPliDp:baresyasttheinmgactiocmrebvinieewd awnitdhmdeiatpah-arnagamlysaitsi.cPbhryesaitohthinegr oTnhepourlymPornaactry 34. 2022; 38(7): 847-57. 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Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 23(6): 832-40. 47. Bernard S, Whittom F, Leblanc P, et al. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159(3): 896-901. 48. Velloso M, do Nascimento NH, Gazzotti MR, Jardim JR. Evaluation of effects of shoulder girdle training on strength and performance of activities of daily living in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013; 8: 187-92. 49. Cardim AB, Marinho PE, Nascimento JF, Jr., Fuzari HK, Dornelas de Andrade A. Does Whole-Body Vibration Improve the Functional Exercise Capacity of Subjects With COPD? A Meta-Analysis. Respir Care 2016; 61(11): 1552-9. 50. Beaumont M, Forget P, Couturaud F, Reychler G. Effects of inspiratory muscle training in COPD patients: A systematic review and meta-analysis. Clin Respir J 2018; 12(7): 2178-88. 51. Charususin N, Gosselink R, Decramer M, et al. Randomised patients with COPD. Thorax 2018; 73(10): 942-50. controlled trial of adjunctive iTnsEpiratory muscle training for 52. Chuang HY, obstructive Chang HY, Fang YY, pulmonary disease: GAuroanSdEo. mThieseedffeexcptseroimf tehnretaslhsotluddiyn.sJpCirlaintoNryurms u2s0c1le7R;t2rIaB6i(nU2i3n-g2i4n):p4a8ti3e0n-t8s. with chronic 53. Beaumont M, Mialon P, Le Ber C, during pulmonary rehabilitation: ceotnatlr.oElflefedcrtsanodfoinmspisieradttorriyalm. EuusrcRleetsrpaiirnJin2g01oD8nI;Sd5yT1s(p1n):o1e7a0i1n1s0e7v.ere COPD patients 54. Singh SJ, Morgan MD, Scott S, Walters D, with chronic airways obstruction. Thorax Hardman AE. 1992; 47(12): Development 1019-24. of aOsRhuttle walking test of disability in patients 55. Dowson C, Laing R, Barraclough R, et al. The use of the Hospital AnOxiPetYy and Depression Scale (HADS) in patients with 56. chronic obstructive pulmonary disease: a Kunik ME, Veazey C, Cully JA, et al. COPD epdiluoctasttiuodnya.nNdZcoMgenditTJiv2eC0b0e1h; a1v1i4o(r1a1l 4th1e):ra4p4y7-g9r.oup treatment for clinically significant symptoms of depression and anxiety in COPD paNtOients: a randomized controlled trial. Psychol Med 2008; 57. 38(3): 385-96. Au DH, Udris EM, Engelberg RA, et al. A randomized -trDiaOl to improve communication about end -of-life care among 58. pCaotlliiennstPsFw, iEthliaCMOP, DKu. rCuhkeuslta2a0ra1t2c;h1y4R1J(,3S):tr7a2tt6o-3nI5AR.LJ.SThe influence of deprivation on malnutrition risk in outpatients with 59. chronic obstructive Collins PF, Stratton RpJu, lKmuornukauryladairsaetacshey(RCTJO,EPERDlia). Clin Nutr 2018; M. Influence of 37(1): 144-8. deprivation on health care use, health care costs, and mortality in COPD. Int J Chron ObstrucMt APulmon Dis 2018; 13: 1289-96. 60. oGbusntaruycEt,ivKeaypmulamzoDn,aSreylcduiskeNasTe,IGEurnHgduTenrgPo,iSnegnpguullmFo, DnaermyirreNh.aEbfiflietcattioofnn. uRtersitpioirnoalolgsyta2t0u1s3in; individuals with 18(8): 1217-22. chronic 6612.. oHNbogsuotynreugncJtMHivT,e,FpCeuorgllmluinsosonnPaFrMCy, PO,daHiPsvueeYkayiRsnTesG. CC, ,lNiCngouNlyluientnsr 2PN0FV.1,E7Pc;ho3an6mo(4mT):iDc1,a1Gn0ad5l-loe9pg. eorsaDtiLo.nNaul tbruitridoennalasstsaotcuisa,tdeidetwairtyhinmtaalkneu,tarnitdiohneianltchh-ronic related quality of life in outpatients with COPD. Int J Chron Obstruct Pulmon Dis 2019; 14: 215-26. 63. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 2005; 82(1): 53-9. 64. Collins PF, Elia M, Stratton RJ. Nutritional support and functional capacity in chronic obstructive pulmonary disease: a systematic review and meta-analysis. Respirology 2013; 18(4): 616-29. 65. King DA, Cordova F, Scharf SM. Nutritional aspects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5(4): 519-23. 66. Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA, Schols AM. Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162(4 Pt 1): 1239-45. 67. Schols A. Nutrition as a metabolic modulator in COPD. Chest 2013; 144(4): 1340-5. 68. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis 1989; 139(6): 1435-8. 69. Kim V, Kretschman DM, Sternberg AL, DeCamp MM, Jr., Criner GJ, National Emphysema Treatment Trial Research G. Weight gain after lung reduction surgery is related to improved lung function and ventilatory efficiency. Am J Respir Crit Care Med 2012; 186(11): 1109-16. 70. Casaburi R. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Med Sci Sports Exerc 2001; 33(7 Suppl): S662-70. 132 71. Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters EF. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994; 7(10): 1793-7. 72. Franssen FM, Wouters EF, Schols AM. The contribution of starvation, deconditioning and ageing to the observed alterations in peripheral skeletal muscle in chronic organ diseases. Clin Nutr 2002; 21(1): 1-14. 73. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 12: CD000998. 74. Schols AM, Soeters PB, Mostert R, Pluymers RJ, Wouters EF. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. Am J Respir Crit Care Med 1995; 152(4 Pt 1): 1268-74. 75. Steiner MC, Barton RL, Singh SJ, Morgan MD. Nutritional enhancement of exercise performance in chronic obstructive pulmonary disease: a randomised controlled trial. Thorax 2003; 58(9): 745-51. 76. Vermeeren MA, Wouters EF, Geraerts-Keeris AJ, Schols AM. Nutritional support in patients with chronic obstructive pulmonary disease during hospitalization for an acute exacerbation; a randomized controlled feasibility trial. Clin Nutr 2004; 23(5): 1184-92. 77. van Wetering CR, Hoogendoorn M, Broekhuizen R, et al. Efficacy and costs of nutritional rehabilitation in muscle- wasted patients with chronic obstructive pulmonary disease in a community-based setting: a prespecified subgroup analysis of the INTERCOM trial. J Am Med Dir Assoc 2010; 11(3): 179-87. 78. Deutz NE, Ziegler TR, Matheson EM, et al. Reduced mortality risk in malnourished hospitalized older adult patients with COPD treated with a specialized oral nutritional supplement: Sub-group analysis of the NOURISH study. Clin Nutr 2021; 79. 40(3): 1388-95. Raveling T, Vonk J, Struik FM, et al. Chronic non-invasive ventilation for chronic obstructivTeEpulmonary disease. 80. Cochrane Database Syst Rev 2021; 8(8): CD002878. Struik FM, Lacasse Y, Goldstein R, Kerstjens HM, Wijkstra PJ. Nocturnal non-invasivRe IpBoUsitive pressure ventilation for 81. stable Marin JcMhr,oSnoicriaonbostJrBu,cCtiavreripzuolmSJo, BnoarldyodviaseAa,sCe.eCllioBchRr.aOnuetcDoamtaebsaisnepSaytsitenRtesvw2i0Dt1hI3Sc;hT(r6o)n: CicDo0b0s2t8ru7c8t.ive pulmonary disease 82. and obstructive sleep apnea: the Tiong LU, Davies R, Gibson PG, et oavl.eLrulanpgsvyonldurmoemree.dAumctiJoRnessuprirgeCrryitfCoarrdeOifMRfuesde 2010; 182(3): emphysema. 325-31. Cochrane Database Syst Rev 2006; (4): CD001001. OPY 83. Herth FJ, Valipour A, Shah PL, emphysema: 6-month results et of athl.eSmegumlteicnetnatlrveo, lpuamraellreeld-gurcotuioTpn,Coupsienng-ltahbeerlm, raalnvdaopmouisreadbclaotniotrnoilnlepdaStTieEnPt-sUwPittrhiasle. vere Lancet Respir Med 2016; 4(3): 185-93. NO 84. Jones PW, Harding G, Assessment Test. Eur Berry Respir P, Wiklund I, Chen WH, J 2009; 34(3): 648-54. K-liDneOLeidy N. Development and first validation of the COPD 85. Kessler R, Stahl E, Vogelmeier C, et al. observational, interview-based study. PCahteisetn2t0IuA0n6Ld;Se1r3st0a(n1d):in1g3,3d-4e2te. ction, and experience of COPD exacerbations: an 86. Johnson-Warrington V, obstructive pulmonary dMisietcahseelal KdEm,iSttinegdhTtoSEJh.RoIsspaiptarlafcotircaeninaccruetme eenxtaaclesrhbuatttiolenw? aRlekstpeirsat tnioened2e0d15fo; r9p0a(3ti)e: n2t0s6w-1i0th. chronic 87. Rochester CL, Vogiatzis I, Holland AE,MetAal. An Official American Thoracic Society/European Respiratory Society Policy Statement: Enhancing 192(11): 1373-86. ImplemIeGntHaTtion, Use, and Delivery of Pulmonary Rehabilitation. Am J Respir Crit Care Med 2015; 88. tJahnejruaapyS,foPrikcehKroCn, iCcaorrbsRt,rCPuocYtleiRvseAp,uFlomrotensacruyedRis,eBaasteav(CiaOMPD. )I.nCteorcvhernatnioenDsattoaibmapseroSvyestaRdehver2e0n2c1e; t9o(9p)h: aCrDm0a1c3o3l8o1g.ical 89. Mazzone PJ. PreoperaCtiOve evaluation of the lung cancer resection candidate. Expert Rev Respir Med 2010; 4(1): 97-113. 90. Celli BR, MacNee W, Force AET. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23(6): 932-46. 91. Schuurmans MM, Diacon AH, Bolliger CT. Functional evaluation before lung resection. Clin Chest Med 2002; 23(1): 159- 72. 92. Smetana GW. Preoperative pulmonary evaluation. N Engl J Med 1999; 340(12): 937-44. 93. Shah PL, Slebos DJ, Cardoso PF, et al. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet 2011; 378(9795): 997-1005. 94. Brunelli A, Charloux A, Bolliger CT, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J 2009; 34(1): 17-41. 95. Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT, American College of Chest P. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007; 132(3 Suppl): 161S-77S. 133 CHAPTER 5: MANAGEMENT OF EXACERBATIONS KEY POINTS: An exacerbation of COPD is defined as an event characterized by dyspnea and/or cough and sputum that worsen over < 14 days. Exacerbations of COPD are often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insults to the lungs. As the symptoms are not specific to COPD relevant differential diagnoses should be considered, particularly pneumonia, congestive heart failure and pulmonary embolism. The goals for treatment of COPD exacerbations are to minimize the negative impact of the current exacerbation and to prevent subsequent events. Short-acting inhaled beta2-agonists, with or without short-acting anUtTicEholinergics, are recommended as the initial bronchodilators to treat an exacerbaTtiRoInB. Mpoasisnibtelen.anIncepatthieernatpsywwithithfrleoqnuge-nactteinxgacberrobnacthioondsilaatnodrselsehvoaDuteIlSdd bbeloionditieaotesidnoapshsiloolenvealss addition of inhaled corticosteroids to the double broOncRhodilator regimen should be considered. OPY In patients with severe exacerbations, systemicTcoCrticosteroids can improve lung function (FEV1), oxygenation and shorten recoverNyOtime including hospitalization duration. Duration of therapy should not norma-llyDbOe more than 5 days. Antibiotics, when treatment failure, iannddichaotesdp,itcaalinzaIsAthiLooSnrtdeunrareticoonv.eDryurtaimtioen, reduce the of therapy risk of should early relapse, be 5 days. Methylxanthines are not recToEmRmended due to increased side effect profiles. MA Non-invasive patients with maceuctheIGarnHeicsTaplirvaetnotriylaftaioilunrsehwouhlod be the first mode have no absolute of ventilation used in COPD contraindication because it improves gas ePxYcRhange, reduces work of breathing and the need for intubation, decreases hospitalizaCtiOon duration and improves survival. Exacerbation recovery time varies, taking up to 4-6 weeks to recover, with some patients failing to return to the pre-exacerbation functional state. Following an exacerbation, appropriate measures for exacerbation prevention should be initiated (see Chapter 3 and Chapter 4). DEFINITION An exacerbation of chronic obstructive pulmonary disease (ECOPD) is defined as an event characterized by increased dyspnea and/or cough and sputum that worsens in < 14 days which may be accompanied by tachypnea and/or tachycardia and is often associated with increased local and systemic inflammation caused by infection, pollution, or other insult to the airways.(1) 134 Considerations Exacerbations of COPD are important events in the management of COPD because they negatively impact health status, rates of hospitalization and readmission, and disease progression.(2,3) COPD exacerbations are usually associated with increased airway inflammation, increased mucus production and marked gas trapping. These changes contribute to increased dyspnea that is the key symptom of an exacerbation. Other symptoms include increased sputum purulence and volume, together with increased cough and wheeze.(4) Patients with COPD are at increased risk of other acute events, particularly decompensated heart failure,(5,6) pneumonia,(7,8) pulmonary embolism(9,10) that may also mimic or aggravate an ECOPD. Thus, while worsening of dyspnea, particularly if associated with cough and, purulent sputum, and no other symptoms or signs in a patient with COPD may be diagnosed as an ECOPD, other patients may have worsening of respiratory symptoms, particularly dyspnea without the classic characteristics of ECOPD, that should prompt careful consideration and/or search of those potential confounders, or contributors. In some patients one or more of these diagnoses may contribute to the clinical presentations and should be addressed appropriately (Table 5.1). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 135 Currently, exacerbations are classified after the event has occurred as: Mild (treated with short acting bronchodilators only, SABDs) Moderate (treated with SABDs and oral corticosteroids antibiotics) or Severe (patient requires hospitalization or visits the emergency room). Severe exacerbations may also be associated with acute respiratory failure. The current grading of the severity of an ECOPD, based on post facto use of healthcare resources, is a major limitation of the current definition. Because of global variability in the available resources to treat patients and local customs affecting the criteria for hospital visits and admissions, there is substantial variability in reported ECOPD outcomes.(11) Table 5.2 shows a proposed clinical approach based on the current best available evidence.(1) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP It has been proposed that these easy to obtain clinical variables can help define the severity of exacerbations on point of contact (The ROME Proposal). These include mild moderate and severe based on clinically measurable thresholds.(1) Based on a thorough review of the available literature and using a Delphi approach to agree on the variable thresholds, the severity classification is summarized in Figure 5.1. In the primary care setting, where laboratories may not be available, severity can be determined with the easily obtainable dyspnea intensity (using a VAS 0 to 10 dyspnea scale with zero being not short of breath at all and 10 the worst shortness of breath you have ever experienced), respiratory rate, heart rate and oxygen saturation level. Where available, blood C-reactive protein (CRP) level is recommended. To determine the need for ventilator support (usually in the emergency room or hospital setting) arterial blood gases or equivalent should be measured. To move from a mild to a moderate level, three of the variables need to exceed the established thresholds. It is hoped that prospective validation will help better define exacerbations and their severity at point of contact, and that documented validation may confirm or help modify the proposed thresholds of the variables now included. It is proposed that prospective 136 research can help determine a more specific marker of lung injury than the more generic CRP, as has been true for other organs acute events. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 137 It is now recognized that many exacerbations are not reported to healthcare professionals for therapy and yet these events, although often shorter in duration, also have a significant impact on health status.(12,13) Thus COPD patients need to receive education about the importance of understanding exacerbation symptoms and when to seek professional healthcare. The WHO has defined a minimum set of interventions for the management of exacerbations.(14) Exacerbations are mainly triggered by respiratory viral infections although bacterial infections and environmental factors such as ambient air pollution and excess heat may also initiate and/or amplify these events.(15,16) Short-term exposure to fine (PM2.5) and coarse (PM10) particulate matter is associated with increased hospitalizations, ER visits, and outpatient visits,(16) as well as increased mortality of COPD exacerbations.(15,17,18) The most common viruses isolated are human rhinovirus (the cause of the common cold), influenza, para-influenza and metapneumovirus which can be detected for up to a week after an exacerbation onset.(19,20) When associated with viral infections, exacerbations are often more severe, last longer and precipitate more hospitalizations, as seen during winter. Filamentous fungi, particularly Aspergillus species, may be identified in sputum samples of patients during moderate or severe exacerbations(21-23) although their clinical relevance remains unclear. Invasive pulmonary aspergillosis is rare (1.3- 3an.9t%ib)i(o24t)icasnodrmpoarreenftreerqaulesntet rionidpsa,tiaenndtshwypitohamlbourmeisneevmeriae.(b25a)sTehlienediaaigrfnloowstiocbasptpruroctaicohn,troeTicEnevnatsuivseeaosfpberrogaildlosspiseicntrtuhmis setting remains challenging.(26) RIBU Exacerbations can be associated with increased sputum production and, ifDpIuSrTulent, they are most likely due to bacterial infection(4,19,27) There is reasonable evidence to support the conOcRept that eosinophils are increased in the airways, lung, and blood in a significant proportion of has been related to susceptibility to viral infection.(27) people with It has been sCOuOPgPgYDes.(t2e8-d30)thTahteepxraecseernbcaetioonf sspaustsuomciaeteodsinwoipthhialina increase in sputum or blood eosinophils may be more responsivTe C to systemic steroids(31) although more prospective trials are needed to test this hypothesis.(31) NO - DO During longer. aACt O8PDweeexakcserubpattioon2, 0in%creoafsepdatsieynmtsptowmilIlAs LnaSoret usually present for 7 to 10 days, but some have recovered to their pre-exacerbation events may last state.(32) COPD eExxaacceerrbbaattiioonnss ccaonntarilbsoutcelutsotedrisineatsime epraongMdreAosnsTicEoenR,t(h33e) ywohcicchuristhmeroereisliikneclryeaifseredcloikveelrihyoforodmofeaxnacoethrbearteiovnesntis(35s,3l6o)w(s.(e34e) Chapter 2). IGHT Some patients are susceptible tPoYfRrequent exacerbations (defined as two or more exacerbations per year), and these patients have worse healthCsOtatus and morbidity than patients with less frequent exacerbations.(3) The exact reason for an individual's increased susceptibility to exacerbation symptoms remains largely unknown. However, the perception of breathlessness is greater in frequent exacerbators than infrequent exacerbators,(37) suggesting that a perception of breathing difficulty may contribute to precipitating the respiratory symptoms rather than solely physiological, or causative factors. The strongest predictor of a patient's future exacerbation frequency remains the number of exacerbations they have had in the prior year.(35) It is recognized that these patients form a moderately stable phenotype, although some studies have shown that a significant proportion of patients change their exacerbation frequency especially with worsening FEV1.(38) Other factors that have been associated with an increased risk of acute exacerbations and/or severity of exacerbations include an increase in the ratio of the pulmonary artery to aorta cross sectional dimension (i.e., ratio > 1),(39) a greater percentage of emphysema or airway wall thickness(40) measured by chest CT imaging and the presence of chronic bronchitis.(41,42) Vitamin D has an immune-modulating role and has been implicated in the pathophysiology of exacerbations. As with many chronic diseases vitamin D levels are lower in COPD than in health. Some, but not all studies have shown that 138 supplementation in people with severe deficiency results in a 50% reduction in episodes and hospital admission.(43,44) Therefore it is recommended that all patients hospitalized for exacerbations should be assessed and investigated for severe deficiency (<10 ng/ml or <25 nM) followed by supplementation if required. TREATMENT OPTIONS Treatment setting The goals of treatment for COPD exacerbations are to minimize the negative impact of the current exacerbation and prevent the development of subsequent events.(45) Depending on the severity of an exacerbation and/or the severity of the underlying disease, an exacerbation can be managed in either the outpatient or inpatient setting. More than 80% of exacerbations are managed on an outpatient basis with pharmacological therapies including bronchodilators, corticosteroids, and antibiotics.(35,46,47) The indications patients with a IBUTE DISTR Y OR COP T NO - DO ERIALS MAT IGHT PYR CfoOrPaDsseexsascineCgrbOtahteionneecodmfoer thootshpeitaelmizaetrigoenncdyurdinegpaartCmOePnDt,eixf ahcyeprobxaetimonicatrheesyhsohwonulidn Table 5.3. When be provided with supplemental oxygen and undergo assessment to determine whether the exacerbation is life-threatening and if increased work of breathing or impaired gas exchange requires consideration for non-invasive ventilation. If so, healthcare providers should consider admission to an area where proper monitoring and care can be provided. In less severe cases, the patient may be managed in the emergency department or hospital ward unit. In addition to pharmacological therapy, hospital management of exacerbations includes respiratory support (oxygen therapy, ventilation). The management of severe, but not life threatening, exacerbations is outlined in Table 5.4. The clinical presentation of COPD exacerbation is heterogeneous, thus we recommend that in hospitalized patients the severity of the exacerbation should be based on the patient's clinical signs and recommend the following classification.(48) No respiratory failure: Respiratory rate: 24 breaths per minute; heart rate < 95 beats per minute, no use of accessory respiratory muscles; no changes in mental status; hypoxemia improved with supplemental oxygen given via Venturi mask 24-35% inspired oxygen (FiO2); no increase in PaCO2. 139 Acute respiratory failure - nonlifethreatening: Respiratory rate: > 24 breaths per minute; using accessory respiratory muscles; no change in mental status; hypoxemia improved with supplemental oxygen via Venturi mask > 35% FiO2; hypercarbia i.e., PaCO2 increased compared with baseline or elevated 50-60 mmHg. Acute respiratory failure - lifethreatening: Respiratory rate: > 24 breaths per minute; using accessory respiratory muscles; acute changes in mental status; hypoxemia not improved with supplemental oxygen via Venturi mask or requiring FiO2 > 40%; hypercarbia i.e., PaCO2 increased compared with baseline or elevated > 60 mmHg or the presence of acidosis (pH 7.25). IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Long-term prognosis following hospitalization for COPD exacerbation is poor, with a five-year mortality rate of about 50%.(49) Factors independently associated with poor outcome include older age, lower BMI, comorbidities (e.g., cardiovascular disease or lung cancer), previous hospitalizations for COPD exacerbations, clinical severity of the index exacerbation and need for long-term oxygen therapy at discharge.(50-52) Patients characterized by a higher prevalence and severity of respiratory symptoms, poorer quality of life, worse lung function, lower exercise capacity, lower lung density and thickened bronchial walls on CT-scan are also at increased risk for a higher mortality following an acute COPD exacerbation.(53) Mortality risk may be heightened during spells of cold weather.(54) An updated Cochrane review concluded that the use of COPD exacerbation action plans with a single short educational component, in conjunction with ongoing support, reduced in-hospital healthcare utilization. Such educational interventions were also found to increase the treatment of COPD exacerbations with corticosteroids and antibiotics.(55) Key points for the management of all exacerbations are given in Table 5.5. 140 IBUTE DISTR Pharmacological treatment OR The three classes of medications most commonly used for COPD exOacPeYrbations are bronchodilators, corticosteroids, and antibiotics. T C Bronchodilators NO O Although there is no high-quality evidence from RCTs, it i-sDrecommended that short-acting inhaled beta2-agonists, with or without short-acting anticholinergics, are IAthLeS initial bronchodilators for acute treatment of a COPD exacerbatio differences n.( in 56,57) A systematic rev FEV1 between using imewetoerfetdheTdEorosReutienhoafledresliv(MerDy o I) f short-acting bro (with or without nchodilators a spacer dev found ice) or no significant nebulizers to deliver the agent,(58,59) although the latterMmAay be an easier delivery method for sicker patients. It is recommended that patients do not receive continuIoGuHs Tnebulization, but use the MDI inhaler one or two puffs every one hour for two or three doses and then every have evaluated the use of P2in-Y4hRahleodurslobnags-eadctoinngthberpoantciheondt'islarteosrpson(eseit.hAelrthboeutgah2,-atghoenreistasre no or clinical studies that anticholinergics or combinations) with or withCouOt ICS during an exacerbation, we recommend continuing these treatments during the exacerbation or to start these medications as soon as possible before hospital discharge. Intravenous methylxanthines (theophylline or aminophylline) are not recommended to use in these patients due to significant side effects.(60,61) If a nebulizer is chosen to deliver the bronchodilator agent, air-driven bronchodilator nebulization is preferable to oxygen- driven in acute exacerbations of COPD in order to avoid the potential risk of increasing the PaCO2 associated with oxygen-driven bronchodilator administration.(62) Glucocorticoids Data from studies (mostly hospital based) indicate that systemic glucocorticoids in COPD exacerbations shorten recovery time and improve lung function (FEV1). They also improve oxygenation,(63-66) the risk of early relapse, treatment failure,(67) and the length of hospitalization.(63,65,68) A dose of 40 mg prednisone-equivalent per day for 5 days is recommended.(69) One observational study suggests that longer courses of oral corticosteroids for COPD exacerbations are associated with an increased risk of pneumonia and mortality.(70) Therapy with oral prednisolone is equally effective to intravenous administration.(71) Nebulized budesonide alone may be a suitable alternative for treatment of exacerbations in some patients,(64,72,73) and provides similar benefits to intravenous methylprednisolone, 141 although the choice between these options may depend on local cost issues.(74,75) Even short bursts of corticosteroids are associated with subsequent increased risk of pneumonia, sepsis and death(76) and use should be confined to patients with significant exacerbations. Recent studies suggest that glucocorticoids may be less efficacious to treat acute COPD exacerbations in patients with lower levels of blood eosinophils(28,31,35,77) and more trials of steroid-sparing treatment regimens are required. Antibiotics Although the infectious agents in COPD exacerbations can be viral or bacterial,(20,78) the use of antibiotics in exacerbations remains controversial.(79-81) The uncertainties originate from studies that did not differentiate between bronchitis (acute or chronic) and COPD exacerbations, studies without placebo-control, and/or studies without chest X-rays that do not exclude that patients may have had underlying pneumonia. There is evidence supporting the use of antibiotics in exacerbations when patients have clinical signs of a bacterial infection e.g., increased sputum purulence.(80,81) Indeed the use of observed sputum color can safely modulate antibiotic therapy with no adverse effects if sputum is white or clear in color. On the other hand observed sputum purulence has 94.4% sensitivity and 52% specificity for high bacterial load, indicative of a causative relationship.(81) A systematic review of placebo-controlled studies has shown that antibiotics reduce thUeTrEisk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44%.(82) The review proTvRidIBes evidence to treat moderately or sev These erely data ill patients with COPD are supported by more exace RCTs rbations and increased co in patients with diagnoses uogfhmaonddersDaptuIeStuCmOPpDu.r(8u4l)eInncaenwRiCthT, antibiotics.(82,83) the addition of doxycycline to oral corticosteroid an outpatient setting did not prolong timOeRto next exacerbation.(85) In the outpatient setting, sputum cultures are not feasible as they take at least two daOyPs Yand frequently do not give reliable results for technical reasons. diagnostic profile. Several biomarkers of airway infection are Earlier studies of C-reactive protein (CRP) being haOveT sCtudied in exacerbations of COPD that have a better reported contradictory findings.(86,87) A randomized trial found a marked reduction in antibiotic prescriptions wOithNout impaired outcomes in UK primary care outpatients with ECOPD in whom antibiotics prescriptions were gu-idDed by point-of-care CRP testing.(88) Another trial in patients hinocsrpeiatsaeliziend tfroeratemxaecnetrbfaaitluiornes). oTfhCeOsePDfinidninTghse nNeIAeetLdhSecrolannfidrms afotiuonndinsimotilhaerrresesuttlitnsg(srebdeufcoerde antibiotic use with a recommendation no to generalize this approach. However, data haTsEinRdicated that antibiotic usage can be safely reduced from 77.4% to 47.7% when CRP is low.(89) MA Procalcitonin is an acute phase reactIaGnHt Tthat increases in response to inflammation and infection and has been studied to determine the use of antibioPtYicRs in COPD exacerbations.(90) The efficacy of this biomarker is controversial. Several studies, mainly done in thCe Ooutpatient setting, suggested that procalcitonin-guided antibiotic treatment reduces antibiotic exposure and side effects with the same clinical efficacy.(91-93) A systematic review and meta-analysis on the use of procalcitonin in hospitalized patients with a COPD exacerbation found no significant reduction in overall antibiotic exposure.(94) In patients with COPD exacerbations treated in an ICU setting, the use of a procalcitonin-based algorithm for initiating or stopping antibiotics was associated with a higher mortality rate when compared to those receiving standard antibiotic regimens.(95) Based on these conflicting results we cannot recommend at this time the use of procalcitonin-based protocols to make the decision on using antibiotics in patient with COPD exacerbations; however, confirmatory trials with rigorous methodology are required. In summary, antibiotics should be given to patients with exacerbations of COPD who have three cardinal symptoms: increase in dyspnea, sputum volume, and sputum purulence; have two of the cardinal symptoms, if increased purulence of sputum is one of the two symptoms; or require mechanical ventilation (invasive or noninvasive).(4,20) A metanalysis demonstrated that 5 days of antibiotic treatment had the same clinical and bacteriological efficacy to longer conventional treatment in outpatients with COPD exacerbations. Furthermore, shorter exposure to antibiotics may decrease the risk developing antimicrobial resistance and complications associated with this therapy. The 142 recommended length of antibiotic therapy is 5-7 days.(96) We recommend a duration of 5 days of antibiotic treatment for outpatient treatment of COPD exacerbations.(95,97) The choice of the antibiotic should be based on the local bacterial resistance pattern. Usually, initial empirical treatment is an aminopenicillin with clavulanic acid, macrolide, tetracycline or, in selected patients, quinolone. In patients with frequent exacerbations, severe airflow obstruction,(98,99) and/or exacerbations requiring mechanical ventilation,(100) cultures from sputum or other materials from the lung should be performed, as gram-negative bacteria (e.g., Pseudomonas species) or resistant pathogens that are not sensitive to the above-mentioned antibiotics may be present. The route of administration (oral or intravenous) depends on the patient's ability to eat and the pharmacokinetics of the antibiotic, although it is preferable that antibiotics be given orally. Improvements in dyspnea and sputum purulence suggest clinical success. Adjunct therapies Depending on the clinical condition of the patient, an appropriate fluid balance, use of diuretics when clinically indicated, anticoagulants, treatment of comorbidities and nutritional aspects should be considered. Among COPD patients hospitalized Hospitalized patients with a suspected with COPD are at an exacerbation, increased risk up to 5.9% of deep vein twhreorme bfoosuisndantdopuUhlaTmvEeonpaurylmeomnbaorylismem(10b1o,1l0i2s)man.(d9) prophylactic measures for thromboembolism should be instituted.(103,104) At all TtiRmIeBs, healthcare providers should strongly enforce the need for smoking cessation. DIS Respiratory support Y OR Oxygen therapy COP This is a key component of hospital treatment of an exacerbationT. Supplemental oxygen should be titrated to improve the patient's hypoxemia with a target saturation of 88-92%.(10N5)OOnce oxygen is started, blood gases should be checked frequently, or as clinically indicated, to ensure satisfa-ctDoOry oxygenation without carbon dioxide retention and/or wbloorosdenoixnyggeancidcoonsitse.nPtualsmeoonxgiminedtirvyidiusanlsotwaitshadcacruIkAreaLrtSeskains arterial blood gas(106) and in particular, may overestimate tones.(107) A study demonstrated that venous blood gas to assess bicarbonate levels and pH is accurate TwEhRen compared with arterial blood gas assessment.(108) Additional data are needed to clarify the utility of venous bMloAod gas sampling to make clinical decisions in scenarios of acute respiratory failure; most compared to patients arterial binlocoluddseadmhpaldesaIGapnHHdT>th7e.3s0eovnerpitryesoefnatiarftlioown, PCO2 levels obstruction were dissimilar when measured by venous was not reported.(108) Venturi masks offer more accurate and controlled dPeYliRvery of oxygen than do nasal prongs.(57) Highflow nasal therapCyO High-flow nasal therapy (HFNT) delivers heated and humidified air-oxygen blends via special devices (e.g., Vapotherm, Comfort Flo, or Optiflow) at rates up to 8 L/min in infants and up to 60 L/min in adults.(109) HFNT has been associated with decreased respiratory rate and effort, decreased work of breathing, improved gas exchange, improved lung volume and dynamic compliance, transpulmonary pressures and homogeneity.(110,111) These physiologic benefits positively improve oxygenation and clinical outcomes in patients with acute hypoxemic respiratory failure.(110- 113) HFNT has been reported to improve oxygenation and ventilation, decrease hypercarbia and improve health-related quality of life in patients with acute hypercapnia during an acute exacerbation, and also in select patients with stable hypercapnic COPD.(110,114-116) However, the small sample sizes, heterogeneity of the patient populations and short duration of follow-up are current limitations in the interpretation of the value of HFNT for the COPD patient population at large.(117) A meta-analysis, based on poor quality studies, showed no clear benefit.(118) HFNT has been reported to improve oxygenation and ventilation, decrease hypercarbia, prolong the time to next moderate exacerbation and improve health-related quality of life scores in patients with acute hypercapnia during an exacerbation or in select patients with stable hypercapnic COPD receiving long term oxygen therapy.(119) HFNT did not prevent intubation in a RCT conducted in patients hospitalized with an acute exacerbation.(120) It should be noted that European Respiratory 143 Society (ERS) Clinical Practice Guidelines recommend trialling NIV prior to use of HFNT in patients with COPD and hypercapnic ARF.(121) There is a need for well-designed, prospective, randomized and controlled multicenter trials to study the effects of HFNT in people with COPD experiencing episodes of either acute or chronic hypercapnic respiratory failure. Ventilatory support Some patients need immediate admission to the respiratory care or intensive care unit (ICU) (Table 5.6). Admission of patients with severe exacerbations to intermediate or special respiratory care units may be appropriate if adequate personnel skills and equipment exist to identify and manage acute respiratory failure. Ventilatory support in an exacerbation can be provided by either noninvasive (nasal or facial mask) or invasive (oro-tracheal tube or tracheostomy) ventilation. Respiratory stimulants are not recommended for acute respiratory failure.(56) IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 144 UTE Noninvasive mechanical ventilation The use of noninvasive mechanical ventilation (NIV) is preferred over invasive vTeRnItBilation (intubation and positive pressure ventilation) as the initial mode of ventilation to treat acute respiraDtoIrSy failure in patients hospitalized for acute exacerbations of COPD. NIV has been studied in RCTs showing a suOcRcess rate of 80-85%.(122-126) NIV has been sdheocrwenasteos irmesppriorvaetooryxyrageten,awtioornkaonfdbraecauttheinrgeaspnidratthoeryseavceidriotysiosfib.er.e, aNOthIPVlYeisnscnreesassbesutpaHlsaonddecdreecarseeassceosmPapClicOa2t.ioNnIVs saulcsho as ventilator associated pneumonia, and length of hospital stay. MT oCre importantly, mortality and intubation rates are reduced by this intervention.(123,127-129) Once patients improveNanOd can tolerate at least 4 hours of unassisted breathing, NIV can be directly discontinued without any need f-oDrOa "weaning" period.(130) The indications for NIV(126) are summarized in Table 5.7. IALS Invasive mechanical ventilation TER The indications for initiating invasive meMchAanical ventilation during an exacerbation are shown in Table 5.8, and include failure of an initial number of indications for itnrivaalsoivfeNImIGVeH.(c1T3h1a) Aniscaelxpveenriteilnacteioins gained with the generalized clinical are being successfully treated with use of NIV in COPD, a NIV, thus eliminating invasive mechanical ventilationPYaRs first line treatment of acute respiratory failure during hospitalization for COPD exacerbation.(131) In patientCsOwho fail non-invasive ventilation as initial therapy and receive invasive ventilation as subsequent rescue therapy, morbidity, hospital length of stay and mortality are greater.(124) The use of invasive ventilation in patients with very severe COPD is influenced by the likely reversibility of the precipitating event, the patient's wishes, and the availability of intensive care facilities.(124) When possible, a clear statement of the patient's own treatment wishes, such as an advance directive or "living will", makes these difficult decisions easier to resolve. Major hazards include the risk of ventilator-acquired pneumonia (especially when multi-resistant organisms are prevalent), barotrauma and volutrauma, and the risk of tracheostomy and consequential prolonged ventilation. Acute mortality among COPD patients with respiratory failure is lower than mortality among patients ventilated for non-COPD causes.(132) Despite this, there is evidence that patients who might otherwise survive are frequently denied admission to intensive care for intubation because of unwarranted prognostic pessimism.(133) A large study of COPD patients with acute respiratory failure reported in-hospital mortality of 17-49%.(134) Further deaths were reported over the next 12 months, particularly among those patients who had poor lung function before invasive ventilation (FEV1 < 30% predicted), had a non-respiratory comorbidity, or were housebound. Patients who did not have a previously diagnosed comorbidity, had respiratory failure due to a potentially reversible cause (such as an infection), or were relatively mobile and not using long-term oxygen, did well after ventilator support. 145 Hospital discharge and followup The cause, severity, impact, treatment and time course of exacerbations varies from patient to patient and facilities in the community, and healthcare systems, differ from country to country. Accordingly, there are no standards that can be applied to the timing and nature of discharge. However, it is recognized that recurrent exacerbations leading to short-term readmission and increased all-cause mortality are associated with the initial hospitalization for an acute episode of deterioration.(135) When features related to re-hospitalization and mortality have been studied, defects in perceived optimal management have been identified including spirometric assessment and arterial blood gas analysis.(136) A systematic review has shown that comorbidities, previous exacerbations and hospitalization, and increased length of stay were significant risk factors for 30- and 90-day all-cause readmission after an index hospitalization with an exacerbation of COPD.(137) Mortality relates to patient age, the presence of acidotic respiratory failure, the need for ventilatory support and comorbidities including anxiety and depression.(138) The introduction of care bundles at hospital discharge to include education, optimization of medication, supervision and correction of inhaler technique, assessment and optimal management of comoUrbTiEdities, early rehabilitation, ttehleesme omneitaosruinregsaanldl sceoenmtinsueendsibplaetitehnetrceoinstiancstuhffaicvieenatlldbaeteanthinavtetshteigyaitnefdluteonacdederietshTseRtrhIrBeesaedimssiusseison(Traabtlees5o.9r )s.h(1o39r)tW-tehrimle mortality(136,138,140,141) and there is little evidence of cost-effectiveness.(138) OnDeISRCT showed that telemonitoring did not change hospitalization or exacerbation rates in people with COPD.O(14R2) Nevertheless, it remains good clinical practice to cover increased if they athreesdeeilsivseureesdbwefitohreandiascphparrogaechanthdatthienicrleufdfeesctmivoentievOsastPiooYnnahleinalttehrvsiteawtu-sbaasneddrheeaadlmthiscsoioanchriantge.s(1m43)ay be T C The only possible exception is early rehabilitation as there is soNmOe evidence that this factor is associated with increased mhoosrptiatlaitlyd,isaclhthaorguegh(i.eth.,e<r4eawseoenkss)remmaayinbeuansksnoocwiante.(d14w1)-itHDhoOiwmepvreorv,eodthsuerrvidvaatla.(14s4u) ggest that early rehabilitation post IALS Eleasrslyefxoalcloewrb-autpio(nw-irtehlianteodneremaodnmtihs)sifoonllso.(w14i5n)AgTTdhEiesRrcehaarrgee should be undertaken when possible and has been many patient issues that prevent early follow-up; related to those not amtetednicdainl cgaeraer,lpyofoolrloswoc-iuapl shuapvpeoirntc,raenadsH/eodTr9Mt0h-edpayremseonrctaeliotyf .mTohrisemseavyerreefldeicsteabsoet.hNpeavteiernthtecloemssp, leiaanrlcyef,olilmloiwte-udpacpceersms ittos a careful review of discharge theYraRpIyGand an opportunity to make any needed changes in therapy. Additional follow-up at threCeOmPonths is recommended to ensure return to a stable clinical state and permit a review of the patient's symptoms, lung function (by spirometry), and where possible the assessment of prognosis using multiple scoring systems such as BODE.(146) In addition, arterial oxygen saturation and blood gas assessment will determine the need for long-term oxygen therapy more accurately at prolonged follow-up compared to shortly after discharge.(147) CT assessment to determine the presence of bronchiectasis and emphysema should be done in patients with recurrent exacerbations/ and or hospitalizations.(148,149) A further detailed assessment of the presence and management of comorbidities should also be undertaken (Table 5.9).(149) Prevention of exacerbations After an acute exacerbation, appropriate measures for prevention of further exacerbations should be initiated (Table 5.5 and Table 5.10). For the following treatment modalities significant effects on exacerbation risk/frequency could be shown in clinical trials. For details and references refer to Chapter 3 and Chapter 4. 146 Based on findings from observational studies in various countries(150-153) there was a major decrease in hospital admissions for COPD exacerbations during the COVID-19 epidemic. It was hypothesized that this phenomenon may be a consequence of shielding measures (e.g., wearing masks, avoiding social contact, regular hand washing etc). An alternative explanation is that patients may not have been seeking medical assistance during an exacerbation due to concern about becoming infected with the SARS-CoV-2 virus. If this was the case, then a corresponding increase in COPD related mortality would be expected. However, two major studies from the US and the UK(150,154) did not report increased COPD associated mortality during the pandemic. 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Association 2016; 149(4): 905-15. of -PsDyOchological Disorders With 30-Day Readmission Rates in Patients 139. hRoinsgpbitaaelkaTd,mGisresieonnsAi,nLapuartsieenntsLCw, iFthracuhsrinogniEc,oBbIrAsotnLrudScutmiveE,pUullrmikoCnSa.rEyfdfeiscetaosfet:ealerahnedaoltmhiczaerdecolinniecxaal ctreirabl.aItniotnJsCahnrodn 140. OHabrsttlruS,ctLoPpuelmz-oCnamDipso2s0J1L5, ;P1o0zo: -1R8o0d1r-i8g.uezTFE,Ret al. Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD AuditM. EAur Respir J 2016; 47(1): 113-21. 141. oJobrsdtaruncRtiEv,eMpaujlomthoinSa,ryHedniseegahsaeInG(CNHORTP,De)t:aaln. Seuvpidpeonrtceedssyenltfh-mesaisnaagnedmeeconnt ofomripcaatnieanlytssisw.iHtheamltohdTeerachtenotol Asessveesrse2c0h1r5o;nic 142. 19(36): Walker 1-516. PP, Pompilio PP, ZPaYnaRboni P, et al. Telemonitoring in Chronic Obstructive Pulmonary Disease (CHROMED). A Randomized Clinical TCriOal. Am J Respir Crit Care Med 2018; 198(5): 620-8. 143. Benzo R, Vickers K, Novotny PJ, et al. Health Coaching and Chronic Obstructive Pulmonary Disease Rehospitalization. A Randomized Study. Am J Respir Crit Care Med 2016; 194(6): 672-80. 144. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011; (10): CD005305. 145. Gavish R, Levy A, Dekel OK, Karp E, Maimon N. The Association Between Hospital Readmission and Pulmonologist Follow-up Visits in Patients With COPD. Chest 2015; 148(2): 375-81. 146. Oga T, Tsukino M, Hajiro T, Ikeda A, Nishimura K. Predictive properties of different multidimensional staging systems in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2011; 6: 521-6. 147. Spece LJ, Epler EM, Duan K, et al. Reassessment of Home Oxygen Prescription after Hospitalization for Chronic Obstructive Pulmonary Disease. A Potential Target for Deimplementation. Ann Am Thorac Soc 2021; 18(3): 426-32. 148. Haruna A, Muro S, Nakano Y, et al. CT scan findings of emphysema predict mortality in COPD. Chest 2010; 138(3): 635- 40. 149. Martinez-Garcia MA, de la Rosa Carrillo D, Soler-Cataluna JJ, et al. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187(8): 823-31. 150. Alsallakh MA, Sivakumaran S, Kennedy S, et al. Impact of COVID-19 lockdown on the incidence and mortality of acute exacerbations of chronic obstructive pulmonary disease: national interrupted time series analyses for Scotland and Wales. BMC Med 2021; 19(1): 124. 153 151. Chan KPF, Ma TF, Kwok WC, et al. Significant reduction in hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in Hong Kong during coronavirus disease 2019 pandemic. Respir Med 2020; 171: 106085. 152. Huh K, Kim YE, Ji W, et al. Decrease in hospital admissions for respiratory diseases during the COVID-19 pandemic: a nationwide claims study. Thorax 2021; 76(9): 939-41. 153. Tan JY, Conceicao EP, Wee LE, Sim XYJ, Venkatachalam I. COVID-19 public health measures: a reduction in hospital admissions for COPD exacerbations. Thorax 2021; 76(5): 512-3. 154. Ahmad FB, Anderson RN. The Leading Causes of Death in the US for 2020. JAMA 2021; 325(18): 1829-30. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 154 CHAPTER 6: COPD AND COMORBIDITIES KEY POINTS: COPD often coexists with other diseases (comorbidities) that may have a significant impact on disease course. In general, the presence of comorbidities should not alter COPD treatment and comorbidities should be treated per usual standards regardless of the presence of COPD. Cardiovascular diseases are common and important comorbidities in COPD. Lung cancer is frequently seen in people with COPD and is a major cause of death. INTRODUCTION o Annual low-dose CT scan (LDCT) is recommended for lung cancer screening in people with population COPD due to smoking according to recommendatUioTnEs for the general TRIB o AnontnduualeLtDoCsTmisokniontgrdeucoemtominesnudfefidcifeonrtludnatgactaonecestrasbclrDieshIeSnbienngeinfitpoevoeprlehawrmith COPD OR Oofstteenopuonrdoesri-sdaiangdndoesepdre, sasniodna/raenaxsiestoyciaarteedfrewqituhenpto,OoimrPhpYeoarlttahnsttcaotumsoarnbdidpitrioesgninosCiOs.PD, are T C Gastroesophageal reflux poorer health status. (GERD) is associateNd Owith an increased risk of exacerbations and - DO When COPD simplicity of tirsepaatmrt eonftaamndulttoimmoiIrnAbiLmidSiitzye care plan, attention polypharmacy. should be directed to ensure MATER YRIGHT COPD often coexists with otChOerPdiseases (comorbidities) that may have a significant impact on prognosis.(1-8) Some of these arise independently of COPD whereas others may be causally related, either with shared risk factors or by one disease increasing the risk or compounding the severity of the other. It is possible that features of COPD, are shared with other diseases and as such this mechanism represents a link between COPD and some of its comorbidities.(9,10) The risk of comorbid disease can be increased by the sequelae of COPD e.g., reduced physical activity or continued smoking. Whether or not COPD and comorbid diseases are related, management of the COPD patient must include identification and treatment of its comorbidities. Importantly, comorbidities with symptoms also associated with COPD may be overlooked e.g., heart failure and lung cancer (breathlessness) or depression (fatigue and reduced physical activity). Comorbidities are common at any severity of COPD(11) and the differential diagnosis can often be difficult. For example, in a patient with both COPD and heart failure, an exacerbation of COPD may be accompanied by worsening of heart failure or vice versa. Although COPD is negatively impacted by multiple comorbid diseases, COPD itself is one of the most important comorbid conditions that adversely affects the outcomes of other disorders. For example, patients with congestive heart failure or those undergoing cardiac procedures such as coronary artery bypass grafting have 155 greater morbidity and mortality when COPD is present compared to when it is absent.(12,13) Below is a brief guide to the management of some common comorbidities occurring in people with COPD with stable disease. The recommendations may be insufficient for the management of all COPD patients and are not a substitute for the use of guidelines for the management of each individual comorbid condition. Cardiovascular diseases (CVD) Heart failure The prevalence of systolic or diastolic heart failure in COPD patients ranges from 20% to 70%,(14) and its annual incidence is between 3-4%. Incident heart failure is a significant and independent predictor of all-cause mortality. Unrecognized heart failure may mimic or accompany acute COPD; 40% of COPD patients that are mechanically ventilated because of hypercapnic respiratory failure have evidence of left ventricular dysfunction.(15,16) Treatment with 1-blockers who also have COPD. Selective improves survival in heart failure and -blockers should be used, and only uisseredc,otmo mtreeantdepdeUoiTnpElepawtiiethntCsOwPitDhfhoeraarptpfraoilvuerde cardiovascular indications; not 1 solely for the purpose of preventing exacerbationsToRf ICBOPD.(17) DIS Acute heart failure should be treated according to usual support an alternative management strategy. Noninvasive vheenatritlaftaioilnurOeadRgdueiddetlionecsosnivnecnetitohnearle is no evidence to therapy improves outcomes for patients with either hypercapnic respiratory failure dOuePYto an exacerbation of COPD as well as heart failure with acute pulmonary edema.(18) NOT C Ischaemic heart disease (IHD) - DO Ischaemic heart disease should Cardiovascular risk may be assessed bbyethceognlsoibdaelrIerAidsLkSincalaclul laCtOoPr,Dwhpiacthiecnatns depending be found on on their risk factor profile. the US National Heart Blood Lung Institute website(19) and treatment inMitAiaTteEdRbased on the current recommendations. (deDatuhr,inmg,yaoncdarfdoiraal tinlefaarsctt9io0nd,asytsroaIkfGtee,Hr,uTancsutateblCeOaPnDgienxaa,ceanrbdattiroannssitehnetreisicshaenminiccraetatsaecdk)riisnk of cardiovascular patients at high events risk of concomitant IHD.(20) HospitalizPatYioRn for an acute COPD exacerbation has been associated with 90-day mortality of acute myocardial cardiac troponins iinnfiasrocltaitoionCn, Oiascreheamt iicncsrteraoskeed, and risk intracranial hemorrhage.(21) Patients who of adverse outcomes including short-term demonstrate (30-day) and abnormal long-term mortality.(22,23) The treatment of ischaemic heart disease should be according to guidelines irrespective of the presence of COPD and vice versa. Arrhythmias Cardiac arrhythmias are common in COPD and vice versa.(24) Atrial fibrillation is frequent and associated with a lower FEV1.(25) In COPD patients presenting with severe worsening dyspnea, associated atrial fibrillation is frequently documented, and it may be either a trigger or a consequence of an acute exacerbation episode.(26) The presence of atrial fibrillation does not alter the treatment of COPD. Bronchodilators have been previously 156 described as potentially pro-arrhythmic agents(27,28); however, available evidence suggests an overall acceptable safety profile for long-acting beta2-agonists,(29) anticholinergic drugs (and ICS).(30-37) Nevertheless, caution is advised when using short-acting beta2-agonists(29,38) and theophylline, which may precipitate atrial fibrillation and make control of the ventricular response rate difficult.(39-41) Peripheral vascular disease Peripheral artery disease (PAD) is commonly associated with atherosclerotic heart disease and may have significant implications for functional activity as well as quality of life in people with COPD.(42) In a large cohort of people with COPD of all degrees of severity, 8.8% were diagnosed with PAD that was higher than the prevalence in non-COPD controls (1.8%).(42) COPD patients with PAD reported a worse functional capacity and worse health status compared to those without PAD. Clinicians should consider PAD in people with COPD to those at risk for vascular events and to fully understand their functional impairments. Hypertension UTE Hypertension is likely to be the most frequently occurring comorbidity in COTPRDIBand may have implications for prognosis.(9,10) Diastolic dysfunction as a result of sub-optimally treated hypertDenISsion may be associated with exercise intolerance and mim These data stress ic symptoms asso the importance ciate of d with an optimal acute exacerbatio blood pressure ncothnOetrrRoelbyinproCvOoPkDing hospitalization patients with in COPD.(14) underlying hypertension.(43,44) OPY T C Hypertension should be treated according to usual guidelNinOes. There is no evidence that hypertension should be trreecaetnetdhdyipffeerrteenntsliyoningtuhiedeplirneessenacnedotfheCrOePiDs .nToheevridoelenco-efDttrhOeaattimnepnetowpliethwsiethleCctOivPeDbaentad-binlocrcekaesresdisclaersdsiopvraosmcuinlaernrtisink cardio-selective beta-blockers either reduce the bIeAnLeSfits of treatment with LABA or increase cardiovascular risk.(45) COPD should be treated as usual as thereTEisRno direct evidence that COPD should be treated differently in the presence of hypertension. MA Lung cancer IGHT PYR Lung from cancer colon, is the breast laenaddipnrgocsaCtauOtsee of death cancer to from malignant disease worldwide, with more deaths from lung cancer than gether and it causes an estimated 1.6 million deaths worldwide each year.(46) Unfortunately, the great majority of lung cancers are diagnosed at an advanced stage, resulting in poor overall survival.(47) Therefore, primary, and secondary prevention and early detection are important to improve survival. There is evidence for an association between COPD and lung cancer that has been systematically confirmed in several epidemiological and observational cohort studies.(10,48-50) These two diseases appear to share more than tobacco exposure as their common origin. Genetic susceptibility, epigenetic changes in DNA methylation, local pulmonary chronic inflammation and abnormal lung repair mechanisms present in COPD are also thought to be the most important potential contributors to lung cancer development.(51-53) Whether the spirometric severity of airflow obstruction is directly or inversely associated with a greater risk for lung cancer development remains controversial.(50,54) The association between lung cancer and degree of emphysema is stronger than that existing between lung cancer and degree of airflow obstruction and the greatest risk is observed in people with the combination of emphysema diagnosed by CT and airflow obstruction determined by spirometry.(55,56) The best preventive measure for lung cancer (as it is for COPD) is smoking prevention and in smokers, smoking cessation.(57) Several studies involving the use of low-dose chest computed tomography (LDCT) screening have shown improved 157 survival.(58-60) The United States Preventive Services Task Force (USPSTF) updated its recommendation for lung cancer screening in 2021.(61) Their recommendation was based on a systematic review that examined the accuracy of screening for lung cancer considering the benefits and harms associated with lung cancer screening. USPSTF also commissioned collaborative modeling studies from the National Cancer Institute (NCI) Cancer Intervention and surveillance modeling Network (CISNET) to provide the optimal age to begin and end lung cancer screening, the optimal screening interval, and to assess the relative benefits and harms of different screening strategies. The UPSTF now recommends annual screening for lung cancer with LDCT in adults aged 50-80 years who have a 20-pack year smoking history and currently smoke or quit smoking within the past 15 years. They recommend stopping screening once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. Additionally, the CISNET modeling analysis supports screening at a younger age with a lower smoking burden to address current racial and gender disparities that exist with lung cancer screening.(61-65) In patients with smoking related COPD, annual screening for lung cancer with LDCT should be conducted in those 50-80 years of age with a 20-pack year smoking history who currently smoke, or who have quit smoking within the past 15 years. COPD has also been reported to be an independent risk factor for lung cancer incidence in never smokers.(66,67) Risk factors include biomass fuel exposure, second-hand smoke, radon, air pollution, ainfpameoilpylehiwstiothryCoOfPlDunwg hcoanacreer,naenvedrassmbeoskteorss eaxnpdoasunrneu.aRl oLuDtCinTesacrneneunailnsgcirseennoitncguwrriethntLlyDTrCEeTcohmasmneont dbeedenbeccoanudsuecttehde possible harms of screening seem to outweigh the possible benefit of finding early lRuInBgUcancer.(68) Although this recommendation is supported by several major medical societieDsISseTveral important questions remain. Several studies have suggested that the yield of CT screening would imOpRrove if additional variables such as age, stomtohkeincguhrriestnotrsyc,rBeMenI,inpgrecsreitnecreiao.(f69a,7ir0)flow obstruction and or empThyCsOemPaYand family history of lung cancer were added The implementation of a screening program, where availabNleO, could be useful, but has to be implemented in the appropriate environment to avoid over diagnosis, greate-rDmOorbidity and mortality with needless diagnostic procedures for the benign abnormalities, anxiety other hand, one Danish study sahnodwiendcothmaptlbeeteinIfAgoLpllSoarwt -up, of a as has been suggeste lung cancer screening d by studies programme in primary care.(71) significantly promo On tes sremsoukltisnginaibmstpinroevnecde(7s2p) iaronmd eatrryevaieswweolfl daMisffAaeTrdeEenRctrsetausdeieisn cmoniccrloundoeddutlehsatsesmenokoinngthceesbsaatsieolnineduCrTin,gthLuDsCTbesncerefiecniainllyg aufsfeec(Ttianbglelu6n.g1)c.ancer and COPD.(Y57R) SIGmHokTing cessation interventions as part of CT scan screening programs could be of COP 158 Inhaled corticosteroids (ICS) and lung cancer incidence ICS are recommended in selected people with COPD and their potential impact on development of lung cancer has been the subject of conflicting reports. Several retrospective analyses of large databases or observational cohorts(73) have suggested a reduction in lung cancer risk with the use of ICS but confounding factors have not been consistently controlled for in all studies.(74-79) A more pronounced protective effect of ICS was reported in former compared to current smokers,(77) those with a concurrent diagnosis of asthma(79) or, those prescribed a higher dose of ICS.(78) A systematic review that included two observational studies and 4 RCTs, reported a protective effect of ICS on lung cancer risk in the observational studies that used a higher dose of ICS, but no benefit in the RCTs.(80) An analysis designed to avoid immortal time bias (81) and an observational study (> 65,000 patients) reported no effect of ICS use on lung cancer incidence.(82) In contrast, one database study reported an increased risk of lung cancer in patients prescribed ICS compared to those not prescribed ICS.(83) Reports from large prospective RCTs focused on lung function decline, exacerbation reduction or mortality, conducted in patients with moderate to severe COPD where cause of death was analyzed using clinical end-point committees reported no difference in cancer deaths in patients randomized to ICS versus non-ICS use.(31,33,37,84-86) Tchhaeracoctnefrliicztaitniognreosfulultnsgbceatnwceeernrioskb,sfeorlvloawtio-unpaltiamned (RshCoTsrtearreinpirnotbearvbelyntdiouneatlotrdiaiflsfe),riemnpcUeasTctEinoftihmempoatriteanl ttimpoepbuilaast,ioannsd, the rigorousness used to detect lung cancer. Based on the available data ICS do notTaRpIpBear to increase or decrease the risk of lung cancer pending studies adequately planned to clarify these importDanISt questions. Bronchiectasis OR With increasing use of computed tomography in the assessment OofPpYeople with COPD, the presence of previously unrecognized bronchiectasis is being identified.(87) The prevaleTnCce of bronchiectasis in COPD patients has been analyzed in several studies with conflicting results ranging froNmO20% to 69% (mean prevalence was 54.3%).(88) Whether this diagnosis based on radiological criteria- DO has the same impact as a clinical diagnosis of bronchiectasis remains unknown at present. Two systematic reviIeAwLsSand meta-analyses have compared the characteristics of COPD patients with and without are more often male with abrloonncgheirecsmtaosiksi.nTghheTiEsrteRosruyl,tsgrinedaticeartdedailtyhaspt upteuomplperwodituhcCtiOonP,Dmaonrde comorbid frequent bronchiectasis exacerbations, poorer lung function, higher level of inflaMmAmatory biomarkers, more chronic colonization by potentially pathogenic microorganisms, higher rate of PseuIdGoHmTonas aeruginosa isolation and increased mortality.(88,89) Bronchiectasis should be trePaYteRd according to usual guidelines. CO Regarding COPD treatment, some patients may need more aggressive and prolonged antibiotic therapy. ICS may not be indicated in patients with bacterial colonization or recurrent lower respiratory tract infections. Obstructive sleep apnea COPD has an estimated prevalence in U.S. adults of 13.9%(90,91) and obstructive sleep apnea (OSA), a sleep disorder hallmarked by repeated episodes of upper airway closure, affects 9% to 26% of the U.S. adult population.(92) Patients with both COPD and OSA have a worse prognosis compared with either condition alone.(93) During sleep, patients with both COPD and OSA suffer more frequent episodes of oxygen desaturation and have more total sleep time with hypoxemia and hypercapnia than OSA patients without COPD.(94) The apneic events in patients with combined OSA and COPD have more profound hypoxemia and more cardiac arrhythmias.(95) Additionally, patients with combined COPD and OSA are more likely to develop daytime pulmonary hypertension(96,97) than patients with just OSA or COPD alone. 159  The use of positive pressure ventilation in patients with COPD and OSA has been reported to reduce all- cause hospitalizations, emergency room visits, moderate and severe exacerbations and associated healthcare costs.(98,99) Periodontitis & dental hygiene The association between COPD and periodontitis has been noted mainly in the dental literature although whether this reflects common causative factors such as age, smoking and socioeconomic circumstances remains speculative. Although both conditions have a common (neutrophilic) relationship whether this reflects cause or effect is difficult to elucidate.(100) In a more complete study the data supported shared pathophysiology between periodontitis and COPD with similar aberrant neutrophil function, especially when associated with alpha-1-antitrypsin deficiency.(101) The risk of developing periodontitis increases with the number of emergency room visits for COPD.(102) High antibody levels to common periodontal pathogens is associated with less exacerbations of COPD.(103) In a recent systematic review low to moderate evidence suggests that periodontal treatment is associated with slower lung function decline, reduced frequency of exacerbations and less use of healthcare resources in patients with COPD and chronic periodontitis.(104) true. In the absence of an effective curative treatment for COPD it is difficuUlTt Eto prove the reverse is also TRIB Nevertheless, periodontitis is common in COPD and often requires treatmenDtIiSn its own right which may lead to a reduction in exacerbations. Y OR Metabolic syndrome and diabetes COP Studies have shown that metabolic syndrome and manifest dTiabetes are more frequent in COPD and the latter is likely to affect prognosis.(3) NO - DO Insulin resistance has been associated with incrIeAaLsSed risk of COPD in women but not in men.(105) The prevalence of metabolic syndrome hasTbEeRen estimated to be more than 30%.(106) Diabetes should be treated MA accordingTto usual guidelines for diabetes. COPD should be treated as usual. IGH Gastroesophageal refluxPY(GRERD) GERD is an independenCtOrisk factor for exacerbations and is associated with worse health status.(107-109) The mechanisms responsible for increased risk of exacerbations are not yet fully established. Proton pump inhibitors are often used for treatment of GERD. One small, single-blind study suggested these agents decrease the risk of exacerbation,(110) but their value in preventing these events remains controversial most effective treatment for this condition in COPD has yet to be established.(111,112) Osteoporosis Osteoporosis is an important and common comorbidity(2,9) which is often under-diagnosed(113) and associated with poor health status and prognosis. Osteoporosis is often associated with emphysema,(114) decreased body mass index(115) and low fat-free mass.(116) Low bone mineral density and fractures are commonly in COPD patients even after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations.(117,118) 160  Osteoporosis should be treated according to usual guidelines. COPD should be treated as usual despite the presence of osteoporosis. An association between ICS and fractures has been found in pharmaco- epidemiological studies; however, these studies have not fully taken severity of COPD or exacerbations and their treatment into account. Systemic corticosteroids significantly increase the risk of osteoporosis and repeated courses for COPD exacerbations should be avoided if possible Anemia Anemia is frequent in people with COPD, with a reported prevalence of 7.5% to 34%.(119) People with COPD and anemia are generally older, have more frequent cardiometabolic comorbidities, greater dyspnea, worse quality of life and airflow obstruction, reduced exercise capacity, an increased risk of severe exacerbations and higher mortality.(119-125) Anemia due to chronic disease is the most common type seen in COPD, followed by iron deficiency anemia,(126,127) and is mainly related to chronic systemic inflammation and impaired iron factors should be investigated including use of long-term oxygen, utthielizoapthioynll.inHeo, waenUvgTeioEr,teonthsienr-cpoonsvseibrlteinrge-veenrzsyimblee inhibitors, angiotensin II receptor inhibitors, renal dysfunction, and androgens.(128T-13R6)IB DIS Alelvtheolsuignhtahneesemipaahtiaesntbseheanveestnaobtliyshetedbeaesnandeimfinpeodr,taanntdciotmisorablsiodituynicnleCaOOrRPwDh,eothpetirmiatsl hemoglobin and correction alters hematocrit outcomes. However, hemoglobin assessment is advisable, particularly in more sOevPeYrely affected patients. If anemia is diagnosed, a systematic search for a treatable cause is recommended in NacOcoTrCdance with appropriate clinical guidelines. Polycythemia - DO Secondary polycythemia has long 6% to 10.2% in COPD outpatients (bweheennredceofignneidzeadIsAahLseSamcoogmlombionnc1o7mgo/drbLiidnitmy ainleCsOaPnDd with a reported prevalence of 15g/dL in females).(121,123,137) Interestingly, in the COPDGene cohorts 9.2%ToEfRmen and 3.5% of women had secondary polycythemia.(138) Although the prevalence of polycythemia in COPDMhAas decreased following the introduction of long-term oxygen therapy (LTOT),(139) one study reported a preIvGaHleTnce of 8.4% in patients with severe COPD receiving LTOT.(122) Data from a large cohort (COPPDYGRene cohort) of individuals with moderate to very severe COPD, indicate that male saessxo, cciuartreedntwsimthoinkicnrge,alsiveidngriCsaktOfhoigrhseacltointuddaery(ep.ogl.y, cDyethnevemri,aC,owlohreardeoa,s,ULSTAO),TimuspeawiraesdaDsLscooc,iaatnedd sweivtehraedheycproexaesmediariwskeroef polycythemia.(138) The coexistence of obstructive sleep apnea has also been associated with increased risk of polycythemia in patients with COPD.(140) Smoking causes an increase in carboxyhemoglobin, thereby increasing red blood cell mass and risk of secondary polycythemia in people with COPD.(141,142) Secondary polycythemia in COPD may be associated with pulmonary hypertension,(143,144) venous thromboembolism,(144) and mortality.(145,146) However, these findings should be interpreted with caution, since secondary polycythemia may be related to the presence of severe uncorrected hypoxemia, which is a predictor of mortality in COPD, as well as to the presence of concomitant interstitial lung disease or pulmonary vascular disease. In COPD, if secondary polycythemia is present, a careful evaluation should be performed to determine uncorrected hypoxemia or to rule out the presence of any comorbidities that require a specific intervention. 161 Anxiety and depression Anxiety and depression are important and underdiagnosed comorbidities in COPD(147-150) and both are associated with a poor prognosis,(149,151) younger age, female sex, smoking, lower FEV1, cough, higher SGRQ score, and a history of cardiovascular disease.(147,150,152) There is no evidence that anxiety and depression should be treated differently in the presence of COPD. COPD should be treated as usual in patients with psychological disorders. The potential impact of pulmonary rehabilitation should be stressed as studies have found that physical exercise has a beneficial effect on depression in general.(153,154) COPD is very common in patients with other psychiatric illnesses, often under-diagnosed and treated.(155,156) A systematic review has shown that COPD patients are 1.9 times more likely to commit suicide than people without COPD.(157) Following a diagnosis of COPD patients are more likely to develop depression and UTE tIhBe risk is greater in patients with worse breathlessness.(158) DISTR Cognitive impairment OR Cognitive impairment (CI) is common in people with COPD.(159P) Y An average prevalence of 32% has been suggested.(160) The prevalence and severity varies by the type of assCeOssment.(161) Extensive neuropsychological testing suggests that up to 56% of patients may suffer CI.(162,163) LongNiOtuTdinal studies suggest greater risk of developing CI in COPD diagnosed in midlife,(159,164) and associate COPD w-itDhOthe development of dementia.(165) CI has been reported in patients across the entIirAeLrSange of spirometric severity.(163) CI has been associated with impairment in bTaEsRic activities of daily living,(166,167) and variably associated with impaired health status.(168,169) MA The coexistence of CI and COPDIGhHasTbeen associated with an increased risk of hospitalization(170) and increased length of stay during acute eCxOaPceYrRbation hospitalization.(171) The impact of CI on self-management skills in COPD patients remains unclear,(166) although inhaler incompetency has been linked to CI.(166) Frailty Frailty can be defined as the presence of five components: weakness, slowness, exhaustion, low physical activity, and unintentional weight loss.(172) In a cohort study, the prevalence of frailty among individuals with COPD was higher than in individuals without COPD and may help identify people with COPD at risk of poor outcomes.(173) COPD as part of multimorbidity An increasing number of people in any aging population will suffer from multi-morbidity, defined as the presence of two or more chronic conditions, and COPD is present in most multi-morbid patients. 162  Multi-morbid patients have symptoms from multiple diseases and thus symptoms and signs are complex and most often attributable to several causes in the chronic state as well as during acute events. 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Effects of anemia on the survivNalOof patients with chronic obstructive pulmonary disease: a 126. systematic review and Schneckenpointner R, Jmorerteas-aRnAa,lMyseisi.dEexnpbearuteRreNv,RKeos-lpleDirrOtMFe, dPf2e0if2e0r;M14, (B1u2d):w1e2is6e7r-7S7. .The clinical significan ce of anaemia 127. aVnadsqduiestzuArb, eLodgioromnahrsoimnoeoJVst.aAsniseimnicahirnoCnhicrorensicpIAiOrLabtSsotrryucfatiivluereP.uIlnmtoJnCalriny Pract 2014; 68(1): 130-8. Disease and the Potential Role of Iron Deficiency. 128. COPD 2016; 13(1): 100-9. Andreas S, Herrmann-Lingen C, Raupach TT,EeRt al. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J 2006; 27(M5)A: 972-9. 129. Bakris GL, Sauter ER, normal subjects and iHnupsasteieynJLtIs,GFwiHsithThererJyWth, rGoacbyetorsAisOa,fWteirnrseenttalRt.rEafnfsepcltasnotfattihoeno.pNhyElnlignleJ on erythropoietin production Med 1990; 323(2): 86-90. in 130. IFnetrerrunccMi Le,dM2a0g0g6i;o1M66,(B1a3n)P:dY1in3Re8l0li-S8,. et al. Low testosterone levels and the risk of anemia in older men and women. Arch 131. Ilan Y, Dranitzki-ElhallCelOM, Rubinger D, Silver J, Popovtzer MM. Erythrocytosis after renal transplantation. The response to theophylline treatment. Transplantation 1994; 57(5): 661-4. 132. Incalzi RA, Corsonello A, Pedone C, et al. Chronic renal failure: a neglected comorbidity of COPD. Chest 2010; 137(4): 831-7. 133. Mrug M, Stopka T, Julian BA, Prchal JF, Prchal JT. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 1997; 100(9): 2310-4. 134. Oren R, Beeri M, Hubert A, Kramer MR, Matzner Y. Effect of theophylline on erythrocytosis in chronic obstructive pulmonary disease. Arch Intern Med 1997; 157(13): 1474-8. 135. Similowski T, Agusti A, MacNee W, Schonhofer B. The potential impact of anaemia of chronic disease in COPD. Eur Respir J 2006; 27(2): 390-6. 136. Vlahakos DV, Marathias KP, Madias NE. The role of the renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis 2010; 56(3): 558-65. 137. Ferrari M, Manea L, Anton K, et al. Anemia and hemoglobin serum levels are associated with exercise capacity and quality of life in chronic obstructive pulmonary disease. BMC Pulm Med 2015; 15: 58. 138. Zhang J, DeMeo DL, Silverman EK, et al. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors. BMC Pulm Med 2021; 21(1): 235. 139. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis 2011; 6: 199-208. 140. Zeng Z, Song Y, He X, et al. Obstructive Sleep Apnea is Associated with an Increased Prevalence of Polycythemia in Patients with Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2022; 17: 195-204. 167 141. Calverley PM, Leggett RJ, McElderry L, Flenley DC. Cigarette smoking and secondary polycythemia in hypoxic cor pulmonale. Am Rev Respir Dis 1982; 125(5): 507-10. 142. Chambellan A, Coulon S, Cavailles A, Hermine O, Similowski T. [COPD and erythropoiesis: interactions and consequences]. Rev Mal Respir 2012; 29(2): 213-31. 143. Nakamura A, Kasamatsu N, Hashizume I, et al. Effects of hemoglobin on pulmonary arterial pressure and pulmonary vascular resistance in patients with chronic emphysema. Respiration 2000; 67(5): 502-6. 144. Samareh Fekri M, Torabi M, Azizi Shoul S, Mirzaee M. Prevalence and predictors associated with severe pulmonary hypertension in COPD. Am J Emerg Med 2018; 36(2): 277-80. 145. Guo L, Chughtai AR, Jiang H, et al. Relationship between polycythemia and in-hospital mortality in chronic obstructive pulmonary disease patients with low-risk pulmonary embolism. J Thorac Dis 2016; 8(11): 3119-31. 146. Xu L, Chen Y, Xie Z, et al. High hemoglobin is associated with increased in-hospital death in patients with chronic obstructive pulmonary disease and chronic kidney disease: a retrospective multicenter population-based study. BMC Pulm Med 2019; 19(1): 174. 147. Hanania NA, Mullerova H, Locantore NW, et al. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J Respir Crit Care Med 2011; 183(5): 604-11. 148. Kunik ME, Roundy K, Veazey C, et al. Surprisingly high prevalence of anxiety and depression in chronic breathing disorders. Chest 2005; 127(4): 1205-11. 149. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med 2007; 150. 167(1): Maurer 60-7. J, Rebbapragada V, Borson S, et al. Anxiety and depression in COPD: current undeTrEstanding, unanswered 151. questions, and research needs. Chest 2008; 134(4 Suppl): 43S-56S. Eisner MD, Blanc PD, Yelin EH, et al. Influence of anxiety on health outcomes in CORPDIB. TUhorax 2010; 65(3): 229-34. 152. pCuhlemnoWna, rTyhdoimseaassJe,:SaadsyasttseamfaavtiiMc r,eFviitezwGearnadldmJMet.aR-aisnkaolyfscisa.rdLaionvcaestcRuelasrpicroMmeoDdrbI2Si0dT1it5y;i3n(p8a):ti6e3n1t-s9w. ith chronic obstructive 153. Bolton Thorax CE, Bevan-Smith EF, Blakey 2013; 68 Suppl 2: ii1-30. JD, et al. British Thoracic Society guideOliRne on pulmonary rehabilitation in adults. 154. Coventry PA, Bower P, Keyworth C, et al. The effect of complex intOerPveYntions on depression and anxiety in chronic 155. oHbimsterulhcoticvheSp,uLlemhomnaanryAd, iKsreeayseen: bsyushtleJm, DataiucmreivtiGew, BarondwnmCe,taD-iaxnToanClyLs.iPs.rePvLaolSenOcneeo2f0c1h3r;o8n(i4c)o: bes6t0r5u3ct2i.ve pulmonary disease among those with serious mental illness. Am J PsycNhOiatry 2004; 161(12): 2317-9. 156. cJohnroensiDc Rp,hMysaiccaialshCe,aBltahrpreroirbalePmJ, sFioshf eprerWsoHn,sHwaritghresaevr-ieoDsuWOs mA,eHnatardl iilnlngeCsMs. .PPsryecvhaialetrncSee,rvse2v0e0r4it;y5, 5a(n1d1)c:o1-2o5cc0u-7rr.ence of 157. aSasma priasikofMacSto, Vr ifeoirrasuWicAid,eB:eArnsayrsdteinmoaItMic,rHeveirevwaIlAaALnMdS,mFleotrae-sa-nMailrysCi,s.PRaeraspnihroMs eLRd.2C0h1r9o;n1ic51o:b1s1tr-u8c.tive pulmonary disease 158. Siraj RA, COPD: A MlarcgKeeUevKepr oTpMu,laGtiibosno-bnaJsEe,dBocolthoonTrCtEEsRt.uIndcyi.dReenscpeiroMf deedp2re0s2s2io; n19a6n:d1a0n6t8i0d4e.pressant prescription in patients with 159. van Beers M, Janssen DJA, Gosker HRM, SAchols A. Cognitive impairment in chronic obstructive pulmonary disease: disease 160. bYouhrdaennn,edseAtMer,mCihneanntWs a,nMdopgoasIAsGiMbHle, TLfeurtouirIe, interventions. Expert Rev Respir Med 2018; 12(12): 1061-74. Connolly MJ. Cognitive Impairment in Chronic Obstructive Pulmonary Disease a1n8d(5C):h4r5o1niec1H-eea1r1t.FailureP: YARSystematic Review and Meta-analysis of Observational Studies. J Am Med Dir Assoc 2017; 161. Pierobon A, Ranzini L,CTOorlaschi V, et al. Screening for neuropsychological impairment in COPD patients undergoing rehabilitation. PLoS One 2018; 13(8): e0199736. 162. Cleutjens FA, Franssen FM, Spruit MA, et al. Domain-specific cognitive impairment in patients with COPD and control subjects. Int J Chron Obstruct Pulmon Dis 2017; 12: 1-11. 163. Cleutjens F, Spruit MA, Ponds R, et al. Cognitive impairment and clinical characteristics in patients with chronic obstructive pulmonary disease. Chron Respir Dis 2018; 15(2): 91-102. 164. Rusanen M, Ngandu T, Laatikainen T, Tuomilehto J, Soininen H, Kivipelto M. Chronic obstructive pulmonary disease and asthma and the risk of mild cognitive impairment and dementia: a population based CAIDE study. Curr Alzheimer Res 2013; 10(5): 549-55. 165. Xie F, Xie L. COPD and the risk of mild cognitive impairment and dementia: a cohort study based on the Chinese Longitudinal Health Longevity Survey. Int J Chron Obstruct Pulmon Dis 2019; 14: 403-8. 166. Baird C, Lovell J, Johnson M, Shiell K, Ibrahim JE. The impact of cognitive impairment on self-management in chronic obstructive pulmonary disease: A systematic review. Respir Med 2017; 129: 130-9. 167. Martinez CH, Richardson CR, Han MK, Cigolle CT. Chronic obstructive pulmonary disease, cognitive impairment, and development of disability: the health and retirement study. Ann Am Thorac Soc 2014; 11(9): 1362-70. 168. von Siemens SM, Perneczky R, Vogelmeier CF, et al. The association of cognitive functioning as measured by the DemTect with functional and clinical characteristics of COPD: results from the COSYCONET cohort. Respir Res 2019; 20(1): 257. 169. Schure MB, Borson S, Nguyen HQ, et al. Associations of cognition with physical functioning and health-related quality of life among COPD patients. Respir Med 2016; 114: 46-52. 168 170. Chang SS, Chen S, McAvay GJ, Tinetti ME. Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults. J Am Geriatr Soc 2012; 60(10): 1839-46. 171. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. Chest 2013; 144(1): 119-27. 172. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56(3): M146-56. 173. Roberts MH, Mapel DW, Ganvir N, Dodd MA. Frailty Among Older Individuals with and without COPD: A Cohort Study of Prevalence and Association with Adverse Outcomes. Int J Chron Obstruct Pulmon Dis 2022; 17: 701-17. 174. National Institute for Health and Care Excellence. Multimorbidity: clinical assessment and management; NICE guideline [NG56]Published date: 21 September 2016 [accessed Oct 2022]. 2016. https://www.nice.org.uk/guidance/ng56. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP 169 CHAPTER 7: COVID19 AND COPD KEY POINTS: People with COPD presenting with new or worsening respiratory symptoms, fever, and/or any other symptoms that could be COVID-19 related, even if these are mild, should be tested for possible infection with SARS-CoV-2. Patients should keep taking their oral and inhaled respiratory medications for COPD as directed. During periods of high prevalence of COVID-19 in the community, spirometry should be restricted to patients requiring urgent or essential tests for the diagnosis of COPD, and/or to assess lung function status for interventional procedures or surgery. INTRODUCTION Panhdysiicnaalcdtiisvtiatyn.cinPgaatniednsthsieslhdoinugld, orstsahyeltinericnogn-itna-cptlawceit,hshtohueldir nfortielneaddsTtaoEnsdocfiaaml isiloielastiobny telecommunication and continue to keep active. enough medication. They should RalIsBoUensure they have DIST Patients should be encouraged to use reputable regarding COVID-19 and its management. resoOuRrces for medical information Guidance for remote (phone/virtual/online) COPODPpYatient follow-up and a printable checklist are provided. NOT C - DO IALS For COPD patients the worry of developing COTEVIRD-19 as well as the effects of the pandemic on the basic functions of society and/or social services pertaining toMtAheir health imposes additional stressors to their condition. The COVID-19 pandemic made routine managemeIGntHaTnd diagnosis of COPD more difficult as a result of reductions in face-to-face consultations, difficulties in care programmes. Patients aplseoPrfYfoaRrcmeidngshsopritraogmesetorfy and limitation in traditional pulmo medication.(1) Some health services nary rehabilitation are still working to and catc home h up. CO The dramatic spread of the SARS-CoV-2 virus was accompanied by an enormous number of publications on the virus and its consequences. Over time knowledge has grown, but the emergence of SARS-CoV-2 variants and the introduction of vaccines limits the interpretation of studies performed at earlier stages of the pandemic. The statements made in this Chapter utilize the published GOLD approach to data review and are based on the best assessment of the current evidence. RISK OF INFECTION WITH SARSCoV2 The spike protein of the virus binds to ACE2 (angiotensin-converting enzyme 2) during viral attachment to host cells and that viral entry is also facilitated by transmembrane protease serine 2 (TMPRSS2).(2) Differences in the expression of ACE2 and TMPRSS2 may modulate the individual susceptibility to and clinical course of SARS-CoV-2 infection. ACE2 mRNA expression is increased in COPD,(3-5) and further increased in COPD patients with a higher BMI and more frequent exacerbations.(6,7) It may be modulated by ICS use.(3,8-10) 170 It is still not known definitively whether having COPD affects the risk of becoming infected with SARS-CoV-2. Very few population studies using random sampling have assessed risk factors for testing positive for SARS-CoV-2, most have looked at samples of patients referred for testing or presenting with symptoms and very few contain information on comorbidities. A comprehensive review compared the prevalence of COPD among COVID-19 populations to the country-specific populations in 16 countries worldwide with high quality data and found no significant differences in ten countries, a higher prevalence of COPD in 4 and a lower prevalence in two countries.(11) Most studies of people in the community tested for SARS-CoV-2 have not shown chronic respiratory disease as an independent risk factor for testing positive,(12,13) although at least one has.(14) Many studies reporting the comorbidities of patients admitted to hospital with COVID-19 have suggested a lower prevalence of COPD than would be expected from population prevalence(15-17); these findings are limited by small sample sizes and incomplete data on comorbidities. A large study with comprehensive data on comorbidities showed a high prevalence of COPD among those admitted (19%),(18) although many patients had multiple comorbidities, and a further study of a primary care cohort of 8.28 million patients also showed having COPD was an independent risk ffarocmtorafroorunhdostphietawl aodrlmd,isfsoiounnd(HthRa1t.a5f5t;er95a%ccCoIu1n.t4in6g-1f.o6r4)c.o(1n4)foAusnydsitnegmvaatriciarbeleviseCwO, PinDclpuadtTiineEgntosnwlyehreigahtqsuliaglhittylyshtuigdhieesr risk of hospitalization (adjusted odds ratio (aOR) 1.45; 95% CI 1.30,1.61).(11) RIBU COPD has also been reported to independently increase the risk of severe diseDasIeSTor death in some series(17-25) but not all.(14,26-28) Globally, looking at high quality studies and after accounting forOcoRnfounding variables, COPD patients were found 1.37,1 to .65 be at slightly higher ).(11) In patients with risk of COPD, ICU admission (aOR 1.28 decreased lung function, ;h9ig5h%OerCPCIYA1T.0s8c,o1r.5e1, ), and mortality (aOR 1.41; 95% CI underweight, depression and prior COPD treated in inpatient or secondary care have been shown toTbCe factors predicting severe COVID-19.(29) NO Many factors have been proposed to account for the inc-reDaOsed risk for poor outcomes including prior poor adherence tpoultmhoenraapryy,redsifefricvuel.t(3ie0,s31)pTehreforermisinegvidseelnf-cme aonfaagfeamllIAeinnLtSh, olsimpiittaeldizaatciocensrsatteos care during the for COPD during pandemic and a reduced the pandemic.(22,32-34) The reasons for this remain unclear, but patientsTeExRperiencing symptoms of an exacerbation should be evaluated in the usual way during the pandemic and hospitMalAized if necessary. In multivariate analyses pre-existinIgGCHOTPD does not appear to increase the risk of patients developing long term symptoms post acute COVIDC.O(35P,3Y6)R There are currently no peer-reviewed studies that have evaluated the effect of smoking on the risk of infection with SARS-CoV-2, but studies suggest that smoking is associated with increased severity of disease and risk of death in hospitalized COVID-19 patients.(37,38) In summary, on current evidence, people with COPD do not seem to be at greatly increased risk of infection with SARS- CoV-2, but this may reflect the effect of protective strategies. They are at an increased risk of hospitalization for COVID-19 and may be at increased risk of developing severe disease and death. 171 INVESTIGATIONS Testing for SARSCoV2 infection People with COPD presenting with respiratory symptoms, fever or other symptoms suggesting SARS-CoV-2 infection, even if mild, should be tested for possible infection (Figure 7.1). False-negative RT-PCR tests have been reported in patients with CT findings of COVID-19 who eventually tested positive with serial sampling.(39) If people with COPD have been exposed to someone with known COVID-19 infection they should contact their health care provider to define the need for specific testing. Antibody testing may be used to support clinical assessment of patients who present late. Detection of SARS-CoV-2 does not exclude the potential for co-infection with other respiratory pathogens.(40) The U.S. Centers for Disease Control and Prevention (CDC) encourages testing for other causes of respiratory illness, in addition to testing for SARS-CoV-2 depending on patient age, season, or clinical setting. Some patients experience re-activation of long-lasting virus carriage or become re-infected, and this might be influenced by comorbidities or drugs that hamper the immune response.(41) Repeat teUsTtiEng should be performed in patients with suspected recurrence or relapse of COVID-19. RIB The lung microbiome is different in people with COPD compared to those withoDuISt.T(42) The lung microbiome can modify the immune response to viral infections but, to date there is no direct evidOeRnce from human or animal studies on the role of lung microbiome in modifying COVID-19 disease(43) nor on itsOpoPtYential effects in people with COPD. Spirometry & pulmonary function testing T C Performing spirometry and pulmonary function testing may lNeOad to SARS-CoV-2 transmission as a result of coughing and droplet formation during the tests.(44,45) During p-eDriOods of high prevalence of COVID-19 in the community, sapssireosms leutnryg fsuhnocutlidonbsetarteusstrfioctreindtetorvpeanttiieonntasl rperqouceiIrdAinuLgrSeusroger nsutrogrereys.sTehnetiAalTtSeasntsdfEoRrSthheavdeiapgronvoisdisedofreCcOoPmDm, eanndda/otirontos regarding testing and precautions that shouldTEbeRtaken.(44,45) Whenever possible, patients should have a RT-PCR test for SARS-CoV-2 performed and the resultsMaAvailable prior to performing the test. Patients with a positive RT-PCR test should normally have procedures should be rtehaessteesssteddealanIydGeHrdeTsuunmtilpntieognaotifvreo.uAtsintehseppirroemvaelternycme aoyf COVID-19 changes be possible.(46-48) over time operating PYR When routine spirometry isCnOot available, home measurement of peak expiratory flow (PEF) combined with validated patient questionnaires could be used to support or refute a possible diagnosis of COPD.(49-52) However, PEF does not correlate well with the results of spirometry(53-55) has low specificity(56) and cannot differentiate obstructive and restrictive lung function abnormalities. When making a diagnosis of COPD, airflow obstruction could also be confirmed by giving patients a personal electronic portable spirometers,(57,58) and instructing them in their use and observing them in their homes using video conferencing technology. Bronchoscopy In some people with COPD, diagnostic and therapeutic bronchoscopy may be required during the COVID-19 pandemic. Elective bronchoscopy should be delayed until patients have a negative PCR test.(59,60) In urgent cases where COVID- 19 infection status is unknown, all cases should be managed as if positive. A disposable bronchoscope should be used if available(59) and staff should wear PPE. Radiology Chest radiography is insensitive in mild or early COVID-19 infection(61) and is not routinely indicated as a screening test 172 for COVID-19 in asymptomatic individuals. Chest radiography is indicated in people with COPD with moderate to severe symptoms of COVID-19 and for those with evidence of worsening respiratory status (Figure 7.1).(62) COVID-19 pneumonia changes are mostly bilateral.(63) Chest radiography can be useful for excluding or confirming alternative diagnoses (e.g., lobar pneumonia, pneumothorax, or pleural effusion). Point-of-care lung ultrasound can also be used to detect the pulmonary manifestations of COVID-19.(64) Computed tomography (CT) screening may show evidence of pneumonia in asymptomatic individuals infected with SARS-CoV-2(65) and false-negative RT-PCR tests have been reported in patients with CT findings of COVID-19 who eventually tested positive.(39) Recommendations have been made on the use of CT as part of diagnostic testing and severity assessment in COVID-19(62) and there are no special considerations for people with COPD. The initial features of COVID-19 on CT and their progression over time have been reviewed.(66) COPD patients with COVID-19 have an increased prevalence of ground-glass opacities, local patchy shadowing, and interstitial abnormalities on CT compared with patients without COPD.(67) A small case series of patients with emphysema and COVID-19 found that many had bilateral ground glass opacities with areas of consolidation; however, the pattern was variable and patients had more pronounced disease in the lung bases.(68) The availability of CT may be limited by infection control requirements(69) and whereUaTcEcess to CT is limited, chest radiography may CT. An increased be preferred occurrence ofof rdpeaetpievnetsnowuitshtChOroVmIDb-o1s9isunanledsspfuelamtuorneasroyftrhersopmirTbaRtooeIBrmy worsening bolism has warrant the use been reported of in patients with COVID-19,(70-75) if pulmonary embolism is suspected chest CT angDioISgraphy should be performed. Y OR COP T NO - DO ERIALS MAT YRIGHT COP 173 PROTECTIVE STRATEGIES FOR PATIENTS WITH COPD People with COPD should follow basic infection control measures to help prevent SARS-CoV-2 infection including social distancing and washing hands which are associated with reductions in the incidence COVID-19 (Table 7.1).(76) At times of high community prevalence of COVID-19, wearing a mask or face covering can reduce the risk of spreading infection (source control).(77) The efficacy of masks and respirators in protecting patients against infection are unknown but both surgical masks and N95 respirators were effective in preventing influenza-like illness and laboratory-confirmed influenza among healthcare workers.(78) The American College of Chest Physicians, American Lung Association, ATS and COPD Foundation have issued a joint statement on the importance of patients with chronic lung disease wearing facial coverings at times of high COVID-19 prevalence during the pandemic.(79) Wearing a tight-fitting N95 mask introduces an additional inspiratory resistance. Respiratory rate, peripheral oxygen saturation and exhaled CO2 levels were adversely affected in COPD patients wearing a N95 mask for 10 minutes at rest followed by 6 minutes of walking (80); however, wearing a surgical mask does not appear to affect ventilation even in patients with severe airflow obstruction(81) and overall the negative effects of using cloth or surgical face masks during physical activity appear negligible.(82) In some countries where wearing face masks wasUcoTmEpulsory in certain settings erexqeumirpetdiopnesocpolueldwibteh mCOaPdDe fsohropualdtiternyttsowwheoaarrme absrkesa.thInlemssoasnt dcacsaensn, oatlotoolseerraftaecweTecRoarvIBienrginagm, oarsekv; ehnowa efavceer,swhiheeldnemvaeyr be tolerable and effective.(83,84) DIS OR The trav normal rules for patients on LTOT el unless essential. Supplementary should be follo oxygen should wbeeddeifliaveirretrdavbOeyPl nYisaspalal ncannendu,(l8a5)( although 86) with a patients should surgical mask be avoid worn and distancing maintained. NOT C Shielding, or sheltering-in-place, is a way to protect peo- pDlOe who are extremely vulnerable from coming into contact with coronavirus. some countries for IptaistieanntsalwteirthnasteivveerteoCfOulPl-Dsc. aIlneIAtphLheSyUsiKcaClOdPisDtapnactiniegntms ewaesruereasdvoirselodctkodoshwienlsd. It was introduced in if they had an FEV1 < 50%, mMRC 3, a history of hospitalization foTrEaRn exacerbation, or required LTOT or NIV. Modeling suggests shielding was an effective strategy to shield it is important to protect that they ainredivgTiidvMeunaAlsadanvidcecoanbtoroulttkheeeimpinpgacatcotfivSeARanS-dCoexVe-2rc.(i8s7i)nIgf people with as much as COPD are possible asked whilst shielded. Plans should be made to eInGsHure supplies of food, medications, oxygen, supportive health services and other basic necessities can be maintaPinYeRd There are likely to be particCuOlar challenges in using shielding in low- and middle-income countries including the fact that many families will not be able to designate a separate room for high-risk individuals and may rely on the income or domestic support that these individuals provide.(88) Vaccination COVID-19 vaccines are highly effective against SARS-CoV-2 infection requiring hospitalization, ICU admission, or an emergency department or urgent care clinic visit, including those with chronic respiratory disease.(89) People with COPD should have COVID-19 vaccination in line with national recommendations. 174 DIFFERENTIATING COVID19 INFECTION FROM DAILY SYMPTOMS OF COPD Differentiating the symptoms of COVID-19 infection from the usual symptoms of COPD can be challenging. Cough and breathlessness are found in over 60% of patients with COVID-19 but are usually also accompanied by fever (> 60% of patients) as well as fatigue, confusion, diarrhea, nausea, vomiting, muscle aches and pains, anosmia, dysgeusia and headaches.(18) In COVID-19 symptoms may be mild at first, but rapid deterioration in lung function may occur (Figure 7.1). The prodrome of milder symptoms is especially problematic in patients with underlying COPD who may already have diminished lung reserve. Lack of recognition of the prodromal symptoms may delay early diagnosis and preliminary data suggest that people with COPD reporting exacerbations and suspected of having COVID-19 infection were infrequently tested for its presence.(90) A high index of suspicion for COVID-19 needs to be maintained in people with COPD who present with symptoms of an exacerbations, especially if accompanied by fever, impaired taste or smell or GI complaints. UTE Persistent symptoms in people with COPD may cause diagnostic difficulty. A studyTfRouIBnd that only 65% of people had returned to their previous level of health 14-21 days after testing positive for DSAISRS-CoV-2.(91) Some patients continue to experience cough, fatigue and breathlessness for weeks and a smaller prOopRortion for months.(91-93) Delayed recovery was more common in people with multiple chronic medical conditPioYns but was not specifically linked to having COPD.(91) CO NOT MAINTENANCE PHARMACOLOGICAL TREATMENT FOR - DO COPD DURING THE COVID19 PANDEMIC IALS TER The use of inhaled and systemic corticosterMoAids has been controversial in the prevention and treatment of COPD during tohfeeCxaOcVeIrDb-a1t9iopnasn(dCehmapict.erIC3S)h. aHvoewaIeGnvHeorTv,etrhaellrperoisteacntivinecerfefaescetdagraisiknsotfexpanceeurmbaotnioiansaisnsoCcOiaPtDedpawtiiethntIsCwS iuthsea, history raising concerns that immunosuppressPioYnRwith ICS could increase susceptibility to infections in some individuals. Laboratory experiments shCowO that corticosteroids reduce the production of anti-viral interferons (type I and III), increasing the replication of rhinovirus and influenza virus.(94-96) In contrast, other laboratory data show that corticosteroids and long acting bronchodilators can reduce the replication of coronaviruses including SARS-CoV-2.(97) These laboratory experiments suggesting a potential protective effect of ICS against COVID-19 have not been validated by clinical studies. A systematic literature review identified no clinical studies in COPD patients concerning the relationship between ICS use and clinical outcomes with coronavirus infections including COVID-19, SARS and Middle East Respiratory Syndrome (MERS).(98) A more recent study has shown ICS use in COPD was not protective and raised the possibility that it increased the risk of developing COVID-19(99) but the results are likely to be confounded by the indication for ICS.(100) A systematic review of more recent studies found no evidence that ICS use was associated with worse outcomes(11); however the conclusions were again limited by similar confounding, lack of reporting of and adjustment for comorbidities, and studies with small sample sizes. In people who do not have COPD, ICS use appears to reduce the risk of admission to hospital or death and reduce the duration of symptoms.(101) There are no conclusive data to support alteration of maintenance COPD pharmacological treatment either to reduce the risk of developing COVID- 175 19, or conversely because of concerns that pharmacological treatment may increase the risk of developing COVID-19. Similarly, there is no data on the use of long-acting bronchodilators, LAMA or LABA, roflumilast, macrolides in people with COPD and clinical outcomes/risk of SARS-CoV-2 infection; thus, unless evidence emerges, these patients should continue these medications required for COPD. IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP Use of nebulizers Aerosol therapy increases the droplet generation and risk of disease transmission. Although most of the aerosol emitted comes from the device(102,103) there is a risk that patients may exhale contaminated aerosol and droplets produced by coughing when using a nebulizer may be dispersed more widely by the driving gas. SARS-CoV-2 has been shown to be viable in aerosols for up to 3 hours(104) and transmission to health care workers exposed to a hospitalized patient with COVID-19 receiving nebulized therapy has been reported.(105) If possible, pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) and soft mist inhalers (SMI) should be used for drug delivery instead of nebulizers. The risks of nebulized therapy spreading infection to other people in patient's homes may can be minimised by avoiding use in the presence of other people, and ensuring that the nebulizer is used near open windows or in areas of increased air circulation.(106) Nebulizers may be needed in critically ill patients with COVID-19 receiving ventilatory support. In this case, it is vital to keep the circuit intact and prevent the transmission of the virus. Using a mesh nebulizer in ventilated patients 176 allows adding medication without requiring the circuit to be broken for aerosol drug delivery.(107) NONPHARMACOLOGICAL TREATMENT FOR COPD DURING THE COVID19 PANDEMIC During the COVID-19 pandemic people with COPD should continue with their non-pharmacological therapy (Chapter 4).(108) Patients should receive their annual influenza vaccination, although the logistics of providing these at times of social distancing can be challenging.(109) There is no reason to modify palliative care approaches because of COVID-19. Many pulmonary rehabilitation programmes were suspended during the pandemic to reduce risks of spreading SARS- CoV-2. When case rates are high, center-based rehabilitation is not appropriate. Patients should be encouraged to keep active at home and can be supported by home-based rehabilitation programmes which, although likely to be less effective than traditional pulmonary rehabilitation with supervision (Chapter 3), are likely to be better than not ousffeefruinl gtoreshuapbpiolitrattihoonm. eTerechhnaboilloitgayt-iboanseddursiongluttihoensp, asnudchemaisc.wAesb-pbraosgerdamormsemsaartrpehroeUnseTtaEartpepdlicgaetnioenrsa(l11p0,r1i1n1)cimplaeys be of infection control should be applied and local guidance followed.(112) TRIB DIS REVIEW OF COPD PATIENTS DURING THE COVID19 Y OR PANDEMIC COP T NO To minimize the spread of consultations using online, SARS-CoV-2 phone and many health video-links. -sRyDosOutetimnes reduced face-to-face visits and introduced remote review of people with COPD can be undertaken remotely(113) and for the remote v we isit, have produced a too set the visit agenda lwtoithsutphpeIAoprLtaSttiheenste, interactions t and provides hat includes instructions a standardized checklist on how to for follow prepare -up (see section on follow-up at the end of Chapter 7)T. ER MA TREATMENT OF COVID19 IN PATIENTS WITH COPD IGHT PYR Randomized clinical trials oCf tOreatments targeting COVID-19 have focused on anti-viral agents and anti-inflammatory treatments. Some have produced positive results, including systemic steroids for hospitalized patients with severe COVID-19.(114) The WHO has produced a COVID-19 therapeutics living guideline(115) which currently recommends antivirals, corticosteroids, IL-6 receptor blockers and baricitinib for the treatment of COVID-19. The European Respiratory Society has also produced a living guideline on the management of hospitalized adults with COVID-19.(116) Sub-group analysis of the effectiveness of these therapies in COPD patients have not been presented. In the absence of subgroup data, we recommend that COPD patients suffering with COVID-19 should be treated with the same standard of care treatments as other COVID-19 patients (Table 7.2). Furthermore, we advocate that COPD patients should be included in randomized controlled trials of COVID-19 treatments and that subgroup analysis of their outcomes are presented. 177 IBUTE DISTR Y OR COP T NO - DO ERIALS MAT YRIGHT COP EXACERBATIONS OF COPD The prevention and treatment of exacerbations are important goals in COPD management (Chapter 4). COVID-19 infection has introduced unique obstacles to the prevention and management of exacerbations.(31) These include limited access to therapies due to their use for COVID-19 patients without COPD, disruptions in global supply chains and the inability of patients to afford medications due to economic hardships associated with the pandemic.(31) Conversely, as countries went into lockdown and industrial activities shut down, pollutant emissions reduced substantially and environmental air quality improved.(117) This could have contributed to the reported reductions in hospital admissions for COPD during the COVID-19 pandemic.(32,33,118) Coronaviruses are among the respiratory viruses that trigger COPD exacerbations.(119) To date MERS-CoV, SARS-CoV, and SARS-CoV-2 infection have not been reported in COPD exacerbations. Nonetheless, any COPD patients with SARS- 178 CoV-2 infection presenting with respiratory symptoms requiring changes in their maintenance medications would fulfil the definition of an exacerbation (Chapter 5). Distinguishing the symptoms of a typical exacerbation from COVID-19 infection can be extremely difficult as many of the symptoms overlap. If COVID-19 infection is suspected, then RT-PCR testing should be conducted. If COVID-19 infection is confirmed, then treatment for COVID-19 infection should be conducted regardless of the presence of COPD. SARS-CoV-2 infection causes a distinct pattern of pathophysiological changes including vascular injury, pneumonitis associated with hypoxemia, coagulopathy, high levels of systemic inflammation ("cytokine storm") and multi-organ involvement.(120,121) These features are very different from typical COPD exacerbations.(122) However, SARS-CoV-2 infection may resemble an exacerbation of COPD. Fever, anorexia, myalgias, and gastrointestinal symptoms are more frequently reported in COVID-19 than in exacerbations of COPD, whereas sputum production is less uncommon. Pronounced lymphopenia is a common finding of SARS-CoV-2 infection.(72,123) COPD patients who develop COVID-19 reported more severe fatigue, dyspnea, and diarrhea than those without COPD.(67) In patients with COVID-19 lymphopenia, thrombocytopenia, elevated D-dimer, C-reactive peptide (CRP), procalcitonin, creatinine higher risk kinase, of poor transaminases, outcomes.(124) creatinine, There is no and lactate dehy reason to suspect drogenase that this is (dLiDffHer)eanrteininCdTOeEPpDenpdaetnietnlytsawssiothciaCtOeVdIDw-i1th9 (Figure 7.1). RIBU Systemic corticosteroids DIST Caution has been raised about the widespread use of systemic corticoOstReroids in patients with COVID-19.(125,126) Observational studies in patients with SARS and MERS reported nOoPaYssociation between systemic corticosteroids (oosftteeonneactrohsiigsh, adnodser)edanudcedimvpirroavl ecdleasurarvnicvea.l(,127b-1u3t0) sTuhgegeWsteHNdOOtThinaCittiaclolyrtirceocsotmermoiednsdiendduacgeadinssitdetheeffreocutsti,neinculusedinogf cdoisrttriecossstseyrnodidrsoimn eCO(AVRIDD-S1)9 ainnfdecCtiOoPnDatetxhaecbeerbgaintinoinnsg,owf- thDheOerepaandsepmeciicfiecxcinedpitcaintitownofcolrinsicyasltesemtticincgos:rtaidcouslttererospidirsatwoarys recognized.(131) IALS A large randomized trial in hospitalized patienTtsEwRith COVID-19 has shown that dexamethasone treatment at 6 mg/day for up to 10 days reduced mortality in patiMenAts receiving either invasive mechanical ventilation or oxygen alone.(114) A small observational study has also IrGepHoTrted that methylprednisolone use was associated with improved survival in CrmeOedVcuhIcDat-ino1in9caopl fvaetmineotnirltatsatilwoitnyithoartAo2RnC8DOpSdr.Pa(e1yYs3s2sR)oiFnrusprutaphtpeieornrsttts.(u1w3d3ii)eths ChOavVeIDa-l1s9o prenpeourmteodnitah,eesbpeenceiafiltlsy othfossyesttehmaticagreluncooctoornticionivdassiovne Systemic steroids should be used in COPD exacerbations according to the usual indications (Chapter 5) whether or not there is evidence of SARS-CoV-2 infection as there is no evidence that this approach modifies the susceptibility to SARS-CoV-2 infection or worsens outcomes (Figure 7.1). Antibiotics Antibiotic treatment for a COPD exacerbation is indicated if patients have at least two of the three cardinal symptoms including increased sputum purulence, or if the patient requires mechanical ventilation (Chapter 5). Bacterial co-infections have been reported infrequently in COVID-19.(134) However, the risk of co-infections increases with the severity of COVID-19. Bacterial co-infections have been detected by multiplex PCR testing in up to 46% of samples collected in a small cohort of COVID-19 patients admitted to an ICU.(135) Diagnosing co-infection in COVID-19 patients may be difficult, particularly in critically ill patients, as the clinical presentation, biomarkers and imaging data may be unhelpful. In practice, most hospitalized patients, particularly the severe ones, have been prescribed empirical 179 antibiotic therapy.(123) Current WHO guidelines recommend broad-spectrum antibiotics in severe COVID-19 patients, guided by local/national guidelines, and in milder COVID-19 infections when there is clinical suspicion of a bacterial infection.(131) In the absence of specific studies, these general considerations would also apply to people with COPD infected with SARS-CoV-2. Antibiotics should be used in COPD exacerbations according to the usual indications (Chapter 5) whether or not there is evidence of SARS-COV-2 infection, particularly as people with COPD who develop COVID-19 are reported to more frequently develop bacterial or fungal coinfections.(67) PULMONARY AND EXTRAPULMONARY COMPLICATIONS ARDS may be part of COVID-19 and could be considered the major pulmonary complication of COVID-19(136) with viral infection in areas of ongoing active injury contributing to persistent and temporally heterogeneous lung damage.(137) Some early reports suggested that ARDS in this setting may differ from the typical ARDS.(138,139) Subsequent studies, however, suggested considerable overlap that classical ARDS also presented with a large variation in between classical ARDS and COVID-19 patients.(141,142) Whether tlhUuenTglEonsegv-teerritmy(1c4o0)nsaenqduethneceres is of this form of ARDS differ from fibrotic lesions described previously is unclear.(143,144T) RIB Although the respiratory tract is the main target of COVID-19, extra-pulDmIoSnary involvement is frequent and contributes to morbidity, disability, and mortality.(121,145) Renal, caOrdRiac, nervous, cutaneous, hepatic and gastrointestinal manifestations occur.(146) It remains unclear, howevOerP, Yif these manifestations are directly caused by infection of angiopathy, SARS-CoV-2, or to secondary phenomena treatment or ischemic damage due to itnhceludiminpOgaTiinrmCapepnrtoporfiattheeorreosvpeirrawtohreylmfiunngctimiomnsu. nCeornecsopmonitsaenst, respiratory comorbidities, such COPD, may aggravate thesOe Nprocesses. Compared to lung viral load, lower levels of SARS-CoV-2 have been reported in the kidneys, liver, he- aDrt, and brain,(147) suggesting secondary rather than primary involvement of these organs. ALS Anticoagulation TERI COVID-19 has been associated with a hypeMrcAoagulable state(70) and venous thromboembolism (VTE) rates in both ICU and ward patients are 2- to 4-foldIGhHigTher than expected despite thromboprophylaxis with low molecular weight heparin (LM hospitalized WwHit)hoCrOuVnIfDra-1ct9iosnhaoPtueYlddRhreepceairvine. (148) People with COPD are already at pharmacologic thromboprophylaxis increased risk o (Figure 7.1). In f VTE(149,150) and those response to the high rates despite prophylactics CmOany institutional protocols have adopted intermediate-intensity (i.e., twice daily LMWH rather than once daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis.(151) Generally, LMWH is favored over unfractionated heparin to reduce staff exposure but clinicians should follow local guidelines on dosing and drug. 180 VENTILATORY SUPPORT FOR COPD PATIENTS WITH COVID19 PNEUMONIA The prevalence of hypoxic respiratory failure in patients with COVID-19 was around 19%.(152) Ventilatory support has been used in up to 20% of patients that develop severe hypoxemia due to COVID-19(153) and approximately 5% of patients require ICU care and advanced respiratory support.(154) Since the introduction of vaccination the rates of ICU admission have fallen.(155) However, some patients still require ventilatory support and these individuals still have a high risk of mortality.(20,156,157) COPD has been reported to increase the risk respiratory failure and ICU admissions in some, but not all studies.(14,19) There was wide variation (2.3% to 33%) in the early reported rates of use of invasive mechanical ventilation (IMV) in hospitalized patients with moderate to severe hypoxemic respiratory failure due to COVID-19.(158) This may, in part, have reflected differences in use of non-invasive ventilation (NIV) and high flow nasal therapy (HFNT),(158) possibly as a result of advocation of early intubation during the pandemic's initial phases because of concerns about viral dissemination.(159,160) Data supporting those concerns are lacking.(161) UTE Although early reports showed mixed outcomes,(162) several studies have nowTsRhIoBwn showed HFNT significantly reduces rates of intubation and IMV, although with variable effects on DIS mortality.(163,164) HFTN should be considered in preference to NIV for acute hypoxemic respiratory failure despite conventOioRnal oxygen therapy as it may have a lower failure rate.(165-167) Prone positioning has also been suggested for awaOkPeYnon intubated hypoxemic patients.(168) NIV is the normal standard of care for COPD patients with acute rTesCpiratory failure (Chapter 5). NIV may be beneficial for the treatment of hypercapnic respiratory in COPD patientsNwOith COVID-19 pneumonia, but it also has the potential to worsen lung injury as a result of high transpulmona-ryDpOressures and tidal volumes.(169) Patients on HFNT or NIV should similar be to monitored closely for worsening that used in other forms of ARDS, acnodnseidaIreAlryLeSidn.t(1u7b0,a17t1io) n A and IMV with PaO2/FiO2 < 1 adoption 50 mmHg of a pro may be tective lung strategy, a useful indicator for NIV failure and increased risk of mortality.(172)TER At the start of the COVID-19 pandemTicM, Athere was a reasonable rationale for using extracorporeal membrane oxygenation ECMO in patients witIhGHvery severe COVID-19-related ARDS, and results from large cohorts suggest outcomes pandemic during the continued, mfirosrttawliatvyPeoYofRfpathtieenptasnsduepmpoicrtwederwe istihmEilCaMr tOo those in non-COVID-19 cohorts.(158,173-179) As the has increased, possibly because of differences in patients referred for ECMOCasOa result of more widespread use of NIV and corticosteroids prior to intubation, changes in mechanical ventilation strategies and possible pathophysiological changes due to emerging viral variants.(180) Indications in COVID-19 remain similar to indications for other causes of ARDS(181,182) and ECMO should be considered only after other strategies fail to achieve goals of oxygenation or ventilation.(176,177,179) Aerosol generation can occur when any form of additional pressures or flows are applied to the upper or lower respiratory tract.(183) Data regarding aerosol dispersion with the use of NIV is limited and contradictory ; (103,183-185) however, staff should use appropriate personal protective equipment (PPE)(167,186) and viral filters fitted to exhalation ports of invasive or noninvasive ventilation devices. Isolation hoods have also been suggested by some to be used to further decrease staff exposure.(187) 181 REHABILITATION COPD patients with COVID-19 are particularly at risk for poor nutritional status and skeletal muscle loss.(188) Hospital treatment should therefore include dietary support and early mobilization. Mechanical ventilation, sedation, and prolonged bed rest, may lead to post-traumatic stress disorder(189) and respiratory, cognitive, and mental health impairments as well as physical deconditioning.(190,191) Older people and people with COPD, are more susceptible to these consequences.(192,193) Rehabilitation should be provided to all COPD patients with COVID-19, particularly to those that have been more severely affected or required ICU admission. A multinational task force has recommended early rehabilitation during the hospital admission and the screening for traits treatable with rehabilitation in all patients at discharge, and at 6-8 weeks after discharge for patients with severe COVID-19.(194) FOLLOWUP OF COPD PATIENTS WHO DEVELOPED COVID19 UTE Several organizations have developed guidelines to address the evaluation and mTaRnIBagement of patients recovering from COVID-19(92,195-198) but none of these have specific recommendationDs ISfor patients with underlying COPD. Assessment protocols generally include a comprehensive physical, cognitivOeR, and psychological assessment and there itshensoereevaasolunatwiohnyatnhdesme asnhaogueldmneontt astlsroataepgpielsy atorepsattililelnatcskiwngit.h COPCDO; hPoYwever. high quality data on the outcomes of The intensity of the monitoring of people with COPD who devNeOloTped COVID-19 should be determined by the severity of the initial episode. - DO Patients who developed mild COVID-19 should beIfAoLllSowed with the usual protocols used for COPD patients (Chapter 3). Patients who developed moderate COVIDT-1E9R, including hospitalization and pneumonia but no respiratory failure, should be monitored more frequently anMd Aaccurately than the usual COPD patients with particular attention to the need for oxygen therapy. IGHT One year after COVID-19 one PthYirRd of patients have residual CT abnormalities,(199) with ground-glass opacities and fibrotic-like changes of CT abnormalities seen was inhCi2gO0h%erofinpasteievenrtes,/cbruitticnaol specific data cases than are available on patients in mild/moderate cases with COPD. The (38% vs. 21%). frequency Gradual improvement is seen on CT over time but fibrotic changes showed little improvement between 4-7 months and one year after COVID-19. If chest X-ray abnormalities have not resolved at hospital discharge, a chest X-ray, possibly a CT scan should be considered at 6 months to one year. Complications occurring during/after the COVID-19 episode should also be monitored. COPD patients are at higher risk of developing severe COVID-19(170,200) and multimorbid survivors frequently have required prolonged ICU stays.(170) Until we have evidence from prospective studies, COPD survivors of severe COVID- 19 should be considered at high risk of developing a "critical illness"(201) or "chronic critical illness",(202) a severe heterogeneous condition linked not only to the acute infectious episode but also to the underlying conditions before they became severely ill.(191) There are informative candidate models for the comprehensive management of complex care delivery that are already published and undergoing study in the primary care setting, and these may be adapted for application after COVID-19.(203) 182 REMOTE COPD PATIENT FOLLOWUP DURING COVID19 PANDEMIC RESTRICTIONS Introduction During the COVID-19 pandemic, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recognized that there was a need for developing new approaches to interact with COPD patients. Remote consultations are superb tools to minimize the risk of transmitting coronavirus and will be necessary for some time. The systems put in place to facilitate remote consultations should also help increase the efficiency and capacity of the health care system into the future.(204) In this short document, GOLD provides guidance to support the remote interaction with COPD patients who are usually seen in primary or secondary care. The tool includes instructions on how i) to prepare for the remote visit; ii) to set up the visit agenda with the patient; and iii) provides a standardized checklist for follow-up of COPD patients whether in- person, by phone or in a virtual/online setting. UTE The principles of good record keeping and clinical practice should always apply: i) trTeRaItBpatients with dignity; ii) respect people's right to privacy and confidentiality; iii) listen to the patient's needs anDdISact in their best interest; and iv) base your recommendations on the best available evidence. Y OR Triage and prioritizing process COP T The process of triage should help decide: a.) whether virtual/online) consultation, and b.) who to prioritize. to offNeOr an in-person as opposed to a remote (telephone or - DO Remote follow-up Patient or ccaorueldgivbeerccoannsiudnedreerdstinanthdethfoellporIwAociLneSgsssiatnudatpiornosv:ide information clearly; Regular COPD follow-up or patient foTlloEwRed for a known condition; Medical records and laboratory teMstAresults are accessible to the healthcare professionals; Prescription necessary. and access toIGmHeTdication is possible and follow-up to the prescription can be arranged if PYR In-person follow-up should CbeOprioritized in these situations: Patient and caregiver have difficulty providing information; Patient needs immediate attention due to the presence of severe medical symptoms; Changes in patient's symptoms require a differential diagnosis work-up with the need for a physical exam and/or laboratory testing; Patient treatment can only be given in person and cannot be given at home. Prioritization of in-person visits should take into consideration the COPD patient disease severity (symptom burden and risk of exacerbations), recent emergency department visit and/or hospital admission, associated significant comorbidities, age, and/or living alone at home. 183 Consideration and instruction for remote COPD followup Ensure documentation of the whole visit (in writing) as you would normally do for an in-person follow-up. The documentation should reflect that this is a remote follow-up (telephone or virtual/online) and should be specific about how the information was obtained. 1. Start the call by a. Introducing yourself and, if necessary, any other health care professional(s) who may be with you (e.g., case manager, student, resident, etc.); b. Verifying who you are speaking with (patient name and date of birth), and patient consent to receive remote follow-up; c. If applicable, informing patient that the speakerphone is on; 2. Welcome the patient to the call a. Verify technical issues; b. Ask the patient if (s)he can hear you well; c. Describe what to do if the connection fails; IBUTE 3. Explain that this is a remote visit and give the reason why; DISTR 4. Check if there are others listening to the conversation, and if patiOenRt consents to all those present; 5. Set the agenda (agree on elements to be discussed, time alloOtPteYd, etc.); T C 6. Conduct the followup visit using the instructions beNloOw in the COPD Follow-up Checklist and remember to keep the focus on the main issues raised by the-pDatOient; 7. End and summarize the visit IALS a. pAlsaknthoer ipnatteirevnetnttoiosnumyomuAahTraiEzveRewahgraetetdheudpiosncu(sifsiaonnyahnodmmeawinorikss);ues have been, reinforce any action b. c. ASegtreuepuapdoanteenfodrinfHgolTtlohMwe -muepe; ting. YRIG COP 184 COPD FOLLOWUP CHECKLIST In-person Follow-up Date: YYYY / MM / DD Phone Follow-up Diagnosis: Virtual/online Follow-up 1. BASELINE SYMPTOMS - Breathlessness on a regular day: mMRC /4 Daily sputum production: no yes, color: Regular cough no yes Recent change in symptoms no yes Maintenance Medication and adherence: If yes, since when: Sputum color: Dyspnea = Cough = Signs of hypercapnia Sputum volume = Fatigue = Other CAT: /40 SABA LABA LAMA Other: LABA+LAMA LABA+ICS LABA+LAMA+ICS Non pharmacological Rx: O2: CPAP: BIPAP : 2. COVID-19 - If patient is feeling unwell, check other symptoms: Fever____ Sore throat Anosmia Others________ Contact with someone COVID-19 positive? no yes Tested for COVID-19? no yesUTIEf yes positive negative 3. WRITTEN ACTION PLAN - no es TRIB Instruction and any additional treatment: _______y___________________________DIS Last time it has been used (date): OR 4. RECENT ADMISSIONS AND EMERGENCY VISITSOPY T C Comments: Hospital/ER Where Date Length RNeOason (Dx) - DO 5. COPD Smoke-free Self-management environment (healthyyesbehnaoIvAioLcSrasn)n-ot Itenltl egrated (patient has used it in his daily life)? Medication adherence yes TEnRo cannot tell Prevention/management of exacerbations Breathing control yyMeesAs no no cannot tell cannot tell Stress management Physical activity and exercise IGHT y y es es no cannot tell no cannot tell Other _____________ Comments and what patient shoPuYldRprioritizyeesbasednoon his/her need: CO 6. MAIN ISSUES 1. 2. 3. 7. SUMMARY, INTERVENTIONS & PLAN (healthcare professional name & signature) 185 Instructions for using the COPD followup checklist 1. Introduction a. Identify dates, Dx and whether this follow-up is being done in-person, by phone or remotely. 2. Section 1 - Baseline symptoms a. Go over the patient symptoms and whether there have been changes in dyspnea, cough, sputum volume and color (from least to most purulent: mucus; mucopurulent; purulent). b. Identify maintenance pharmacological and non-pharmacological treatment and whether the patient is observing treatment as prescribed. 3. Section 2 - COVID19 a. Assess whether the patient has any symptoms of COVID-19 and would need to be tested. Have at hand local numbers where the patient can be referred to for testing and treatment. b. If the patient has already been tested identify when the results will be obtained, or whether the result was positive or negative. If positive, is there a follow-up test planned, and dates. c. Verify patient is practicing COVID-19 precautions (face masks, hand washing, social distancing, or shielding if necessary). 4. Section 3 - Action Plan UTE a. LDievisncgribweeilfl wthiethpCaOtiePnDtparloregaradmy h[a1s].aDwesrcitrtiebne aifctthioenepdluanca. tSieoen efoxramthTpiRsleIaBcotfioann palcatniohnapslaanlrefraodmy btheeen done. Describe if the written action plan includes a prescriptioDnISto be self-administered at home or whether the patient need to call his contact person / physOicRian to obtain the prescription. Describe 5. Section when it was used the last time 4 - Recent Admissions and ER and if visits used appropriaOtePlyY. a. Write down recent admissions and ER visits, dateTsCand where they took place. 6. Section 5 - COPD SelfManagement behaviors NO a. pGeortoivneernet atochthoef tphaetiseenltf-tmreaantaagbelemteranittsb-e(dDhyaOsvpionresadaensdc/riobreedxiancethrbealitsiot.nY)o[u2]s.hDoeuslcdricboevwerhwethhaetristhe patient has integrated these strateIAgLieSs in their daily life (yes), not at all (e.g., it has not been 7. Section discussed or not 6 - Main issues applicable)A, aTnEdRwhether the patient is unsure "cannot tell". a. fIdoer nthtiefydwuritahtitohneopfatthieeHncTtatlMhl.eAmvoaiidnciossvueersinogfttohoe call. Up to a many issues maximum of in one visit. 3 items that can be covered 8. Section 7 - Summary, InYteRrIvGention and Plan a. aFignraeleizdebbyytdCheeOspcPraitbieinngt,ththeeinptlearnv,einnctiloundsindgownehedtuhreinr gthteheparetimenotteneveisdits,ttohebeonreefsetrorebdetpouottihneprlsaecrev,icaensd, healthcare professionals, etc. and when the next follow-up will take place (describe whether will it be in-person or remote). 186 REFERENCES 1. Mahase E. Covid-19: Increased demand for steroid inhalers causes "distressing" shortages. BMJ 2020; 369: m1393. 2. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181(2): 271-80 e8. 3. Maes T, Bracke K, Brusselle GG. COVID-19, Asthma, and Inhaled Corticosteroids: Another Beneficial Effect of Inhaled Corticosteroids? Am J Respir Crit Care Med 2020; 202(1): 8-10. 4. Leung JM, Yang CX, Tam A, et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. 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