European Respiratory Society
COPD in the 21st Century

COPD remains a major cause of ill health, disability, healthcare costs and premature mortality. Scientists and clinicians across many countries have made great efforts to understand this important disease, and these have yielded positive results. This Monograph provides an up-to-date overview of what is happening in this exciting field, both at a basic and a clinical level. Beginning, crucially, with the patient’s perspective, the chapters that follow consider the best way to define COPD, changes in the disease’s incidence and prevalence, and offer new insights into the role of the microbiome in COPD, advances in imaging and treatment options, both pharmacological and non-pharmacological. Taken together, these chapters are an important contribution to the Monograph series and the COPD field in general.

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  4. Page 1
    Abstract
    Corresponding author: Courtney Coleman (courtney.coleman@europeanlung.org)

    This chapter aims to capture the patient's perspective on living with COPD, and their hopes for future research and care. The review combines data from the published literature, and insights from a group discussion with people affected by COPD and patient organisations from Europe. COPD can impact every aspect of a person's life, including their physical health, psychological wellbeing, personal relationships and overall quality of life. Patients’ experiences of diagnosis and COPD care are often negative, and they would like to have access to empathic and supportive services that encompass treatment for physical symptoms of COPD, psychological impacts, self-management support, patient education and palliative care. The patients’ priorities for future research include striving to find a cure and better treatment options, understanding how to best meet the changing needs of people with COPD from different demographic backgrounds, and understanding the impacts of air quality on the development and course of COPD.

    Cite as: Senek M, Badyda A, Barbaglia S, et al. The patients’ perspective on living with COPD and their priorities for future research and care. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 1–15 [https://doi.org/10.1183/2312508X.10006123].

  5. Page 16
    Abstract
    Corresponding author: Peter M.A. Calverley (pmacal@liverpool.ac.uk)

    The past three decades have seen enormous advances in our concepts of and treatment for COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition has facilitated epidemiological and clinical studies of COPD, while new imaging methods have provided insights into the earliest stages of the illness. Treatment is now evidence-based and there are clear roles for both pharmacological and non-pharmacological interventions. Personalising treatment to maximise effectiveness is now possible. This chapter reviews some of the key developments in our thinking up to 2020.

    Cite as: Calverley PMA. COPD as the new millennium began. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 16–29 [https://doi.org/10.1183/2312508X.10006223].

  6. Page 30
    Abstract
    Corresponding author: David M.G. Halpin (d.halpin@nhs.net)

    Agreeing a definition of COPD fit for the 21st century is a challenge. This chapter addresses key questions about defining COPD. Are there characteristic clinico-pathological features that can be used to identify COPD? At what point is it possible to distinguish COPD from non-COPD? What tests should be used? What is the threshold for defining COPD? Can we define a state or states of pre-COPD that either define healthy people at significant risk of developing COPD or people with clinico-pathological features that do not yet meet the threshold for diagnosis, and is this necessary or useful? On the basis of the available evidence, the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition appears the best way of defining COPD in the 21st century.

    Cite as: Halpin DMG. Defining COPD in the 21st century. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 30–44 [https://doi.org/10.1183/2312508X.10007123].

  7. Page 45
    Abstract
    Corresponding author: Alvar Agustí (aagusti@clinic.cat)

    Our understanding of the natural history of COPD has changed dramatically over the past few years. Recent research has moved the traditional paradigm of COPD being a self-inflicted disease caused by tobacco smoking and occurring in older males to a disease caused by varied, cumulative and dynamic interactions between many environmental factors and the genetic and epigenetic background of the individual throughout the lifetime (GETomics). As a result, it is now recognised that COPD can occur in both males and females and can have roots very early in life. This new understanding opens novel windows of opportunity for prevention and earlier diagnosis and management. This chapter reviews and discusses this new evidence, as well as the implications for clinical practice and public health policy.

    Cite as: Agustí A, Faner R. A new understanding of the natural history of COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 45–62 [https://doi.org/10.1183/2312508X.10007223].

  8. Page 63
    Abstract
    Corresponding author: David M. Mannino (dmannino@uky.edu)

    COPD is an important cause of morbidity, mortality and healthcare expenditure globally. Epidemiological studies allow us to determine the burden of disease, identify modifiable factors responsible for development and progression of disease, and distinguish effective interventions from ineffective ones. This information helps guide public health efforts and areas for investment and further research. In this chapter, we will discuss the historic view of COPD, examine current epidemiological data, and consider future directions in the epidemiology of COPD.

    Cite as: Khan MI, Khan MMKS, Mannino DM. The new epidemiology of COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 63–80 [https://doi.org/10.1183/2312508X.10006323].

  9. Page 81
    Abstract
    Corresponding author: Tetsuro Maeda (tmaeda@uabmc.edu)

    Cardiac comorbidities are more prevalent in patients with COPD than in those without the disease and significantly affect outcomes. In this chapter, we explore whether they occur by chance or as a consequence of COPD, reviewing several potential mechanisms linking COPD to cardiac disease. These include shared pathobiology (inflammation, accelerated ageing, endothelial dysfunction and elastin degradation), changes caused by COPD affecting the heart (hypoxaemia and hypercapnia, lung hyperinflation), autonomic dysfunction and medications for each condition affecting the other. We also review relevant clinical studies to delineate the consequences of cardiac disease for COPD and vice versa.

    Cite as: Maeda T, Dransfield MT. Cardiac comorbidity and COPD: chance or consequence? In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 81–99 [https://doi.org/10.1183/2312508X.10007323].

  10. Page 100
    Abstract
    Corresponding author: Louise E. Donnelly (l.donnelly@imperial.ac.uk)

    COPD is a common respiratory condition characterised by airway limitation and changes in airway structure. There is currently no curative treatment for COPD and there is an urgent unmet need for new therapeutics that could modify the course of the disease. The mechanisms underlying COPD pathology are complex and are composed of chronic inflammatory processes, oxidative stress induced by continued exposure of the lungs to harmful particles and accelerated ageing due to an increased number of senescent cells within the airways. The main challenge of current studies is to explore how these underlying mechanisms coalesce to drive disease pathophysiology. This chapter aims to describe recent developments in our understanding of COPD mechanisms, from the inflammatory response to the induction of cellular senescence in the lung. Understanding these mechanisms may result in the development of new therapeutics that could be effective for COPD but also for other age-related diseases.

    Cite as: Devulder JV, Donnelly LE. Mechanisms and mediators of disease. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 100–117 [https://doi.org/10.1183/2312508X.10006423].

  11. Page 118
    Abstract
    Corresponding author: Sanjay H. Chotirmall (schotirmall@ntu.edu.sg)

    The lung microbiome plays an important role in maintaining health and is altered during disease. Perturbations of the lung microbiome are implicated in COPD. While lung microbiome studies have gained significant interest over the last decade, challenges remain including optimal and representative sample acquisition and preparation for sequencing, and computationally intense bioinformatic analyses, including their interpretation and reproducibility. Many best-practice approaches are now accessible to mitigate some of these challenges, while fresh avenues of exploration have emerged, including the integration of microbiome data with other ’omics potentially revealing mechanisms of microbial–metabolite and microbial–host interaction that contribute to COPD pathogenesis and disease progression. Whether microbiomes represent potential targets for future therapy in COPD remains unclear; however, understanding mechanisms to restore a healthy microbiome and assimilating microbial information into clinical practice in COPD warrants exploration, and may aid in disease endophenotyping efforts toward personalised care.

    Cite as: Tiew PY, Chotirmall SH. The microbiome and COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 118–134 [https://doi.org/10.1183/2312508X.10006823].

  12. Page 135
    Abstract
    Corresponding author: James P. Allinson (j.allinson@imperial.ac.uk)

    Chronic bronchitis refers to symptoms of sputum production across the preceding 2 years. The meaning of this term has changed across the last century, and how best to define this symptomatic state is still debated. Active smoking is a major, but not the only, cause of chronic bronchitis. Chronic bronchitis increasingly emerges with adult ageing, and may remit and relapse over time. This dynamic symptom pattern often mirrors changing smoking behaviour and reflects the rate of lung function loss. In mid-life, these symptoms appear predictive of future COPD development. Among those with already established COPD, chronic bronchitis predicts poorer quality of life, poorer physical function, accelerated decline in FEV1 and higher mortality. The role of chronic bronchitis in COPD development and progression suggests that it may reflect an underlying pathological process and identifies it as a major potential target for therapy.

    Cite as: Allinson JP. Chronic bronchitis revisited. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 135–148 [https://doi.org/10.1183/2312508X.10006723].

  13. Page 149
    Abstract
    Corresponding author: Dave Singh (dsingh@meu.org.uk)

    Elevated blood and pulmonary eosinophil counts are observed in a subset of COPD patients. Together with exacerbation risk, blood eosinophil counts (BECs) serve as a predictive biomarker of the corticosteroid response in COPD. In COPD, BECs are associated with a pattern of type 2 inflammation in the lungs, which is the likely pharmacological target of ICSs. BECs can be used as a biomarker to help identify patients with COPD who are suitable for biological treatments that target type 2 inflammation. In COPD, low eosinophil counts are associated with a distinct Proteobacteria-dominant microbiome and increased pneumonia risk with corticosteroids. The interplay between eosinophils, type 2 inflammation and the microbiome may determine therapeutic responses in COPD.

    Cite as: Beech A, Singh D. Eosinophils and COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 149–167 [https://doi.org/10.1183/2312508X.10007023].

  14. Page 168
    Abstract
    Corresponding author: Eric A. Hoffman (eric-hoffman@uiowa.edu)

    COPD diagnosis and quantification of its severity is traditionally based on spirometric measurements. Recent advances in lung imaging have provided new insight into the pathogenesis of COPD at the airway, lung parenchyma and vascular levels. In this chapter, we describe how CT has advanced our knowledge of the disease using visual assessment but mainly using automated quantitative methods. Quantitative measurements have made possible the indirect characterisation of small airways disease as well regional assessment of ventilation/perfusion relationships. In addition to advances in CT methods, we introduce the role of magnetic resonance imaging that provides dynamic characterisation of the lung including a measure of gas exchange at the alveolar–capillary interface. These quantitative methods are transformative in regard to the future clinical management of COPD.

    Cite as: Fortis S, Comellas AP, Hoffman EA. Advances in the characterisation of COPD using quantitative imaging. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 168–184 [https://doi.org/10.1183/2312508X.10006523].

  15. Page 185
    Abstract
    Corresponding author: Stephen Milne (stephen.milne@sydney.edu.au)

    Far from being a relic of the 20th century, modern physiological measurements reveal fascinating and clinically relevant insights into COPD. In this chapter, we describe advanced techniques including respiratory oscillometry, inert-gas washout and functional imaging. We highlight the current evidence for the clinical associations of these measurements and describe their potential roles in 21st-century clinical practice. Along the way, we provide detailed but concise summaries of the physiological theory behind these measurements. Finally, we offer perspectives on why these techniques should be incorporated into the assessment of patients with COPD, and what we must do to overcome barriers to their implementation.

    Cite as: Milne S, Tonga KO, Eddy RL, et al. New physiological measurements in COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 185–203 [https://doi.org/10.1183/2312508X.10006923].

  16. Page 204
    Abstract
    Corresponding author: Jørgen Vestbo (Jorgen.Vestbo@manchester.ac.uk)

    In recent years, many guideline documents have used high-level methodology but addressed only a few and very specific questions, with the consequence that their applicability in clinical routine may be limited. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document uses a different approach by covering all relevant aspects of COPD. This document, which was first published in 2001 and revised annually, has evolved over time. Initially the level of airflow limitation served as a basis for treatment recommendations. This was replaced by an assessment scheme tailored to the patient's symptoms and risk of exacerbations. Additionally, a more specific exacerbation definition and an assessment building on signs and symptoms have been introduced. In parallel, the evidence base has become much better, with high-quality clinical trials. Future guidelines will need to address the complexities of multimorbidity.

    Cite as: Vestbo J, Vogelmeier C. Guidelines and strategies of management. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 204–211 [https://doi.org/10.1183/2312508X.10007423].

  17. Page 212
    Abstract
    Corresponding author: Maarten van den Berge (m.van.den.berge@umcg.nl)

    This chapter focuses on the pharmacological treatment of stable COPD. The main treatments of stable COPD are initially short-acting or long-acting bronchodilators, comprising β-agonists (SABAs and LABAs) or antimuscarinics (SAMAs and LAMAs), preferably combined in a single-inhaler dual therapy (LABA/LAMA). A subset of patients may benefit from ICS added to LABA/LAMA treatment, preferably in a single-inhaler triple therapy (SITT; LABA/LAMA/ICS). These treatments improve symptoms and quality of life and reduce exacerbations. Since ICS have side-effects (e.g. pneumonia), they should be given only to patients with higher blood eosinophil counts (>100, preferably >300 cells·μL−1), and their benefits must be balanced with their risks. In patients not controlled by SITT, additional treatments are roflumilast, macrolide maintenance, and possibly dupilumab for eosinophilic COPD.

    Cite as: van den Berge M, Beghé B, Lahousse L, et al. Current pharmacotherapy of COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 212–232 [https://doi.org/10.1183/2312508X.10007523].

  18. Page 233
    Abstract
    Corresponding author: Christopher E. Brightling (ceb17@le.ac.uk)

    There are multiple areas of pharmacotherapy currently in development for the management of COPD. These range from new inhaled bronchodilators that may simplify management to the more distant future of lung-regeneration therapies. Modulating type 2 cell inflammation in relevant patients via monoclonal antibodies has been shown to reduce exacerbations, improve lung function and enhance quality of life. Other anti-inflammatory approaches such as p38 mitogen-activated protein kinase inhibitors and phosphoinositide 3-kinase-δ inhibitors remain under development. New combined phosphodiesterase 3/4 (PDE3/4) inhibitors may be beneficial, while attenuating the side-effects that limit use with PDE4 inhibitors. The advent of “multi-omics” methods of characterising endotypes will allow us to treat patients with greater precision and identify phenotypes earlier. This may facilitate treatments that can modify the disease course, preventing significant structural lung disease and irreversible airflow obstruction. We may be on the brink of a “paradigm shift” in COPD management with biomarker-guided care and early intervention becoming standard, allowing better care for all.

    Cite as: Flynn CA, Aung H, Greening NJ, et al. The future drug treatment of COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 233–254 [https://doi.org/10.1183/2312508X.10016423].

  19. Page 255
    Abstract
    Corresponding author: Sally J. Singh (sally.singh@uhl-tr.nhs.uk)

    Pulmonary rehabilitation (PR) is a key treatment for people with COPD with a strong evidence base that demonstrates improvements in breathlessness, exercise capacity and health-related quality of life. The evidence is so strong that further evidence to demonstrate the effectiveness of PR is not required, rather increasing access and uptake and exploring alternative models of delivery may be beneficial. This chapter explores the future of PR in relation to increasing uptake of the intervention and broadening its scope. We also detail the impact of health inequalities and experiences of delivering PR in LMICs. Finally, as digital technologies embed into society, we explore the potential benefits and challenges of digital and remote options for delivery of PR.

    Cite as: Singh SJ, Daynes E, Sooronbaev TM. The future of pulmonary rehabilitation in COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 255–266 [https://doi.org/10.1183/2312508X.10007723].

  20. Page 267
    Abstract
    Corresponding author: Jadwiga A. Wedzicha (j.wedzicha@imperial.ac.uk)

    Exacerbations are the main cause of death and hospitalisation from COPD. Exacerbation risk increases with disease severity, delayed diagnosis and multimorbidity. As the burden of COPD continues to increase in LMICs, more research is urgently needed to understand exacerbation epidemiology and pathogenesis in these areas in order to develop effective prevention strategies. Respiratory viruses and airway microbiome dysbiosis are common triggers for exacerbations. Exacerbations are associated with both neutrophilic and eosinophilic airway inflammation, as well as mucus hypersecretion. Air pollution is increasingly recognised as a potential trigger of COPD exacerbations. However, further work is needed to understand the relationship between air pollution, airway inflammation and exacerbation risk.

    Cite as: Finney LJ, MacLeod M, Wedzicha JA. New insights into the pathophysiology and epidemiology of COPD exacerbations. In: Wedzicha JA, Allinson J, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 267–282 [https://doi.org/10.1183/2312508X.10007923].

  21. Page 283
    Abstract
    Corresponding author: Marc Miravitlles (marcm@separ.es)

    The pharmacological treatment of exacerbations of COPD has not significantly changed in the last decades. The use of short-acting bronchodilators to improve symptoms, systemic corticosteroids to reduce inflammation and antibiotics to treat bacterial infections is the basis of treatment. Some recent studies have described different phenotypes (or endotypes) of exacerbations and identified biomarkers that may help to personalise treatment, such as purulence of sputum and point-of-care CRP to guide antibiotic treatment and blood eosinophils to guide corticosteroid treatment. Severe exacerbations also require other strategies, such as oxygen therapy, noninvasive or invasive mechanical ventilation, and high-flow oxygen. The right treatment of an exacerbation and the implementation of a discharge bundle may result in a prolonged time to the next episode, but prevention of exacerbations of COPD is also based on an optimal treatment of stable COPD, including rehabilitation and physical activity.

    Cite as: Baraldi F, Barrecheguren M, Papi A, et al. Managing exacerbations of COPD: how much progress have we made? In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 283–296 [https://doi.org/10.1183/2312508X.10008023].

  22. Page 297
    Abstract
    Corresponding author: Winfried Randerath (randerath@klinik-bethanien.de)

    COPD is characterised by damage of the alveolar and vascular structures and peripheral airways. These characteristics are associated with a loss of gas-exchange surface, heterogeneous distribution of ventilation over the lungs, an increase in ventilation–perfusion mismatch, lung hyperinflation and increased work of breathing. Therapeutic approaches to address hypoxic failure include oxygen supply and positive end-expiratory pressure. Hyperinflation with a flattened diaphragm and a horizontal course of the ribs reduces the efficiency of the respiratory muscles. The work of breathing may overcharge the capability of the ventilatory system. The treatment of choice for hypercapnic failure is noninvasive ventilation (NIV), which can be used to avoid invasive ventilation, prevent ventilatory failure after extubation and improve long-term outcome in chronic respiratory failure. The efficacy of NIV depends crucially on optimal adaptation of the interface, precise selection and setting of the machine, and training and education of the patient and relatives. Evidence has shown that NIV improves the long-term survival of COPD patients with chronic hypercapnic failure.

    Cite as: Herkenrath S, Matthes S, Randerath W. Noninvasive ventilation in COPD. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 297–312 [https://doi.org/10.1183/2312508X.10008123].

  23. Page 313
    Abstract
    Corresponding author: Pallav L. Shah (pallav.shah@imperial.ac.uk)

    Patients with COPD have airflow obstruction, which can lead to hyperinflation. Lung volume reduction can benefit patients with emphysema and hyperinflation and lead to improvements in lung function and quality of life. Selection of appropriate patients for intervention is essential, and selection of the correct treatment for each patient depends on multiple factors including the patient's comorbidities, lung function, emphysema distribution and collateral ventilation (CV) status. Patients with heterogeneous emphysema distribution can benefit from lung volume reduction surgery, regardless of CV, while patients with heterogeneous emphysema distribution and without CV can benefit from endobronchial valves. Homogeneous emphysema distribution may be amenable to valves if the patient is sufficiently hyperinflated. Sealant approaches can be used for patients with CV (e.g. combined with endobronchial valves), while patients with upper-lobe-predominant emphysema may benefit from bronchoscopic thermal vapour ablation. Heterogeneous or homogeneous emphysema distribution would be amenable to endobronchial coil insertion, regardless of CV (where coils are available).

    Cite as: Tonkin J, Conway FM, Shah PL. Lung volume reduction for emphysema. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 313–324 [https://doi.org/10.1183/2312508X.10007823].

  24. Page 325
    Abstract
    Corresponding author: Peter M.A. Calverley (pmacal@liverpool.ac.uk)

    The preceding chapters provide an overview of current COPD knowledge, highlighting areas of uncertainty and unmet need. Alongside tobacco smoke, we now better recognise many additional harmful exposures and the potentially sizeable impact of childhood experience, thereby identifying a spectrum of potentially modifiable factors. Newer imaging technologies are helping to show how structure influences function, and thus leads to COPD. In addition to those topics covered in preceding chapters, advances are also being made in mucin biology, genetics, proteomics, transcriptomics, and towards understanding the earlier stages of COPD development. These insights could transform our understanding of what COPD is. A tipping point can be reached through a series of small changes, combining to trigger a more important change. Within the field of COPD, we could achieve this by pushing for the timely implementation of the proven advances in COPD prevention, identification, and modification, while seeking to address the individual needs of each patient in a proactive, positive and engaging way.

    Cite as: Wedzicha JA, Allinson JP, Calverley PMA. COPD at a tipping point. In: Wedzicha JA, Allinson JP, Calverley PMA, eds. COPD in the 21st Century (ERS Monograph). Sheffield, European Respiratory Society, 2024; pp. 325–333 [https://doi.org/10.1183/2312508X.10035523].

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