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Disease Overview

Declaration of sponsorship Novartis Pharma AG
Last updated:11th Oct 2022
Published:22nd Jun 2020

The 2021 Global Initiative for Asthma (GINA) report notes that asthma is a heterogeneous disease, usually characterised by recurrent or chronic airway inflammation or both. Prognosis is related to many factors, including effective diagnosis, matching appropriate therapies for the patient’s clinical need to achieve asthma control, addressing each patient’s beliefs, behaviours and environmental triggers, maximising patient compliance and adherence and, last but not least, minimising the risk of poor outcomes including exacerbations ('asthma attacks').

What are the underlying disease processes driving inflammation in asthma? Where are the areas of biggest unmet need and how do exacerbations impact on patients’ lives? How should asthma be diagnosed, and what tests are available to assess asthma control? Explore these questions in this section of the learning zone.

Pathophysiology

An understanding of the disease processes driving asthma provides insight into how to manage the disease. Explore the pathophysiology of asthma in this section.

MSA_Pathophysiology.jpegAsthma is a chronic inflammatory disease, driven by airway inflammation and variable airway obstruction due to bronchoconstriction.1 Regardless of the inflammatory pathway, asthma is characterised by airway hyperresponsiveness, airway obstruction, and airway remodelling. These changes lead to loss of lung function, decreased response to therapy, and asthma symptoms, the worsening of which can result in asthma exacerbations.1–3

 

Chronic inflammation

In patients with asthma, various triggers result in an influx of inflammatory cells into the airway epithelium. Once there, these inflammatory cells produce a range of pro-inflammatory mediators, including cytokines, chemokines and growth factors, that enhance and prolong the inflammatory process (Figure 1).4–6 Left unchecked, chronic inflammation can lead to airway hyperresponsiveness and, over time, to airway remodelling.4,7,8

Whilst the role of chronic inflammation in asthma is well documented, there is no single inflammatory pathway that drives the process. Many patients with asthma display different inflammatory endotypes and our understanding of these continues to evolve, as more immune cell types and cytokines are identified as important drivers of asthma. Eosinophilic asthma and neutrophilic asthma are two examples of differing inflammatory sub-types commonly found in patients with asthma.5,6

Pathophysiology Figure 1 jpeg.jpg

Figure 1. Numerous triggers can cause a prolonged immune response in patients with asthma, leading to chronic inflammation within the airway epithelium.

Bronchoconstriction

Bronchoconstriction is driven by airway smooth muscle (ASM) contraction (Figure 2).1 When triggered in asthmatic patients, bronchoconstriction contributes to airflow obstruction, loss of lung function and can, if left untreated, lead to airway remodelling.8–10

In asthma, contraction and dilation of ASM is modulated by the binding of two neurotransmitters to their receptors in the lungs. Acetylcholine binds to muscarinic M3 receptors to trigger contraction, whilst simultaneously causing mucus secretion, and adrenaline targets the β2-adrenoreceptors. It is likely that there is crosstalk between these receptors, which amplifies their downstream bronchoconstrictive effects.9,11

IRT_Fig2.How effective are bronchodilators for asthma.jpg

Figure 2. Asthmatic airways are characterised by thickened and inflamed walls, which, alongside airway smooth muscle contraction and mucus hypersecretion, can lead to exacerbations.

Airway remodelling

In patients with asthma, airway remodelling occurs due to prolonged inflammation and bronchoconstriction. Repeated ASM contraction and excessive production of pro-inflammatory mediators trigger a host of downstream structural changes that affect both the large and small airways. 8,12 These changes can include increased ASM mass, mucus hypersecretion and loss of epithelial integrity (Figure 3).12 Over time, these changes can lead to exacerbations and negatively impact patients’ quality of life.3 Airway remodelling may be present in young children with mild asthma, but the extent of remodelling usually increases with asthma severity and longer asthma duration.10,12

Pathophysiology Figure 3 jpeg.jpg

Figure 3. Structural changes contributing to asthmatic airway remodelling (light blue) and clinical consequences (dark blue).

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Pathophysiology

Within the pathophysiology section of the COPD Learning Zone you will gain access to information about the following aspects of COPD: 

  • Risk factors for COPD
  • Pathogenesis of the disease

Risk Factors

Inhalation of noxious particles and reactive oxygen species, particularly from cigarette smoke, is undoubtedly the most significant risk factor for chronic obstructive pulmonary disease (COPD). A number of other risk factors have also been established.

Smoking

Cigarette smoke is well established as the most significant risk factor for the development and progression of COPD. However, it is now recognised that a substantial number of adults with COPD have never smoked, accounting for about 30% of COPD in the community, and that not all smokers will develop COPD, indicating that genetic, gender, socioeconomic status and environmental factors influence the risk of COPD development1,2,3. Nevertheless, around 50% of lifelong smokers will develop COPD4.

Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of lung function decline and a greater COPD mortality rate compared with non-smokers3.


In a meta-analysis of 67 population-based studies (representing >111,000 cases of COPD from 28 countries), the prevalence of COPD was significantly higher among smokers (15.4%) and ex-smokers (10.7%) than among individuals who had never smoked (4.3%)5. Similarly, in a large prospective population-based cohort study, 17.8% (1663/9169) of ever smokers – current or former – had COPD (incident and prevalent cases) compared with 6.4% of never smokers (318/4997)6. Among smokers, the prevalence of COPD according to the GOLD criteria was 11% in those aged 46–47 years, 42% in those aged 61–62 years, and 50% in those aged 66–67 years7. Prevalence of COPD is therefore highest in countries where cigarette smoking is common. Smoking cessation is the single most effective intervention in reducing the risk of developing COPD and disease progression3.

Occupational exposure to noxious particles

According to the GOLD strategy document, occupational exposure to noxious particles (including organic and inorganic dusts, chemical agents and fumes) is an under-appreciated risk factor for COPD3. A meta-analysis of 15 epidemiological studies evaluated the correlation between the exposure to biomass smoke and development of COPD worldwide, and found that the odds ratio for developing COPD was 4.30 in men, while in women it was 2.738, establishing biomass smoke as a significant risk factor for development of COPD, and identifying it as a particular challenge in low- and middle-income countries9.

Air pollution

The role of outdoor air pollution in causing COPD is unclear, but appears to be small in comparison with that of cigarette smoking3. Two studies in northern Europe found an increased risk of COPD in individuals living in close proximity to busy roads10,11. In the developing world, exposure to indoor air pollution from open fires appears to be a significant risk factor for COPD3,8,9, and inhalation of passive cigarette smoke may also be responsible for a proportion of COPD diagnoses in people who have never smoked. In the Burden of Obstructive Lung Disease Initiative (BOLD) study, never-smokers (defined as smoking <20 packs of cigarettes in a lifetime; n=4291) made up 42.9% of the study population12. Among never-smokers, 12.7% met the criteria for COPD Stage I+; 6.8% had mild (GOLD Stage I) and 5.9% clinically significant (GOLD Stage II+) COPD. Severe childhood respiratory tract infections, exposure to passive smoking and reported asthma were associated with irreversible airways obstruction in never smokers in this study.

Impaired lung development

Reduced lung function owing to the impairment of lung development is a risk factor for COPD. Consequently, any factor that adversely affects lung growth during foetal development and childhood could increase an individual’s risk of developing COPD during adulthood3. Low birth weight and acute respiratory infections during childhood have both been linked to reduced pulmonary function in later life3,13.

Genetic risk factors

The genetic risk factor best documented in COPD is a severe hereditary deficiency of alpha-1 antitrypsin (AAT; an important protease inhibitor). This rare recessive trait is seen in all ethnic and racial groups globally14 and may account for 2–3% of COPD cases15.

Reducing risk factors

The intervention with the highest capacity for altering the natural history of COPD is smoking cessation3.


Smoking cessation in middle-aged patients with COPD improves lung function, alleviates symptoms such as dyspnoea and cough, reduces the frequency of exacerbations and lowers risk of mortality16. Reduction of total personal exposure to occupational dusts, fumes and gases and to indoor and outdoor air pollutants is also advised3.

Pathogenesis

Cigarette smoking is undoubtedly the most important factor in the development of chronic obstructive pulmonary disease (COPD). The pathological changes characteristic of COPD occur in the trachea, bronchi, bronchioles, respiratory bronchioles, alveoli and pulmonary vasculature. These changes include chronic inflammation and structural changes caused by repeated injury and repair17.

Figure 1 provides an overview of the pathogenesis of COPD. The chronic airflow limitation that is characteristic of COPD is caused by a mixture of small airways disease (obstructive bronchiolitis) and parenchymal destruction (emphysema)17.

Inhaled Therapies_Pathophysiology_Fig1__5AC486E3-997C-421D-95CF1B71A7E914E4.png

Figure 1. Overview of COPD pathogenesis17.
CXCL, CXC-chemokine ligand; IL-8, interleukin-8; LTB4, leukotriene B4.


The following processes are involved in the pathogenesis of COPD, but their relative importance to, and interaction within, the characteristic COPD disease state are still unclear.

Chronic inflammation

The chronic inflammation seen in the respiratory tract of patients with COPD seems to be an amplification of the normal inflammatory response to the inhalation of irritants and noxious particles, such as cigarette smoke17. COPD is characterised by a specific pattern of inflammation, involving neutrophils, macrophages and lymphocytes17,7,18; Table 1 gives an overview of their pathological roles in COPD.

Table 1. Inflammatory cells involved in the pathogenesis of COPD.

Inhaled therapies_Pathophysiology_Table1__C1934F39-8CE5-40A7-ADBD96D92D9E27C2.png


Oxidative stress

A number of studies have indicated that oxidative stress has a significant role in the pathogenesis of COPD19,20. Biomarkers of oxidative stress are increased in the breath and sputum of COPD patients17. Free radicals are secreted by certain inflammatory cells, and are introduced during the inhalation of cigarette smoke20,21. Oxidative stress in the lungs amplifies the inflammatory response, inactivates protease inhibitors and stimulates mucus production17,19.

Protease‒antiprotease imbalance

Within the lungs of patients with COPD, the normal balance between proteases, which degrade connective tissue, and protease inhibitors, which prevent this destruction, is disrupted17,21. This imbalance is at least partly due to the secretion of proteases by macrophages and neutrophils17. Protease-mediated destruction of elastin in lung parenchyma reduces lung elasticity, and is likely to be irreversible17. Damage due to the increase in protease production is further compounded by the reduction or inhibition of protease inhibitors17,21.

Direct airway damage

In addition to eliciting an inflammatory response and inducing oxidative stress, cigarette smoke causes direct damage to airways22. The continued inhalation of smoke damages cilia, reducing their ability to clear mucus. Consequently, thick plugs of mucus can accumulate in the airways, intensifying the inflammatory response and increasing the risk of infection. The scarring and remodelling due to bronchiolitis thickens airway walls, leading to widespread narrowing (peripheral airways obstruction), which progressively traps air during expiration and increases the amount of air remaining in the lungs following expiration (hyperinflation)17. Figure 2 illustrates the causes of small airway obstruction seen in patients with COPD22

Inhaled Therapies_Pathophysiology_Fig2__02A54386-A730-4990-8F6F645E95BADAE5.png

Figure 2. Chronic inflammation causes structural changes and narrowing of the small airways22.


Reduced elastic recoil of the lungs further reduces the driving pressure that forces air out of the lungs, leading to greater air trapping and hyperinflation23. As a result, these patients use a large amount of energy to exhale, which contributes to fatigue.

Irreversible destruction of gas-exchanging airspaces (i.e. respiratory bronchioles, alveolar ducts and alveoli)24 reduces the surface area of respiratory membrane available for gas transfer, and as a consequence the amount of gas that can transfer across in a given time, resulting in hypoxaemia (decreased oxygen in the blood) and hypercapnia (elevated CO2 in the blood) (Figure 3)17

Inhaled Therapies_Pathophysiology_Fig3__411918B9-9B3F-4067-9E0B4FDD1850BB03.png

Figure 3. The alveoli wall destruction in COPD is likely to be irreversible3,24.


Systemic features of COPD

In COPD patients, the development of certain systemic features can have a major impact on quality of life and survival. The inefficient respiration associated with advanced COPD places enormous stress on the respiratory and circulatory systems, resulting in the development of several co-morbid conditions. Reduced pulmonary function limits physical function, including lower limb function, exercise performance, skeletal muscle strength, and basic physical actions3 consistent with the activity limitation reported by many patients with COPD25

Mild-to-moderate pulmonary hypertension may develop as pulmonary vascular resistance increases due to pulmonary vasoconstriction (caused by hypoxia) and the destruction of pulmonary vascular tissue associated with emphysema26. Progression of pulmonary hypertension can lead to cor pulmonale (enlargement of the right ventricle of the heart). As resistance in pulmonary vascular tissue increases, the right ventricle has to eject blood against a greater pressure gradient, and a sustained increase in pulmonary vascular resistance may eventually lead to right ventricular failure26

Weight loss, weakness and fatigue, due to the loss of skeletal muscle through increased apoptosis and/or muscle disuse, further reduce the exercise capacity and health status of patients with severe COPD27.  

Comorbidities

Patients with COPD often have a variety of comorbidities. These include cardiovascular disease, chronic renal failure, type 2 diabetes and asthma28,29,30. Comorbidities may share common causes with COPD, such as smoking, which is associated with ischaemic heart disease and lung cancer; arise as complications of COPD, such as pulmonary hypertension and heart failure; or occur concurrently due to factors such as old age, such as hypertension, diabetes mellitus, depression and osteoarthritis31. It has also been suggested that several comorbidities, such as musculoskeletal wasting, metabolic syndrome and depression, which are unlikely to be caused by smoking may be linked to COPD by a common underlying inflammatory mechanism32.

The presence of comorbidities increases the likelihood of adverse outcomes, including mortality, in patients with COPD33,34. Comorbid cardiovascular disease has also been shown to increase the risk of COPD-related hospitalisations and accident and emergency visits and to greatly increase medical costs35.

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Asthma references

Quick links: Pathophysiology, Burden of disease, Symptoms, Diagniosis and assessment.

Pathophysiology

  1. Global Initiative for Asthma (GINA 2021). Global Strategy for Asthma Management and Prevention. Last accessed July 2021. Available from: ginasthma.org.
  2. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716–725.
  3. Barnes PJ, Szefler SJ, Reddel HK, Chipps BE. Symptoms and perception of airway obstruction in asthmatic patients: clinical implications for use of reliever medications. J Allergy Clin Immunol 2019;144:1180–1186.
  4. Ishmael FT. The inflammatory response in the pathogenesis of asthma. J Am Osteopath Assoc 2011;111:S11–17.
  5. Wang F, He XY, Baines KJ, et al. Different inflammatory phenotypes in adults and children with acute asthma. Eur Respir J 2011;38:567–574.
  6. Kuruvilla ME, Lee FE, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allerg Immu 2019;56:219–233.
  7. Chapman DG, Irvin CG. Mechanisms of airway hyper‐responsiveness in asthma: the past, present and yet to come. Clin Exp Allergy 2015;45:706–719.
  8. Doeing DC, Solway J. Airway smooth muscle in the pathophysiology and treatment of asthma. J Appl Physiol 2013;114:834–843.
  9. Gosens R, Gross N. The mode of action of anticholinergics in asthma. Eur Respir J 2018;52:pii:1701247.
  10. Fehrenbach H, Wagner C, Wegmann M. Airway remodelling in asthma: what really matters. Cell Tissue Res 2017;367:551–569.
  11. Buels KS, Fryer AD. Muscarinic receptor antagonists: effects on pulmonary function. Handb Exp Pharmacol 2012;208:317–341.
  12. Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: From benchside to clinical practice. Can Respir J 2010;17:e85‒e93.

Burden of disease

  1. GBD Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life-years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990‒2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017;5:691‒706.
  2. The Global Asthma Report 2014. Last accessed Sep 2019. Available from: http://www.globalasthmareport.org/resources/resources.php.
  3. World Health Organization 2019. Global Surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Last accessed Sep 2019. Available from: www.who.int/gard/publications/GARD_Manual/en.
  4. Global Initiative for Asthma (GINA 2021). Global Strategy for Asthma Management and Prevention. Last accessed July 2021. Available from: www.ginasthma.org.
  5. Accordini S, Corsico AG, Braggion M, et al. The cost of persistent asthma in Europe: an international population-based study in adults. Int Arch Allergy Immunol 2013;160:93–101.
  6. Stock S, Reddaelli M, Luengen M, et al. Asthma prevalence and cost of illness. Eur Respir J 2005;25:47–53.
  7. Centers for Disease Control and Prevention, 2012. National surveillance of asthma: United States, 2001‒2010. Last accessed Sep 2019. Available from: http://www.cdc.gov/nchs/data/series/sr_03/sr03_035.pdf.
  8. Larsson K, Ställenberg B, Lisspers K, et al. Prevalence and management of severe asthma in primary care: an observational cohort study in Sweden (PACEHR). Respir Res 2018;19:12.
  9. Asthma UK, 2019. Living in limbo: The scale of unmet need in difficult and severe asthma. Last accessed Sep 2019. Available from: www.asthma.org.uk/severe.
  10. Andersson F, Borg S, Ståhl E. The impact of exacerbations on the asthmatic patient’s preference scores. J Asthma 2003;40:615–623.
  11. Stucky BD, Sherbourne CD, Edelen MO, et al. Understanding asthma-specific quality of life: moving beyond asthma symptoms and severity. Eur Respir J 2015;46:680–687.
  12. Suruki RY, Daugherty JB, Boudiaf N, et al. The frequency of asthma exacerbations and healthcare utilization in patients with asthma from the UK and USA. BMC Pulmonary Med 2017;17: Article 74.

Symptoms

  1. Global Initiative for Asthma (GINA 2021). Global Strategy for Asthma Management and Prevention. Last accessed July 2021. Available from: www.ginasthma.org.
  2. Doeing DC, Solway J. Airway smooth muscle in the pathophysiology and treatment of asthma. J Appl Physiol 2013:114;834–843.
  3. World Health Organization (WHO) Fact Sheets on Asthma 2016. Last accessed Sep 2019. Available from: http://www.who.int/mediacentre/factsheets/fs307/en/.
  4. Holgate ST, Wenzel S, Postma DS, et al. Asthma. Nat Rev Dis Primers 2015;1:Article 15025.
  5. Holgate ST, Davies DE. Rethinking the pathogenesis of asthma. Immunity Essay 2009;31:362‒67.

Diagnosis and assessment

  1. Global Initiative for Asthma (GINA 2021). Global Strategy for Asthma Management and Prevention. Last accessed July 2021. Available from: www.ginasthma.org.
  2. Massoth L, Anderson C, McKinney KA. Asthma and chronic rhinosinusitis: Diagnosis and medical management. Medical Sciences 2019;7:53.
  3. Global Initiative for Asthma (GINA). Difficult-to-treat and severe asthma in adolescent and adult patients. Pocket Guide 2019. Last accessed Sep 2019. Available from: https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf.
  4. Moore VC. Spirometry: step by step. Breathe 2012;8:232–240.
  5. GINA, 2015. Global Initiative for Asthma (GINA) Teaching slide set 2015 update. Last accessed Sep 2019. Available from: https://slideplayer.com/slide/4880376/.
  6. Scottish Intercollegiate Guidelines Network (SIGN) 158 British guideline on the management of asthma Revised edition published July 2019. Last accessed Sep 2019. Available from: https://www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-asthma.html.
  7. Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. European Respiratory Journal 2017;49:1601526.
  8. Schneider A, Schwarzbach J, Faderl B, et al. Whole-Body Plethysmography in Suspected Asthma. Dtsch Arztebl Int 2015;112:405–411.
  9. Heinzerling L, Mari A, Bergmann KC, et al. The skin prick test - European standards. Clin Transl Allergy 2013;3:3.
  10. Matucci A, Vultaggio A, Maggi E, et al. Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question? Respir Res 2018;19:113.
  11. Kostikas K, Brindicci C, Patalano F. Blood eosinophils as biomarkers to drive treatment choices in asthma and COPD. Current Drug Targets 2018;19:1882–1896.
  12. Halaby C, Feuerman M, Barlev D, et al. Chest radiography in supporting the diagnosis of asthma in children with persistent cough. Postgrad Med 2014;126:117–122.
  13. Mulgirigama A, Barnes N, Fletcher M, et al. A review of the burden and management of mild asthma in adults — Implications for clinical practice. Respiratory Medicine 2019;152:97–104.

COPD references

Quick links: Pathophysiology, Epidemiology, Symptoms, Diagnosis and assessment.

Pathophysiology

  1. Tan WC, Sin DD, Bourbeau J, et al. Characteristics of COPD in never-smokers and ever-smokers in the general population: Results from the CanCOLD study. Thorax. 2015;70(9):822-829.
  2. Syamlal G, Doney B, Mazurek JM. Chronic Obstructive Pulmonary Disease Prevalence Among Adults Who Have Never Smoked, by Industry and Occupation - United States, 2013-2017. MMWR Morb Mortal Wkly Rep. 2019;68(13):303-307.
  3. Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.; 2021. www.goldcopd.org. Accessed July 2021.
  4. Gibson GJ, Loddenkemper R, Sibille Y LB. Chapter 13: Chronic obstructive pulmonary disease. In: Respiratory health and disease in Europe: the new European Lung White Book. http://www.erswhitebook.org/files/public/Chapters/13_COPD.pdf . Accessed November 25, 2019.
  5. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: Systematic review and meta-analysis. Eur Respir J. 2006;28(3):523-532.
  6. Terzikhan N, Verhamme KMC, Hofman A, Stricker BH, Brusselle GG, Lahousse L. Prevalence and incidence of COPD in smokers and non-smokers: the Rotterdam Study. Eur J Epidemiol. 2016;31(8):785-792.
  7. Lundbäck B, Lindberg A, Lindström M, et al. Not 15 But 50% of smokers develop COPD? - Report from the Obstructive Lung Disease in Northern Sweden studies. Respir Med. 2003;97(2):115-122.
  8. Hu G, Zhou Y, Tian J, et al. Risk of COPD from exposure to biomass smoke: A metaanalysis. Chest. 2010;138(1):20-31.
  9. Van Gemert F, Chavannes N, Kirenga B, et al. Socio-economic factors, gender and smoking as determinants of COPD in a low-income country of sub-Saharan Africa: FRESH AIR Uganda. npj Prim Care Respir Med. 2016;26.
  10. Lindgren A, Stroh E, Montnémery P, Nihlén U, Jakobsson K, Axmon A. Traffic-related air pollution associated with prevalence of asthma and COPD/chronic bronchitis. A cross-sectional study in Southern Sweden. Int J Health Geogr. 2009;8(1).
  11. Schikowski T, Sugiri D, Ranft U, et al. Long-term air pollution exposure and living close to busy roads are associated with COPD in women. Respir Res. 2005;6.
  12. Lamprecht B, McBurnie MA, Vollmer WM, et al. COPD in never smokers: Results from the population-based burden of obstructive lung disease study. Chest. 2011;139(4):752-763.
  13. Lawlor DA, Ebrahim S, Smith GD. Association of birth weight with adult lung function: Findings from the British Women’s Heart and Health Study and a meta-analysis. Thorax. 2005;60(10):851-858.
  14. de Serres FJ, Blanco I, Fernández-Bustillo E. Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of α1-antitrypsin deficiency in Asia. Eur Respir J. 2006;28(6):1091-1099.
  15. García-Palenzuela R, Timiraos Carrasco R, Gómez-Besteiro MI, Lavia G, Lago Pose M, Lara B. Detection of alpha-1 antitrypsin deficiency: A study on patients diagnosed with chronic obstructive pulmonary disease in primary health care. Semergen. 2017;43(4):289-294.
  16. Andreas S, Hering T, Mühlig S, Nowak D, Raupach T, Worth H. Smoking cessation in chronic obstructive pulmonary disease: an effective medical intervention. Dtsch Arztebl. 2009;106(16):276-282.
  17. Saetta M, Turato G, Facchini FM, et al. Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. Am J Respir Crit Care Med. 1997;156(5):1633-1639.
  18. Celli BR, MacNee W, Agusti A, et al. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-946.
  19. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur Respir J. 2003;22(4):672-688.
  20. Repine JE, Bast A, Lankhorst I. Oxidative Stress in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 1997;156(2):341-357.
  21. Turino GM. The origins of a concept: The protease-antiprotease imbalance hypothesis. Chest. 2002;122(3):1058-1060.
  22. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. In: Lancet. Vol 364. ; 2004:709-721.
  23. O’Donnell DE, Laveneziana P. The clinical importance of dynamic lung hyperinflation in COPD. COPD J Chronic Obstr Pulm Dis. 2006;3(4):219-232.
  24. Barnes PJ. Mechanisms in COPD: Differences from asthma. Chest. 2000;117:10S-14S.
  25. Eisner MD, Iribarren C, Yelin EH, et al. Pulmonary function and the risk of functional limitation in chronic obstructive pulmonary disease. Am J Epidemiol. 2008;167(9):1090-1101.
  26. Rennard S, Decramer M, Calverley PMA, et al. Impact of COPD in North America and Europe in 2000: Subjects’ perspective of Confronting COPD International Survey. Eur Respir J. 2002;20(4):799-805.
  27. Frew AJ, Doffman SR, Hurt K B-TR. Respiratory Disease. In: Kumar and Clark’s Clinical Medicine, 9th Edition.; 2017.
  28. Agusti A. Systemic Effects of Chronic Obstructive Pulmonary Disease: What We Know and What We Don’t Know (but Should). Proc Am Thorac Soc. 2007;4(7):522-525.
  29. Terzano C, Conti V, Di Stefano F, et al. Comorbidity, hospitalization, and mortality in COPD: Results from a longitudinal study. Lung. 2010;188(4):321-329.
  30. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: A comprehensive analysis using data from primary care. Thorax. 2010;65(11):956-962.
  31. Sidney S, Sorel M, Quesenberry CP, DeLuise C, Lanes S, Eisner MD. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest. 2005;128(4):2068-2075.
  32. de Miguel Díez J, García TG, Maestu LP. Comorbidities in COPD. Arch Bronconeumol. 2010;46(SUPPL.11):20-25.
  33. Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest. 2011;139(1):165-173.
  34. Roberts CM, Stone RA, Lowe D, Pursey NA, Buckingham RJ. Co-morbidities and 90-day outcomes in hospitalized COPD exacerbations. COPD J Chronic Obstr Pulm Dis. 2011;8(5):354-361.
  35. Dalal AA, Shah M, Lunacsek O, Hanania NA. Clinical and economic burden of patients diagnosed with COPD with comorbid cardiovascular disease. Respir Med. 2011;105(10):1516-1522.

Epidemiology

  1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.; 2020. www.goldcopd.org. Accessed November 25, 2019.
  2. Frew AJ, Doffman SR, Hurt K B-TR. Respiratory Disease. In: Kumar P and Clark ML. Kumar & Clark’s Clinical Medicine. 9th ed. Elsevier; 2017.
  3. Barnes PJ. Mechanisms in COPD: Differences from asthma. Chest. 2000;117(2 SUPPL.):10S-14S.
  4. O’Donnell DE, Laveneziana P. Physiology and consequences of lung hyperinflation in COPD. In: European Respiratory Review. Vol 15. ; 2006:61-67.
  5. Marieb EN KS. Essentials Of Human Anatomy & Physiology. 12th ed. Harlow, Essex: Pearson Education Ltd.; 2018. http://fliphtml5.com/pecr/iwgi/basic. Accessed November 25, 2019.
  6. World Health Organization. Fact sheets. The top 10 causes of death. https://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death. Published 2018. Accessed November 25, 2019.
  7. Global Health Estimates 2016: disease burden by cause, age, sex, by country and by region, 2000‒2016. Geneva: World Health Organization. http://origin.who.int/healthinfo/global_burden_disease/estimates/en/. Published 2018. Accessed November 25, 2019.
  8. Joish VN, Brady E, Stockdale W, Brixner DI, Dirani R. Evaluating diagnosis and treatment patterns of COPD in primary care. Treat Respir Med. 2006;5(4):283-293.
  9. Soriano JB, Zielinski J, Price D. Screening for and early detection of chronic obstructive pulmonary disease. Lancet. 2009;374(9691):721-732.
  10. Arne M, Lisspers K, Ställberg B, et al. How often is diagnosis of COPD confirmed with spirometry? Respir Med. 2010;104(4):550-556.
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  15. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (The BOLD Study): a population-based prevalence study. Lancet. 2007;370(9589):741-750.
  16. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196.
  17. Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: Systematic review and meta–analysis. J Glob Health. 2015;5(2).
  18. Ciapponi A, Alison L, Agustina M, Demián G, Silvana C, Edgardo S. The epidemiology and burden of COPD in latin America and the caribbean: Systematic review and meta-analysis. COPD J Chronic Obstr Pulm Dis. 2014;11(3):339-350.
  19. Bao H, Fang L, Wang L. Prevalence of chronic obstructive pulmonary disease among community population aged ≥40 in China: A Meta-analysis on studies published between 1990 and 2014. Chinese J Endem. 2016;37(1):119-124.
  20. Landis SH, Muellerova H, Mannino DM, et al. Continuing to confront COPD international patient survey: Methods, COPD prevalence, and disease burden in 2012-2013. Int J COPD. 2014;9:597-607.
  21. J Bousquet, N Khaltaev. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Geneva, Switzerland. Chron Respir Dis. 2007:1-146.
  22. Hernandez P, Balter M, Bourbeau J, Hodder R. Living with chronic obstructive pulmonary disease: A survey of patients’ knowledge and attitudes. Respir Med. 2009;103(7):1004-1012.
  23. Taking Her Breath Away: The Rise of COPD in Women | American Lung Association. https://www.lung.org/our-initiatives/research/lung-health-disparities/the-rise-of-copd-in-women.html. Accessed November 25, 2019.
  24. Gut-Gobert C, Cavaillès A, Dixmier A, et al. Women and COPD: Do we need more evidence? Eur Respir Rev. 2019;28(151).
  25. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. MMWR Surveill Summ  Morb Mortal Wkly report Surveill Summ / CDC. 2002;51(6):1-16.
  26. O’Farrell A, De A, Harpe L, et al. Trends in COPD Mortality and In-Patient Admissions in Men & Women: Evidence of Convergence. Vol 104.; 2011.
  27. WHO | Health statistics and information systems: projections of mortality and burden of disease, 2004‒2030. WHO. 2018.
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  30. Patel JG, Coutinho AD, Lunacsek OE, Dalal AA. COPD affects worker productivity and health care costs. Int J COPD. 2018;13:2301-2311.
  31. Fletcher MJ, Upton J, Taylor-Fishwick J, et al. COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population. BMC Public Health. 2011;11(1):612.

Symptoms

  1. Global Initiative for Chronic Obstructive Lung Disease (GOLD 2020). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.; 2020. www.goldcopd.org. Accessed November 25, 2019.
  2. Eisner MD, Iribarren C, Yelin EH, et al. Pulmonary function and the risk of functional limitation in chronic obstructive pulmonary disease. Am J Epidemiol. 2008;167(9):1090-1101.
  3. van der Molen T, Miravitlles M, Kocks JWH. COPD management: Role of symptom assessment in routine clinical practice. Int J COPD. 2013;8:461-471.
  4. Parada A, Klaassen J, Lisboa C, Saldías F, Mendoza L, Patiño OD. Reduction of physical activity in patients with chronic obstructive pulmonary disease. Rev Med Chil. 2011;139(12):1562-1572.
  5. Benzo RP, Chang CCH, Farrell MH, et al. Physical activity, health status and risk of hospitalization in patients with severe chronic obstructive pulmonary disease. Respiration. 2010;80(1):10-18.
  6. Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11(1):122. http://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-11-122. Accessed November 25, 2019.
  7. Reardon JZ, Lareau SC, ZuWallack R. Functional Status and Quality of Life in Chronic Obstructive Pulmonary Disease. Am J Med. 2006;119(10 SUPPL.):32-37.
  8. ZuWallack R. How are you doing? What are you doing? Differing perspectives in the assessment of individuals with COPD. In: COPD: Journal of Chronic Obstructive Pulmonary Disease. Vol 4. ; 2007:293-297.
  9. Gysels M, Higginson IJ. Access to Services for Patients with Chronic Obstructive Pulmonary Disease: The Invisibility of Breathlessness. J Pain Symptom Manage. 2008;36(5):451-460.
  10. Partridge MR, Karlsson N, Small IR. Patient insight into the impact of chronic obstructive pulmonary disease in the morning: An internet survey. Curr Med Res Opin. 2009;25(8):2043-2048.
  11. Partridge M, Karlsson N, Small I. Erratum: Patient insight into the impact of chronic obstructive pulmonary disease in the morning: An internet survey. Curr Med Res Opin. 2012;28(8):1405. doi:10.1185/03007995.2012.708625
  12. Kuyucu T, Güçlü SZ, Şaylan B, et al. A cross-sectional observational study to investigate daily symptom variability, effects of symptom on morning activities and therapeutic expectations of patients and physicians in COPD-SUNRISE study. Tuberk Toraks. 2011;59(4):328-339.
  13. Espinosa de los Monteros MJ, Peña C, Soto Hurtado EJ, Jareño J, Miravitlles M. Variability of Respiratory Symptoms in Severe COPD. Arch Bronconeumol (English Ed. 2012;48(1):3-7.
  14. O’Hagan P, Chavannes NH. The impact of morning symptoms on daily activities in chronic obstructive pulmonary disease. Curr Med Res Opin. 2014;30(2):301-314.
  15. Rennard S, Decramer M, Calverley PMA, et al. Impact of COPD in North America and Europe in 2000: Subjects’ perspective of Confronting COPD International Survey. Eur Respir J. 2002;20(4):799-805.
  16. Barnett M. Chronic obstructive pulmonary disease: A phenomenological study of patients’ experiences. J Clin Nurs. 2005;14(7):805-812.
  17. O’Donnell DE. Impacting patient-centred outcomes in COPD: Breathlessness and exercise tolerance. In: European Respiratory Review. Vol 15. ; 2006:37-41.
  18. Cleland JA, Lee AJ, Hall S. Associations of depression and anxiety with gender, age, health-related quality of life and symptoms in primary care COPD patients. Fam Pract. 2007;24(3):217-223.
  19. Tsiligianni IG, van der Molen T, Moraitaki D, et al. Assessing health status in COPD. A head-to-head comparison between the COPD assessment test (CAT) and the clinical COPD questionnaire (CCQ). BMC Pulm Med. 2012;12.
  20. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786-796.
  21. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85:25-31.
  22. Westwood M, Bourbeau J, Jones PW, Cerulli A, Capkun-Niggli G, Worthy G. Relationship between FEV1change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: A systematic review. Respir Res. 2011;12.

Diagnosis and assessment

  1. Global initiative for chronic Obstructive Lung Disease (GOLD 2020). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. www.goldcopd.org (2021).
  2. Global initiative for chronic Obstructive Lung Disease (GOLD 2020). Pocket guide to COPD diagnosis, management, and prevention. A guide for healthcare professionals. 2020 Report. www.goldcopd.org (2021).
  3. Price, D. B., Yawn, B. P. & Jones, R. C. M. Improving the differential diagnosis of chronic obstructive pulmonary disease in primary care. Mayo Clinic Proceedings vol. 85 1122–1129 (2010).
  4. Tinkelman, D. G. et al. Symptom-Based Questionnaire for Differentiating COPD and Asthma. Respiration 73, 296–305 (2006).
  5. Price, D. & Brusselle, G. Challenges of COPD diagnosis. Expert Opinion on Medical Diagnostics vol. 7 543–556 (2013).
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