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Disease Overview

Declaration of sponsorship Novartis Pharma AG
Last updated:30th Oct 2023
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

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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

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

Burden of disease

Understanding the epidemiology of asthma enables the social and economic burden of asthma impact on society to be explored. Read more to understand the global implications of asthma, as well as the striking variations in some particularly vulnerable subpopulations, such as paediatric and severe asthma patient populations.

Prevalence of asthma

Asthma is one of the most common chronic diseases worldwide, affecting over 350 million people globally with the number expected to increase to over 400 million by 2025.1

The increasing prevalence of asthma is likely driven by rising sensitivity to common allergens2,3 and what is worrying is that a large proportion of patients remain undiagnosed or under-treated (Figure 1).

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Figure 1. Worldwide prevalence of asthma.1,4

Economic burden of asthma

Healthcare expenditure on asthma is very high. Around 1–2% of the total healthcare budget is spent on asthma in developed countries, with higher projections in developing economies due to the increasing prevalence of asthma. The total cost of asthma is estimated at approximately €17.7 billion per annum by the European Respiratory Society (ERS) white book published in 2003.5

The economic burden of asthma is the result of both direct and indirect costs (Figure 2).6 Over 46 million days of school or work were missed in the USA due to asthma in 2008.7 Investment in preventive strategies will be increasingly important to yield cost savings in emergency care.4

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Figure 2. Economic burden of asthma.6

Severity of asthma

Most patients with asthma have mild or moderate disease but reports suggest between 5 and 10% of the asthmatic population have severe disease. Uncontrolled asthma is not always synonymous with severe disease. However, poor asthma control has a high burden and is associated with exacerbations, the need for systemic corticosteroids (SCS), and increased emergency department visits.8

Deaths due to asthma are uncommon, yet are of serious concern because many asthma deaths are preventable. According to Asthma UK, two thirds of deaths from asthma could have been prevented.9 Most deaths certified as caused by asthma occur in older adults. In younger age groups, mortality rates have fluctuated markedly in several of the high-income countries due to changes in medical care and the introduction of new asthma medications.4

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Figure 3. Age-standardised asthma mortality rates for all ages 2001–20102

Asthma exacerbations are a leading cause of emergency room visits and hospitalisations and can be fatal, even in patients with mild asthma.10,11 The frequency of asthma exacerbations increases with disease severity.12 Reducing the risk of exacerbations is a key goal of asthma management.4

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Figure 4. Burden of exacerbations in patients with asthma

Symptoms

Inflammation of the airways drives the four major symptoms of asthma: coughing, chest tightness, wheezing and shortness of breath.1 Explore the aetiology of these symptoms here.

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Figure 1. Mechanisms of airflow obstruction in asthma and their consequences.2

Asthma symptoms vary over time in their presentation, frequency and intensity, and from person to person. Asthma is usually associated with airway hyperresponsiveness to direct or indirect stimuli and chronic airway inflammation. These features often persist, even when symptoms are absent or when lung function is normal. Symptoms may resolve spontaneously or in response to medication and may sometimes be absent for weeks or months. Nevertheless, patients can experience episodic flare-ups (exacerbations) of asthma, which, in some cases, may be life-threatening and impose a significant burden on patients and the community.1

Risk factors and triggers

The fundamental causes of asthma are still not fully understood, but the strongest risk factors centre around host factors and environmental factors leading to airway irritation, bronchoconstriction and airway inflammation.1,3 Host factors predispose or protect individuals from asthma and environmental factors. These influence an individual’s susceptibility to develop asthma or precipitate an exacerbation (Figure 2).3

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Figure 2. The major risk factors of asthma.3

Although most cases of asthma begin in childhood due to IgE-dependent sensitisation to common environmental allergens, asthma can develop or can enter remission in adolescence or young adulthood only to re-emerge later in life. Adult asthma has various phenotypes.4,5

Diagnosis and assessment

This section outlines the recommendations in the 2021 GINA report for diagnosis, important diagnostic tools and how to assess symptom control and the exacerbation risk. Explore how to diagnose and assess children, young people and adults with asthma as well as the importance of capturing patient-reported outcomes.

Diagnostic tools

AdobeStock_158928163.jpegAs asthma is biologically and clinically heterogeneous, there is no single gold-standard test to detect asthma. So, the diagnosis of asthma depends on recognising a characteristic pattern of respiratory symptoms, confirming variable airflow limitation, and excluding other conditions in the differential diagnosis. The diagnostic work-up of a patient with suspected asthma involves (Figure 1):1,2

 

  • A detailed medical history: patients with asthma typically report symptoms such as wheezing, shortness of breath (dyspnoea), chest tightness or cough. The pattern of symptoms helps the differential diagnosis of asthma from other acute or chronic conditions (Figure 2)
  • A physical examination that focuses on the upper airways (such as for allergic rhinitis and chronic rhinosinusitis), lungs (such as for asthma) and skin (such as for commonly related conditions such as atopic eczema)
  • Lung function, measured using spirometry to show variable expiratory airflow limitation; spirometry may include reversibility testing, by comparing lung function before and after a patient uses a bronchodilator; if spirometry is not available, healthcare professionals can use a peak flow meter

Consider lung function and symptoms separately

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Figure 1. Making the diagnosis of asthma1

Healthcare professionals should document the evidence supporting the diagnosis in the patient’s notes. The diagnostic work-up should be performed before starting a corticosteroid or another controller medication: confirming a diagnosis of asthma is more difficult after treatment starts.1 Figure 2 shows the stages in the diagnosis of asthma.

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Figure 2. Diagnostic flow chart for asthma in clinical practice.
ICS, inhaled corticosteroid; PEF, peak expiratory flow; SABA, short-acting beta2-agonist.

Diagnostic tests

While there isn’t a definitive diagnostic test for asthma, there are a number of tests available to support a diagnosis of asthma.

Spirometry

Spirometry is a lung function test that measures the air that is inspired or expired and its flow rate.3

Key spirometry measurements are:

  • Forced vital capacity (FVC): the volume delivered during expiration made as forcefully and completely as possible starting from full inspiration
  • Forced expiratory volume in one second (FEV1): the volume delivered in the first second of an FVC manoeuvre.

Testing should be carried out by well-trained operators with well-maintained, calibrated equipment. A FEV1/FVC ratio of less than 0.75–0.80 in adults and 0.90 in children suggests airflow limitation.

Spirometers often show age-specific predicted values for people of different ethnic backgrounds.1

Once lung function tests suggest airflow limitation, healthcare professionals should assess the variability based on FEV1 or peak expiratory flow (PEF), which typically differ by >12% and >200 mL from baseline. Once asthma has been confirmed, changes in FEV1 or PEF can monitor responses to treatment. Marked variation in PEF suggests poorly controlled asthma.1

GINA highlights considering the differential diagnosis when the symptoms and lung function results are discordant and variable expiratory airflow is not apparent. For example, a person with frequent symptoms but a normal FEV1 may have a cardiovascular disease or poor cardiopulmonary fitness. A person who experiences few symptoms, but shows low FEV1, may have a poor perception of their airflow limitation – which can arise from poorly controlled inflammation.1

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Figure 3. Typical spirometry tracings.4
Each FEV1 represents the highest of three reproducible measurements. BD, bronchodilator; FEV1, forced expiratory volume in 1 second.

Peak expiratory flow (PEF )

AdobeStock_57132390.jpegPEF can help diagnose or exclude asthma, including work-related asthma, as well as assessing triggers, predicting exacerbations (usually in people who have poor perception of their airflow limitation, difficult-to-control or severe asthma, or those who experience sudden severe exacerbations) and determining the response to treatment, including monitoring recovery after an exacerbation.1

PEF uses a handheld ‘peak flow’ meter to measure how quickly patients can blow air from their lungs. So, PEF allows healthcare professionals to easily monitor airway limitation at routine assessments. Patients can also monitor PEF as part of their self-management plan.1,5

Diurnal PEF variability is calculated from two daily readings following the formula: highest reading-lowest reading/mean of the day’s highest and lowest x 100. The average of each day’s value is then calculated over 1‒2 weeks. A diurnal reading of >10% and >13% is regarded as excessive.1

Bronchoprovocation (challenge) tests

Bronchoprovocation assesses bronchial hyperresponsiveness in order to exclude or confirm suspected asthma in patients with inconclusive spirometry. Lung function is measured before and after challenging a patient with a direct (such as inhaled histamine or methacholine) or indirect (for example exercise or inhaled mannitol) bronchoconstrictor. A diagnosis of asthma is supported if FEV1 decreases by >20% after bronchoprovocation.1,6

A negative bronchoprovocation test in a patient not taking inhaled corticosteroids (ICS) can help exclude asthma, while a positive test does not always mean a patient has asthma. Healthcare professionals should consider the pattern of symptoms and other clinical features to ensure a correct differential diagnosis.1,5

Whole body plethysmography (WBP)

This test is designed to measure the total amount of air held in a patient’s lungs (total lung volume). WBP is more sensitive than spirometry alone and can detect even slight changes in the airways. WBP offers high added diagnostic value especially when used in conjunction with bronchoprovocation.7

Skin prick test (SPT)

Identifying allergic triggers for asthma is an important aspect of diagnosis. During the skin prick test (SPT), a small needle is used to prick the skin for subcutaneous placement of an allergen droplet. The test is interpreted in the context of a positive (such as histamine dihydrochloride) and negative control (vehicle). Healthcare professionals should enquire prior to testing if patients are using any medications that might influence the results, such as anti-histamines or topical, systemic, nasal or inhaled steroids.9 Further, the relevance of positive results on a sensitisation test must be consistent with patient history.1

Blood tests can also be used for allergen testing, such as allergen specific IgE immunoassays and radioallergosorbent tests (RAST).8

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Figure 4. Skin prick test results.

Other tests in asthma

Additional tests may assist asthma diagnosis or severity assessment in certain situations as follows:

  • Arterial blood gas (ABG)
    • An ABG measurement may be used to determine the degree of hypoxia, hypercapnia or both for a patient experiencing a severe asthma attack; blood gas levels may help differentiate asthma and severe COPD.1
  • Sputum cytology
    • A raised eosinophil count is an important indicator of pro-inflammatory and epithelial damaging cells in atopic and non-atopic asthma.10 Histological examination by staining sputum smears for eosinophils and neutrophils may help guide targeted treatment.1
  • Fractional exhaled nitric oxide (FENO)
    • Eosinophilic airway inflammation and Type 2 inflammation can be inferred by the concentration of fractional exhaled nitric oxide (FENO). FENO has not been established as a method to confirm or exclude asthma and several exogenous factors (including smoking and respiratory infections) can influence FENO levels.1,10
  • Chest radiography (X-ray)
    • A chest radiograph should be considered for all patients hospitalised with an acute asthma attack to assess for complications or alternative causes of wheezing.1,11 Chest radiographic findings indicative of an airway obstruction may support the differential diagnosis of asthma, especially in younger children unable to perform spirometry.11

Once asthma is diagnosed, additional tests may assist in determining the underlying causes of exacerbations. For more information, refer to the GINA 2021 report.

Differential diagnosis

The differential diagnosis in patients with suspected asthma varies with age. The following alternative diagnosis may also coincide with asthma.1

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Table 1. Differential diagnosis of asthma in adults, adolescents and children 6‒11 years.1

For further details on how to make the diagnosis of asthma in other contexts see GINA 2021 main report. 

Asthma Assessment

Every opportunity should be taken to assess a patient with asthma. Obviously, this is most important when they are symptomatic or following an exacerbation, but a routine review should be scheduled at least once a year and during opportunistic situations (such as timing of prescription refills). Regular assessment of asthma control enables informed decisions to be made based on asthma severity and the effect of a given treatment. This allows the healthcare professional and patient to determine if a step-up or step-down in treatment is required.1

Asthma control is assessed based on:1

  • Symptom control; poor symptom control can be burdensome to patients and increases the risk of exacerbations.
    • Assess the frequency of daytime and night-time (including awakenings) asthma symptoms, reliever use, and activity limitation (Table 2)
  • Risk factors for future outcomes should be investigated even when symptoms are well controlled
    • Factors that increase the risk of a exacerbation include a history of at least one exacerbation in the last year, poor adherence, incorrect inhaler technique, low lung function, smoking, and blood eosinophilia
    • Lung function, particularly low FEV1 (less than 60% of predicted)

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Table 2. Assessment of current clinical asthma control (preferably over 4 weeks).1
ACT, Asthma Control Test; ACQ, Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; PEF, peak expiratory flow.

Healthcare professionals can use screening tools, such as the Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ), in primary care to quickly identify patients who need more detailed assessment.5

Table 3 summarises tools that aid assessment of asthma symptom control.5

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Table 3. Tools that can assess current control of asthma symptoms.5

Asthma severity

Asthma severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations as outlined in the GINA 2021 management report:

  • Mild asthma: Well controlled with as needed low dose ICS-formoterol or low dose ICS (Step 1 or 2); about 50–75% of patients have mild asthma13
  • Moderate asthma: Well controlled with low or medium dose ICS plus a long-acting beta2-agonist (LABA) (Step 3/4)
  • Severe asthma: Requires, or is uncontrolled with, high dose ICS plus LABA with or without add-on therapies, such as targeted treatments (Step 5)

It is important to distinguish between severe and poorly controlled asthma due to, for example, incorrect inhaler technique, poor adherence or both.1

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Figure 5. How to distinguish between uncontrolled and severe asthma.1
ICS, inhaled corticosteroids; GORD, gastro-oesophageal reflux disease; NSAIDs, non-steroidal anti-inflammatory drugs.

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.

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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.

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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

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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

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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.

Epidemiology

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

  • The definition from GOLD
  • Its prevalence both in Europe and globally
  • How prevalence is influenced by age and gender 
  • The burden of COPD

Definition

According to the Global Initiative for Chronic Obstructive Lung Disease1:

‘COPD is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases and influenced by host factors including abnormal lung development. Significant comorbidities may have an impact on morbidity and mortality.’

The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema)1 (Figure 1). The relative contributions of these conditions to airflow limitation in COPD vary from person to person1.

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Figure 1. The characteristic, chronic airflow limitation of COPD is caused by a combination of small airway disease and lung parenchymal destruction1.

 

Obstructive bronchiolitis is due to chronic inflammation of the small airways (bronchiolitis). This inflammation results in scarring and remodelling of the small airways, resulting in thickening of the walls and leading to widespread narrowing2.  

Emphysema is characterised by the destruction of gas-exchanging airspaces, such as the respiratory bronchioles, alveolar ducts and alveoli. This destruction of parenchymal tissue is irreversible. It leads to limitation of expiratory airflow, small airway collapse and air trapping3

Hyperinflation occurs when a greater amount of air remains in the lungs following expiration. In patients with COPD, parenchymal tissue destruction also reduces the elastic recoil of the lungs and consequently the driving pressure that forces air out of the lungs4. As a result, a large amount of energy is required to exhale, which contributes to fatigue5.

 

Prevalence

Chronic obstructive pulmonary disease (COPD) is an important and growing cause of morbidity and mortality worldwide and the third leading cause of death in the world6. It is the seventh leading cause of disease burden (DALY) globally in 2016, even more than diabetes mellitus and birth asphyxia/trauma7

It is likely that the available data underestimates the prevalence of COPD. It is often not diagnosed until moderately advanced8,9,10,11.  In addition, there has traditionally been a lack of awareness of COPD among primary care12. According to data from several countries, the prevalence of formally diagnosed COPD has been estimated at less than 6% of the general population13.

Prevalence of COPD in Europe

Since the 1970s, there have been more than 100 studies of COPD prevalence, with most large-scale studies reporting a prevalence of between 5% and 10%. These studies vary in survey methods, diagnostic criteria, analytical approaches and age distribution, making comparison between study results difficult14. Data from the Burden of Obstructive Lung Disease studies also show a considerable variation in prevalence of spirometry-defined COPD (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] <0.70, FEV<80% predicted) between European countries (Figure 2)15.

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Figure 2. Prevalence of COPD in Europe in A) men and B) women, aged ≥40 years old, categorised by GOLD stage and ranked by national prevalence of current smoking (data from multiple publications from the BOLD study)15.


Prevalence of COPD globally

The estimated number of people with COPD worldwide is 328 million16. In a systematic review and meta-analysis of 123 studies, spirometry-defined global prevalence of COPD in 2010 was estimated to be 11.7% in people aged ≥30 years17. In addition, across WHO regions, the highest prevalence was found in the Americas (15.2%) and the lowest in South-East Asia (9.7%) (Figure 3).

Inhaled Therapies_Epidemiology_Fig3__EEC87A10-69C6-4173-895632CA4AF6EC49.png

Figure 3. Globally, 11.7% of adults (aged ≥30 years) have COPD17.
*The Americas include Canada, USA and Latin America; Eastern Mediterranean includes Iran, Lebanon, Tunisia, UAE, Saudi Arabia.


An epidemiological study of COPD in Latin America and the Caribbean estimated COPD prevalence, defined by GOLD criteria, to be 13.4%18.  The overall prevalence of COPD in people aged >40 years in China was estimated to be 9.9%19, while estimates of the prevalence of COPD in the US population have ranged from 9‒12% 20.

Age and Gender

Although it is well known that COPD prevalence increases with age, it also occurs in younger adults (aged 20–44 years)21,20,17. In the ‘Continuing to Confront COPD’ survey, almost 50% of subjects were <60 years old20. Similarly, in a survey of Canadian patients living with COPD conducted in 2006–2007, 48% of respondents with physician-diagnosed COPD were aged <65 years22. The prevalence of COPD is increasing in younger age groups, particularly in women23 (Figure 4).

Inhaled Therapies_Epidemiology_Fig4__53CC5A42-56F7-4DFC-83A7E38A3BEE24B7.png

Figure 4. COPD is not just a disease of the very old23,20. Around 50% of patients with COPD in the USA are <60 years old and COPD prevalence is increasing in younger age groups, particularly in women23,20.


Traditionally, COPD has been diagnosed more frequently in men than women; however, the increase in the prevalence of COPD in women has equalled that of women since 200824. The increase in smoking among women since the 1940s is thought to underlie this trend25,26. Data from the US have revealed that the number of deaths from COPD among women has quadrupled since 198023. In the year 2000, the number of women who died from COPD was for the first time greater than the number of men who died from the condition25,23. COPD has become the leading cause of death in women in the US24.

Burden

COPD is a considerable and growing cause of disability. In 2012, COPD was the sixth most common cause of disability in the world, accounting for 3.4% of total disability-adjusted life years (DALYs) lost worldwide, increasing its ranking from eighth in 20007. According to projections from the Global Burden of Disease Study, it will rank as the fifth leading cause of disability in 2030. Depressive disorders, ischaemic heart disease, traffic accidents and cerebrovascular disease are the only conditions that will present a greater burden in 2030, with COPD overtaking both HIV/AIDS and diabetes mellitus in terms of DALY score27

Economic cost

In addition to the burden of mortality and morbidity, COPD carries huge economic costs resulting from both direct healthcare costs and indirect costs related to loss of productivity of the patient and caregivers. In the USA, projected costs related to COPD in 2010 amounted to $50 billion, with $20 billion in direct costs and $30 billion in indirect healthcare expenditure (Guarascio et al., 2013). Similarly, annual direct (healthcare) and indirect (lost productivity) costs due to COPD in the EU in 2011 were estimated at €48.4 billion (€23.3 direct and €25.1 indirect)29

Working-age patients with COPD are costly to employers. They incur approximately double the costs as workers without COPD. A retrospective, observational, matched cohort US study aimed to measure the true burden of COPD in insured, working individuals by calculating incremental direct and indirect costs30. The study found that productivity loss was significantly greater in patients with COPD, with an average of 5 more days/year of absence from work and incremental indirect costs from short-term disability of $641 (p<0.001).

Direct costs for frequent exacerbators ($17,651/year) were significantly higher by 22% than for infrequent exacerbators ($14,501/year) and significantly higher by 55% than for non-exacerbators ($11,395) (p<0.001). There were several statistically significant predictors of high incremental costs, associated with COPD, including the frequency of exacerbations.

Impact on the working population

Although the prevalence of COPD is highest in those over 65 years old, nearly half of patients are of working age31. In a recent international survey investigating the effects of COPD in patients aged 45–67 years, COPD was found to have a significant detrimental impact on work, income and lifestyle choices31. Of those patients who were in paid work, 23% reported that their work productivity was reduced by their COPD, and of those not in work, over one quarter had given up work because of their COPD. Respondents reported that their household income was reduced as a direct consequence of their COPD, and they were concerned about its future impact. The average annual financial loss per patient from lost working hours was £556 ($880) and a lifetime loss of £4,661 ($7,365); for those retiring prematurely due to COPD, the average lifetime earnings losses were estimated to be £200,000 ($316,000) per individual. The survey also found that patients’ daily activities and quality of life, particularly in younger patients, were substantially impaired by their COPD31.

Symptoms

In this section of the COPD Learning Zone you will gain access to information about the following aspects of the symptoms of COPD:

  • Symptoms and how they impact the lives of patients
  • Exacerbations
  • Extra pulmonary symptoms
  • Why symptoms are worse in the morning

Symptoms and Impact

The characteristic chronic symptoms of chronic obstructive pulmonary disease (COPD) are dyspnoea, cough and sputum production. In addition to these symptoms, patients may develop a number of extra pulmonary symptoms, such as fatigue, anorexia and weight loss1

Dyspnoea

Dyspnoea, or breathlessness, is the hallmark symptom of COPD; it is the most common reason why patients seek medical attention1. Dyspnoea in COPD is typically persistent and progressive. Greater impairment in pulmonary function is associated with poorer exercise performance2. During the early stages of disease, dyspnoea is only noticed on unusual effort (e.g. running up a flight of stairs) and may be avoided by behavioural changes. As lung function deteriorates, dyspnoea increasingly accompanies normal everyday activities, and eventually will be present even at rest.

Patients report that shortness of breath is the most bothersome symptom and is the reason most seek medical attention1,3.


Dyspnoea and reduced physical activity

COPD also impairs the capacity of patients to undertake physical activity, even in those with mild COPD4. Reduced levels of physical activity may be associated with an increased risk of morbidity, beyond that directly attributable to COPD5.  

Shortness of breath and reduced exercise endurance are seen in patients with all severities of COPD6.


Exertional dyspnoea often causes patients with COPD to reduce unconsciously their activities of daily living to reduce the intensity of their distress. This leads to deconditioning which, in turn, further increases dyspnoea (Reardon et al., 2006)7 (Figure 1).

Inhaled Therapies_Symptoms_Fig1__6470D2FA-D3EA-4DB0-B601D0EFAFE06328.png

Figure 1. Patients restrict activities to avoid shortness of breath7,8,9. Adapted from Reardon et al., 20067.


Cough

Often the first symptom to develop, chronic cough is frequently discounted by the patient as an expected consequence of smoking or environmental exposures1. Initially, the cough may be intermittent, but later is present every day. Chronic cough associated with COPD can be productive or unproductive. Notably, some patients can develop considerable airflow limitation without the presence of a cough.

Sputum production

Excess sputum production is a key symptom of COPD, and patients frequently raise small quantities of viscous sputum after coughing bouts1. Sputum production is often difficult to evaluate because many patients swallow rather than expectorate it.

COPD is a progressive disease of the respiratory system that results in permanent decline in lung function. Accordingly, the classic symptoms of COPD – dyspnoea, cough and sputum production – increase over the course of the disease.


Morning Symptoms

An international survey of 803 COPD patients found that morning was the worst time of day for patients with COPD, especially those with severe disease10 (Figure 2).

Inhaled Therapies_Symptoms_Fig2__70AE1A96-59A2-468C-B7135CF7DE5FD453.png

Figure 2. Many patients report mornings as being the worst time of day for experiencing COPD symptoms and performing daily activities10,11. The graph shows the time when COPD symptoms were reported as  worse than normal. Morning was defined as from the time respondents woke up until they were dressed, had breakfast and were ready to start the day; midday as the time around lunch; afternoon as the time before they had dinner; evening as from the time they had dinner until they went to bed; and night as from the time they went to bed until they woke up in the morning. Multiple answers were possible. 
*p<0.001 versus ‘midday’, ‘afternoon’, ‘evening’, ‘night’ and ‘difficult to say’ groups; p=0.006 versus ‘no particular time of day’ (all patients with COPD);
†p<0.001 versus ‘midday’, ‘afternoon’, ‘evening’, ‘no particular time of day’ and ‘difficult to say’ groups; p=0.001 versus ‘night’. Data are weighted for age and severity11.


Shortness of breath was the most frequently-reported symptom and had a strong correlation with performing morning activities, such as walking up and down the stairs, putting on shoes and socks and making the bed10 (Figure 3).

Inhaled Therapies_Symptoms_Fig3__413CD5B7-B64F-4C44-B99A38B8AA217C59.png

Figure 3. Breathlessness affects simple morning activities10.
*Rated on a scale from 1 to 10, where 1=it is not affected at all and 10=it is greatly affected. Data are weighted for age and COPD severity.


The majority of patients in this study were not taking their medication in time for it to exert its optimal effect, indicating a need for long-acting medication and advice to patients on the optimal time to administer their therapy.

Other studies have also shown that the severity and nature of COPD symptoms varies over time. For example, a study of Turkish patients with COPD indicated that variability in the symptoms of dyspnoea, sputum production and cough reached a peak in the morning hours, whereas wheezing peaked at night and angina peaked during the day12. In a Spanish study, 84% of patients with COPD reported at least one respiratory symptom in the previous week and 61% noted that their symptoms varied over the course of the day or week, with the most intense symptoms occurring in the morning13.

The impact of the common COPD symptoms on patients’ lives was evaluated in a recent survey that revealed that these symptoms significantly affect patients’ routine activities, such as waking and carrying out simple tasks (e.g. stairs, shower, grooming, and dressing). The time to complete these simple activities was extended by 10-15 minutes for the patients, while more strenuous activities (doing morning chores around the house) took around 30 minutes longer than previously14. The multiple symptoms have a significant impact on patient wellbeing15,16,17,18,19,3,1 (Figure 4).

Inhaled Therapies_Symptoms_Fig4__585623E8-A57C-4706-B3888202D5C3BC68.png

Figure 4. The multiple symptoms of COPD have a significant impact on patient well-being


Exacerbations

An exacerbation of COPD can be defined as:

'an acute worsening of respiratory symptoms that result in additional therapy'1

Exacerbations have substantial detrimental effects on patients and are associated with impairment of quality of life, worsening of symptoms and lung function that may take several weeks to resolve, accelerated decline in lung function, significant mortality, and high socioeconomic costs1. Figure 5 illustrates the possible triggers and effects of exacerbations in patients with COPD20.

Inhaled Therapies_Symptoms_Fig5__B439B338-B399-4E06-9B0B8EFA54E5C51E.png

Figure 5. Exacerbation triggers and effects21.

The long-term prognosis following admittance to hospital following a COPD exacerbation is poor: five-year mortality rate is approximately 50%1.


Extra-Pulmonary Symptoms

While COPD primarily affects the lungs, factors such as breathlessness, fatigue, muscle wasting, sleep and mood disturbances, and frequent exacerbations also impact on patients’ daily life, health, and wellbeing. Assessments of health-related quality of life using validated instruments, for example, the St George’s Respiratory Questionnaire (SGRQ) show significant associations between health status and a wide range of specific markers of impaired health21. A recent meta-analysis of studies of bronchodilators also showed that there was a significant correlation between increases in forced expiratory volume in 1 second (FEV1) and improvements in health status (SGRQ score)22.

Patients with COPD are at increased risk for a number of comorbid conditions as a result of the stress placed on their respiratory and circulatory systems by COPD. 

Diagnosis

A clinical diagnosis of COPD should be considered in any patient who has dyspnoea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease1,2 (Figure 1).

Inhaled Therapies_Diagnosis_Fig1__9F59838C-8236-4B63-9A09AB684BF3CF37.png

Figure 1. Symptoms, a history of risk factors, and spirometry all contribute to the diagnosis of COPD1,2.
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

 

Medical history

On presentation of a patient with the primary symptoms of COPD (dyspnoea, chronic cough and sputum production), a detailed medical history should be taken to assess the patient’s exposure to risk factors e.g. smoking, family history of COPD or other chronic respiratory disease, the pattern of symptom development, history of exacerbations or previous hospitalizations for respiratory disorder, presence of comorbidities, impact of disease on patient’s life, social and family support available to the patient and the possibility of reducing risk factors e.g. smoking cessation1,2.

Physical examination

A number of physical signs may be present in COPD, but they do not usually occur until after significant lung impairment has occurred, so that their absence does not exclude the diagnosis1,2. A list of physical signs in COPD:

  • Increased lung volumes due to hyperinflation may manifest as a barrel-shaped chest, abdominal distension and decreased hepatic dullness to percussion
  • Dyspnoea at rest – may manifest itself as an increased respiratory rate (more than 20 breaths per minute) and may also be accompanied by the use of the accessory muscles of respiration
  • Central cyanosis – may manifest as a bluish discoloration of the lips
  • Pursed-lip breathing (the so called ‘pink puffer’) – reflects a physiological reflex to increase end-expiratory pressure, thereby reducing airway collapse secondary to the decreased elastic recoil associated with emphysema
  • In severe disease, increased fluid retention is associated with impaired right heart function and metabolic derangement resulting in raised jugular venous pressure (JVP) and ankle oedema. When seen in this context the syndrome is referred to as ‘cor pulmonale’
  • Auscultation (listening to the chest) may reveal wheeze, decreased breath sounds, rales and rhonchi
  • Due to the obstructive nature of the disease, prolonged forced expiratory time may be clinically apparent, but lung function testing is the gold standard for detecting obstruction

Measurement of airflow limitation

As a reproducible, standardised and objective way of measuring airflow limitation, spirometry is the gold standard for confirming a diagnosis of COPD. Spirometry should be performed after the administration of a bronchodilator in order to minimise variability and to ensure airways are maximally dilated when the test is performed. According to GOLD, a post-bronchodilator ratio of FEV1 to forced vital capacity (FVC) of less than 0.70 confirms a diagnosis of COPD1,2.

Additional investigations

Further investigations may be necessary to confirm that the respiratory symptoms and airflow limitation result from COPD rather than other chronic lung or cardiac conditions, for example, bronchiectasis, lung cancer, chronic heart failure3:

  • Chest radiography is useful for excluding alternative diagnoses such as heart failure
  • Arterial blood gas measurement may be appropriate in patients with an initial diagnosis of advanced COPD
  • Alpha-1 antitrypsin deficiency screening should be considered in patients from areas where this genetic disorder is common3,1,2

Diagnosis may also be helped by using specifically designed questionnaires and algorithms4.

Differential Diagnosis

COPD and asthma are two distinct diseases with fundamental differences that influence both diagnosis and treatment (Price et al, 2010; GOLD, 2020). GOLD 2020 makes it clear that it no longer supports the concept of asthma and COPD overlap (ACOL). Rather the two conditions are considered to be distinct entities and separate, though they may co-exist within the same individual. If a diagnosis of asthma is suspected alongside COPD, pharmacological treatment should be primarily guided by the asthma1,2.

Differentiation between asthma and COPD is extremely important as treatment strategies and prognoses differ for the two conditions.


Characteristics that differentiate COPD and asthma are summarised in Table 1.

Table 1. Key differentiators between COPD and asthma3,5,1,2.

Inhaled therapies_Diagnosis_Table1__8E4CF75D-5132-4032-96D441E38224E736.png

Historically, the differential diagnosis of asthma and COPD has been poor, largely due to a lack of awareness of COPD and the limited use of spirometry at primary care level. Despite the challenges faced in differentiating COPD from asthma, accurate diagnosis of these distinct conditions is imperative to ensure optimal management strategies are instigated. Further information can be found in the Guidelines section.

Correct diagnosis of COPD will help to ensure patients are given access to pulmonary rehabilitation, a key aspect of COPD management3,5,1,2. Patients with asthma may require anti-inflammatory medication, such as inhaled corticosteroids (ICS), for optimal control of their symptoms. In contrast, in patients with COPD and a low risk of exacerbations, ICS provide little benefit and may increase the risk of adverse events, such as pneumonia. ICS are therefore not recommended for patients with COPD and a low risk of exacerbations.

A full list of references are available for the Asthma and COPD disease overview sections.

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.
  11. Jones RCM, Price D, Ryan D, et al. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: A retrospective study of a clinical cohort. Lancet Respir Med. 2014;2(4):267-276.
  12. Sundblad B-M, Larsson K, Nathell L. Low awareness of COPD among physicians. Clin Respir J. 2008;2(1):11-16.
  13. Rycroft CE, Heyes A, Lanza L, Becker K. Epidemiology of chronic obstructive pulmonary disease: A literature review. Int J COPD. 2012;7:457-494.
  14. Gibson GJ, Loddenkemper R, Sibille Y LB. Chronic obstructive pulmonary disease. In: Respiratory Health and Disease in Europe: The New European Lung White Book. ; 2013:148-159.
  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.
  28. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clin Outcomes Res. 2013;5(1):235-245.
  29. Gibson GJ, Loddenkemper R, Lundbäck B, Sibille Y. European Lung White Book. The economic burden of lung disease. Eur Respir J. 2013;42(3):559-563.
  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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