Pathophysiology of Chronic Obstructive Pulmonary Disease (COPD)

PATHOPHYSIOLOGY

Medical Diagnosis:

Chronic Obstructive Pulmonary Disease (COPD)

Definition:

Chronic Obstructive Pulmonary Disease (COPD) is chronic inflammation and fibrosis of the air ways, specifically the peripheral airways and lung parenchyma (Barnes, 2017).

Cellular Description:

Chronic Obstructive Pulmonary Disease (COPD) is chronic inflammation of the air ways, specifically the peripheral airways and lung parenchyma (alveoli and bronchioles) which leads to expiratory airflow limitation.  The disease is a combination of diseases including emphysema, chronic asthma, and chronic bronchitis.  Emphysema is destruction of lung parenchyma, bronchitis is inflammation and excess mucus production, and asthma is tight and swollen airways (Wu, 2019).  COPD manifestations include mucus hypersecretion, airway narrowing and fibrosis, destruction of parenchyma, and vascular changes (Chronic obstructive, n.d.).

The mechanism of inflammation is prompted by mast cells in response to foreign particles or infection in the airways.  Mast cells release histamine, PGD2, and cys-LTs all of which contract the smooth muscles of the airways, increase the production of mucus, attract inflammatory cells, induce tissue destruction, impair defense mechanisms, and increase microvascular leakage.  Lipid mediators, cytokines, and chemokines also seek to recruit inflammatory cells to the lungs.  Lung cells including endothelial cells, epithelial cells, and fibroblasts contribute to the inflammatory process by releasing chemical mediators.  Both the innate and adaptive immunity are active in COPD.  The innate immune system attracts macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid cells, and dendritic cells.  The adaptive immune system brings in T and B lymphocytes.

Macrophages contribute immensely to the marked inflammation in chronic obstructive pulmonary disease.  In patients with COPD, an increase in the number of macrophages in the lungs, airways, and parenchyma is observed.  These macrophages seem to have a greater chemotactic response, or increased activation, to CXCL1, a chemokine, than do the macrophages from normal smokers and from non-smokers (Barnes, 2017, p. 11).  This immense infiltration of macrophages yields more inflammatory proteins and reactive oxygen species.  “Macrophages likely play an orchestrating role in COPD inflammation by releasing mediators such as tumor necrosis factor-a (TNF-a), interleukin 8 (IL-8), and leukotriene B4 (LTB4), which promote neutrophilic inflammation” (Chronic obstructive, n.d.).  Macrophages also demonstrate decreased phagocytic uptake of bacteria which “may predispose [the patient] to chronic colonization of the lower airways by bacteria such as

Haemophilus influenzae

or

Streptococcus pneumoniae”

(Barnes, 2017, p. 12).  Colonization of bacteria predisposes COPD patients to increased acute exacerbations.  COPD macrophages also fail to clear apoptotic cells in the lungs which can contribute to the lack of resolution of inflammation.

Neutrophilic chemotactic factors are released from the respiratory tract to attract neutrophils.  Once present, neutrophils “secrete serine proteases, including neutrophil elastase (NE), cathepsin G and proteinase-3, as well as MMP-8 and MMP-9, which may contribute to alveolar destruction” (Barnes, 2017, p. 13).  Neutrophil elastase and serine proteases stimulate goblet and submucosal cells in the central and peripheral airway to increase in number (metaplasia) which yields mucus hypersecretion.  This explains why neutrophils are found exceedingly in sputum samples of COPD patients.  Patients with COPD typically have paralyzed cilia which inhibits the excess mucus from effectively being removed thus it occupies the airway lumen increasing obstruction (Barnes, 2017).  The mucus hypersecretion in the peripheral airways causes damage to and decline in function of the alveoli.

T lymphocytes are also present in COPD along with macrophages and neutrophils.  T lymphocytes, specifically CD8+, released perforin, granzyme-B, and tissue necrosis factor-a all of which cause cytolysis and apoptosis of alveolar epithelial cells.  This is thought to be responsible for the persistent inflammation seen in COPD (Chronic obstructive, n.d.).

The invasion of these cells into the lungs is most often caused by cigarette smoke.  “Cigarette smoke activates macrophages and epithelial cells to produce TNF-a and may also cause macrophages to release other inflammatory mediators, including IL-8 and LTB4” (Chronic obstructive, n.d.).  The inflammation caused by cigarette smoke or the inflammatory response leads to repeated cycles of repair and damage to the peripheral airways.  In the effort to repair the airways epithelial cells and macrophages secrete fibrogenic mediators to activate mesenchymal cells including fibroblasts and myofibroblasts.  Fibroblasts attempt to repair the damage in the alveoli but leave behind scar tissue and collagen.  This is known as fibrosis and is an irreversible narrowing of the airways.  Fibrosis limits the lungs ability to recoil and increases airway resistance.

As inflammatory cells infiltrate the lungs, bronchoconstriction occurs in response to mediators released by the cells.  Blood to the airways is reduced in COPD due to a decrease in vascular-endothelial growth factor which can lead to tissue hypoxia.  Endothelial damage within the vessels also occurs and alters the vascular tone and cell proliferation. “Thickening of the intima is the first structural change, followed by an increase in vascular smooth muscle and the infiltration of the vessel wall by inflammatory cells, including macrophages and CD8+ T lymphocytes14” (Chronic obstructive, n.d.).  This all leads to pulmonary hypertension.

If neutrophilic inflammation, fibrosis, and ineffective bacterial phagocytosis by macrophages is persistent, lower airway inflammation will inevitably lead to pathologic changes and progression of chronic obstructive pulmonary disease.  Systemic inflammation also follows as inflammatory cells circulate throughout the body.

In addition to inflammation, the body experiences an imbalance in proteinases and anti-proteinases and oxidative stress.  These manifestations are thought to arise as a consequence of inflammation or by environmental or genetic factors.  Inflammatory cells release proteinases which some are capable of degrading the alveolar elastin and collagen and others cause mucus gland hyperplasia.  Oxidant/antioxidant imbalance is also seen in COPD with a variable amount of hydrogen peroxide and nitric oxide generated by cigarette smoke or released from inflammatory cells.  The imbalance is typically more oxidants than antioxidants.  This imbalance can lead to cell dysfunction or death and lung extracellular matrix damage.  It also adds to the imbalance between proteinases and anti-proteinases by inactivating anti-proteinases and activating proteinases.  Oxidants promote inflammation, contribute to airway narrowing, and constricts airway smooth muscles (Chronic obstructive, n.d.).

With the extensive effect COPD has on the airways, it is of no surprise that there are multiple co-morbidities associated with the disease including cardiovascular disease, diabetes, depression, skeletal muscle dysfunction, lung cancer, metabolic syndrome, and osteoporosis (Rosenberg & Kalhan, 2017).

Epidemiology:

• COPD is the 4th commonest cause of death worldwide, and 3rd in developed countries like the UK.
• COPD is the 5th ranked cause of disability.
• There are 251 million cases of COPD globally.
• It affects 10% of people over the age of 45.
• In developed countries, it is predominantly caused by cigarette smoking.
• COPD effects women and men about equally, which demonstrates the about equal use of cigarette smoking in males and females.
• In low- and middle-income countries, COPD is most often due to wood smoke (biomass) exposure and not due to cigarette smoking.
• Systemic inflammation was associated with a 2-4-fold increased risk of cardiovascular disease, diabetes, lung cancer and pneumonia.
• 70% of COPD patients have systemic inflammation, and 16% of those have persistent inflammation with increased mortality and exacerbations.
• “System inflammation is (also) associated with greater decline in lung function.”

(Barnes, 2017).

• “Those hospitalized for acute exacerbations of COPD are at an increased risk of one-year mortality of at least 18%” (Rosenberg & Ravi, 2017).

• $50 billion dollars is spent every year in the US to treat acute exacerbations of COPD.

(Rosenberg & Kalhan, 2017)

Risk Factors:

• Cigarette smoking
• Secondhand smoking
• Workplace irritants
• Industrial chemicals
• Cooking fumes
• Air pollution
• Pipe smoke
• Age
• Genetics
• Low socioeconomic status
• Prematurity

(Wu, 2019)

Signs & Symptoms


(Differentiate between Early vs. Late signs/symptoms)

Treatment

Medications



(drug classification and a


brief


description of how the med works)



,, Diet,








Lifestyle, Surgery,








Activity

• Shortness of breath (early)
• Breathlessness (early)
• Inability to exercise (early)
• Difficulty breathing (early)
• Chest tightness (early)
• Fatigue (early)
• Fever
• Frequent respiratory infections
• Confusion
• Exacerbations of these symptoms
• Chronic cough
• Producing more mucus than normal
• Swelling in the ankles, feet, legs (severe COPD)
• Weight loss (severe COPD)
• Reduced muscle strength
• Reduced endurance (early)
• Wheezing (early)
• Tissue hypoxia (late)
• Cyanosis (late)
• Respiratory acidosis (late)
• Fibrosis of lower airways (late)
• Pulmonary hypertension (late)
• Hypertension
• Decline in lung function measured by amount of air forcibly exhaled in one second (FEV1)

(Wu, 2019)

COPD cannot be cured but there are therapies to decrease the complications and side effects.

• 
  Corticosteroids-
  
  reduce inflammation.

• 
  Antibiotics
  
  (ex. macrolide)- kill existing bacteria and inhibit growth of bacteria.

(Barnes, 2017)

• 
  Long acting beta-2 agonists
  
  – relaxes airway smooth muscle tone which leads to reduced respiratory muscle activity and decreases airway resistance. Helps the patient breathe easier.
• 
  Long acting muscarinic antagonists
  
  (ex.  tiotropium)- bronchodilator.
• 
  Dual agent long-acting bronchodilators
  
  (ex. fluticasone/salmeterol)- inhalers with combined medicines to improve lung function, reduce exacerbations, dilate the smooth muscle of the bronchi.
• 
  Bronchoscopic therapies
  
  (work in progress)- lung volume reduction surgery to prolong life for people with COPD.

(Rosenberg & Kalhan, 2017)

• 
  Smoking cessation.
  
• 
  Oxygen therapy.
  
• 
  Pulmonary rehabilitation.
  

(Wise, 2018)

Diagnostics


(Labs, Radiology, Biopsy, others)

Tests:








List all diagnostic tests that you would expect to be completed with this diagnosis. Give expected values and/or descriptions of each test.

• 
  Chest x-ray
  
  – changes can include lung hyperinflation, rapid tapering. Of hilar vessels, bullae, prominent hilla.
• 
  Chest CT
  
  – may reveal abnormalities.
• 
  Pulmonary function testing
  
  – FEV1, forced vital capacity (FVC), flow-volume loops.
• Abnormalities in these may indicate COPD

• Increased total lung capacity
• Increased functional residual capacity
• Increased residual volume
• Decreased vital capacity
• Decreased single-breath diffusing capacity for carbon monoxide

• 
  Alpha-1 antitrypsin levels
  
  – to detect deficiency.
• 
  ECG
  
  – done to exclude any cardiac conditions that could cause symptoms of dyspnea.
• 
  Echocardiography
  
  – assesses for pulmonary hypertension.
• 
  Evaluate PaO2 and PaCO2.
  
• 
  Assessment of sputum
  
  – indicates neutrophil levels, bacteria present (infection).

(Wise, 2018)

ADD: what are the normal values for these and what are the values in COPD?

References (APA format)

• Barnes, P. J. (2017, March 1).
  
  Cellular and molecular mechanisms of asthma and COPD
  
  , pp. 1 -24. Retrieved November 2, 2019, from https://spiral.imperial.ac.uk:8443/handle/10044/1/51388.
• Chronic obstructive pulmonary disease pathogenesis, pathology, and pathophysiology (n.d.).
  
  In Institute for continuing education
  
  . Retrieved November 3, 2019, from http://ceu.org/cecourses/990709/copd_course_patho.htm.
• Rosenberg, S. R., & Kalhan, R. (2017, June 9).
  
  Recent advances in the management of chronic obstructive pulmonary disease
  
  . Retrieved November 2, 2019, from   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473415/.
• Wise, R. A. (2018, November).
  
  Chronic obstructive pulmonary disease (COPD) – pulmonary disorders
  
  . Retrieved November 2, 2019, from https://www.merckmanuals.com/professional/pulmonary-disorders/chronic-obstructive-pulmonary-disease-and-related-disorders/chronic-obstructive-pulmonary-disease-copd.
• Wu, Brian (2019, September 30).
  
  Pathophysiology of COPD: What happens, causes, and symptoms
  
  . Retrieved November 2, 2019, from  https://www.medicalnewstoday.com/articles/315687.php.

PATHOPHYSIOLOGY

Medical Diagnosis:

Chronic Obstructive Pulmonary Disease (COPD)

Definition:

Chronic Obstructive Pulmonary Disease (COPD) is chronic inflammation and fibrosis of the air ways, specifically the peripheral airways and lung parenchyma (Barnes, 2017).

Cellular Description:

Chronic Obstructive Pulmonary Disease (COPD) is chronic inflammation of the air ways, specifically the peripheral airways and lung parenchyma (alveoli and bronchioles) which leads to expiratory airflow limitation.  The disease is a combination of diseases including emphysema, chronic asthma, and chronic bronchitis.  Emphysema is destruction of lung parenchyma, bronchitis is inflammation and excess mucus production, and asthma is tight and swollen airways (Wu, 2019).  COPD manifestations include mucus hypersecretion, airway narrowing and fibrosis, destruction of parenchyma, and vascular changes (Chronic obstructive, n.d.).

The mechanism of inflammation is prompted by mast cells in response to foreign particles or infection in the airways.  Mast cells release histamine, PGD2, and cys-LTs all of which contract the smooth muscles of the airways, increase the production of mucus, attract inflammatory cells, induce tissue destruction, impair defense mechanisms, and increase microvascular leakage.  Lipid mediators, cytokines, and chemokines also seek to recruit inflammatory cells to the lungs.  Lung cells including endothelial cells, epithelial cells, and fibroblasts contribute to the inflammatory process by releasing chemical mediators.  Both the innate and adaptive immunity are active in COPD.  The innate immune system attracts macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid cells, and dendritic cells.  The adaptive immune system brings in T and B lymphocytes.

Macrophages contribute immensely to the marked inflammation in chronic obstructive pulmonary disease.  In patients with COPD, an increase in the number of macrophages in the lungs, airways, and parenchyma is observed.  These macrophages seem to have a greater chemotactic response, or increased activation, to CXCL1, a chemokine, than do the macrophages from normal smokers and from non-smokers (Barnes, 2017, p. 11).  This immense infiltration of macrophages yields more inflammatory proteins and reactive oxygen species.  “Macrophages likely play an orchestrating role in COPD inflammation by releasing mediators such as tumor necrosis factor-a (TNF-a), interleukin 8 (IL-8), and leukotriene B4 (LTB4), which promote neutrophilic inflammation” (Chronic obstructive, n.d.).  Macrophages also demonstrate decreased phagocytic uptake of bacteria which “may predispose [the patient] to chronic colonization of the lower airways by bacteria such as

Haemophilus influenzae

or

Streptococcus pneumoniae”

(Barnes, 2017, p. 12).  Colonization of bacteria predisposes COPD patients to increased acute exacerbations.  COPD macrophages also fail to clear apoptotic cells in the lungs which can contribute to the lack of resolution of inflammation.

Neutrophilic chemotactic factors are released from the respiratory tract to attract neutrophils.  Once present, neutrophils “secrete serine proteases, including neutrophil elastase (NE), cathepsin G and proteinase-3, as well as MMP-8 and MMP-9, which may contribute to alveolar destruction” (Barnes, 2017, p. 13).  Neutrophil elastase and serine proteases stimulate goblet and submucosal cells in the central and peripheral airway to increase in number (metaplasia) which yields mucus hypersecretion.  This explains why neutrophils are found exceedingly in sputum samples of COPD patients.  Patients with COPD typically have paralyzed cilia which inhibits the excess mucus from effectively being removed thus it occupies the airway lumen increasing obstruction (Barnes, 2017).  The mucus hypersecretion in the peripheral airways causes damage to and decline in function of the alveoli.

T lymphocytes are also present in COPD along with macrophages and neutrophils.  T lymphocytes, specifically CD8+, released perforin, granzyme-B, and tissue necrosis factor-a all of which cause cytolysis and apoptosis of alveolar epithelial cells.  This is thought to be responsible for the persistent inflammation seen in COPD (Chronic obstructive, n.d.).

The invasion of these cells into the lungs is most often caused by cigarette smoke.  “Cigarette smoke activates macrophages and epithelial cells to produce TNF-a and may also cause macrophages to release other inflammatory mediators, including IL-8 and LTB4” (Chronic obstructive, n.d.).  The inflammation caused by cigarette smoke or the inflammatory response leads to repeated cycles of repair and damage to the peripheral airways.  In the effort to repair the airways epithelial cells and macrophages secrete fibrogenic mediators to activate mesenchymal cells including fibroblasts and myofibroblasts.  Fibroblasts attempt to repair the damage in the alveoli but leave behind scar tissue and collagen.  This is known as fibrosis and is an irreversible narrowing of the airways.  Fibrosis limits the lungs ability to recoil and increases airway resistance.

As inflammatory cells infiltrate the lungs, bronchoconstriction occurs in response to mediators released by the cells.  Blood to the airways is reduced in COPD due to a decrease in vascular-endothelial growth factor which can lead to tissue hypoxia.  Endothelial damage within the vessels also occurs and alters the vascular tone and cell proliferation. “Thickening of the intima is the first structural change, followed by an increase in vascular smooth muscle and the infiltration of the vessel wall by inflammatory cells, including macrophages and CD8+ T lymphocytes14” (Chronic obstructive, n.d.).  This all leads to pulmonary hypertension.

If neutrophilic inflammation, fibrosis, and ineffective bacterial phagocytosis by macrophages is persistent, lower airway inflammation will inevitably lead to pathologic changes and progression of chronic obstructive pulmonary disease.  Systemic inflammation also follows as inflammatory cells circulate throughout the body.

In addition to inflammation, the body experiences an imbalance in proteinases and anti-proteinases and oxidative stress.  These manifestations are thought to arise as a consequence of inflammation or by environmental or genetic factors.  Inflammatory cells release proteinases which some are capable of degrading the alveolar elastin and collagen and others cause mucus gland hyperplasia.  Oxidant/antioxidant imbalance is also seen in COPD with a variable amount of hydrogen peroxide and nitric oxide generated by cigarette smoke or released from inflammatory cells.  The imbalance is typically more oxidants than antioxidants.  This imbalance can lead to cell dysfunction or death and lung extracellular matrix damage.  It also adds to the imbalance between proteinases and anti-proteinases by inactivating anti-proteinases and activating proteinases.  Oxidants promote inflammation, contribute to airway narrowing, and constricts airway smooth muscles (Chronic obstructive, n.d.).

With the extensive effect COPD has on the airways, it is of no surprise that there are multiple co-morbidities associated with the disease including cardiovascular disease, diabetes, depression, skeletal muscle dysfunction, lung cancer, metabolic syndrome, and osteoporosis (Rosenberg & Kalhan, 2017).

Epidemiology:

• COPD is the 4th commonest cause of death worldwide, and 3rd in developed countries like the UK.
• COPD is the 5th ranked cause of disability.
• There are 251 million cases of COPD globally.
• It affects 10% of people over the age of 45.
• In developed countries, it is predominantly caused by cigarette smoking.
• COPD effects women and men about equally, which demonstrates the about equal use of cigarette smoking in males and females.
• In low- and middle-income countries, COPD is most often due to wood smoke (biomass) exposure and not due to cigarette smoking.
• Systemic inflammation was associated with a 2-4-fold increased risk of cardiovascular disease, diabetes, lung cancer and pneumonia.
• 70% of COPD patients have systemic inflammation, and 16% of those have persistent inflammation with increased mortality and exacerbations.
• “System inflammation is (also) associated with greater decline in lung function.”

(Barnes, 2017).

• “Those hospitalized for acute exacerbations of COPD are at an increased risk of one-year mortality of at least 18%” (Rosenberg & Ravi, 2017).

• $50 billion dollars is spent every year in the US to treat acute exacerbations of COPD.

(Rosenberg & Kalhan, 2017)

Risk Factors:

• Cigarette smoking
• Secondhand smoking
• Workplace irritants
• Industrial chemicals
• Cooking fumes
• Air pollution
• Pipe smoke
• Age
• Genetics
• Low socioeconomic status
• Prematurity

(Wu, 2019)

Signs & Symptoms


(Differentiate between Early vs. Late signs/symptoms)

Treatment

Medications



(drug classification and a


brief


description of how the med works)



,, Diet,








Lifestyle, Surgery,








Activity

• Shortness of breath (early)
• Breathlessness (early)
• Inability to exercise (early)
• Difficulty breathing (early)
• Chest tightness (early)
• Fatigue (early)
• Fever
• Frequent respiratory infections
• Confusion
• Exacerbations of these symptoms
• Chronic cough
• Producing more mucus than normal
• Swelling in the ankles, feet, legs (severe COPD)
• Weight loss (severe COPD)
• Reduced muscle strength
• Reduced endurance (early)
• Wheezing (early)
• Tissue hypoxia (late)
• Cyanosis (late)
• Respiratory acidosis (late)
• Fibrosis of lower airways (late)
• Pulmonary hypertension (late)
• Hypertension
• Decline in lung function measured by amount of air forcibly exhaled in one second (FEV1)

(Wu, 2019)

COPD cannot be cured but there are therapies to decrease the complications and side effects.

• 
  Corticosteroids-
  
  reduce inflammation.

• 
  Antibiotics
  
  (ex. macrolide)- kill existing bacteria and inhibit growth of bacteria.

(Barnes, 2017)

• 
  Long acting beta-2 agonists
  
  – relaxes airway smooth muscle tone which leads to reduced respiratory muscle activity and decreases airway resistance. Helps the patient breathe easier.
• 
  Long acting muscarinic antagonists
  
  (ex.  tiotropium)- bronchodilator.
• 
  Dual agent long-acting bronchodilators
  
  (ex. fluticasone/salmeterol)- inhalers with combined medicines to improve lung function, reduce exacerbations, dilate the smooth muscle of the bronchi.
• 
  Bronchoscopic therapies
  
  (work in progress)- lung volume reduction surgery to prolong life for people with COPD.

(Rosenberg & Kalhan, 2017)

• 
  Smoking cessation.
  
• 
  Oxygen therapy.
  
• 
  Pulmonary rehabilitation.
  

(Wise, 2018)

Diagnostics


(Labs, Radiology, Biopsy, others)

Tests:








List all diagnostic tests that you would expect to be completed with this diagnosis. Give expected values and/or descriptions of each test.

• 
  Chest x-ray
  
  – changes can include lung hyperinflation, rapid tapering. Of hilar vessels, bullae, prominent hilla.
• 
  Chest CT
  
  – may reveal abnormalities.
• 
  Pulmonary function testing
  
  – FEV1, forced vital capacity (FVC), flow-volume loops.
• Abnormalities in these may indicate COPD

• Increased total lung capacity
• Increased functional residual capacity
• Increased residual volume
• Decreased vital capacity
• Decreased single-breath diffusing capacity for carbon monoxide

• 
  Alpha-1 antitrypsin levels
  
  – to detect deficiency.
• 
  ECG
  
  – done to exclude any cardiac conditions that could cause symptoms of dyspnea.
• 
  Echocardiography
  
  – assesses for pulmonary hypertension.
• 
  Evaluate PaO2 and PaCO2.
  
• 
  Assessment of sputum
  
  – indicates neutrophil levels, bacteria present (infection).

(Wise, 2018)

ADD: what are the normal values for these and what are the values in COPD?

References (APA format)

• Barnes, P. J. (2017, March 1).
  
  Cellular and molecular mechanisms of asthma and COPD
  
  , pp. 1 -24. Retrieved November 2, 2019, from https://spiral.imperial.ac.uk:8443/handle/10044/1/51388.
• Chronic obstructive pulmonary disease pathogenesis, pathology, and pathophysiology (n.d.).
  
  In Institute for continuing education
  
  . Retrieved November 3, 2019, from http://ceu.org/cecourses/990709/copd_course_patho.htm.
• Rosenberg, S. R., & Kalhan, R. (2017, June 9).
  
  Recent advances in the management of chronic obstructive pulmonary disease
  
  . Retrieved November 2, 2019, from   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473415/.
• Wise, R. A. (2018, November).
  
  Chronic obstructive pulmonary disease (COPD) – pulmonary disorders
  
  . Retrieved November 2, 2019, from https://www.merckmanuals.com/professional/pulmonary-disorders/chronic-obstructive-pulmonary-disease-and-related-disorders/chronic-obstructive-pulmonary-disease-copd.
• Wu, Brian (2019, September 30).
  
  Pathophysiology of COPD: What happens, causes, and symptoms
  
  . Retrieved November 2, 2019, from  https://www.medicalnewstoday.com/articles/315687.php.