COPD Pathophysiology Lecture Set PDF

Chronic Obstructive Pulmonary Disease (COPD) Pathophysiology Jeffrey Wong, BScPharm, ACPR, PharmD  Acknowledgments Eric F. Schneider, Rita Dhami, Feng Cheng for original content development 2 GLOBAL INITIATIVE FOR CHRONIC...

Chronic Obstructive Pulmonary Disease (COPD) Pathophysiology Jeffrey Wong, BScPharm, ACPR, PharmD  Acknowledgments Eric F. Schneider, Rita Dhami, Feng Cheng for original content development 2 GLOBAL INITIATIVE FOR CHRONIC OBSTRUCTIVE LUNG DISEASE (GOLD):  Learning Objectives Discuss the epidemiology of COPD Define COPD and describe factors related to its development Explain the pathogenesis and contributors to the enhanced inflammatory response seen in COPD Describe the pathophysiologic features of COPD Assess a patient’s severity of COPD based on spirometric data 4 Epidemiology  Epidemiology https://health-infobase.canada.ca/datalab/copd-blog.html 6 7 8  Epidemiology of COPD Statistics Canada, Catalogue no. 82-624-X, Health at a Glance, Nov 2015 One of top 3 causes of death worldwide Accounts for 6% of deaths globally Cause for 4.4% of all deaths in Canada among those 40 and older in 2011 Death rate for men decreased from 1998-2011 – While increasing steadily for women between 1950- 2011 – Thus, the historical gender gap has disappeared – Smokers are 12-13 times more likely to die from COPD than never smokers 9 10 11  Epidemiology ~90,000 hospitalizations in 2016-2017 1 in 5 patients readmitted within 30 days Hospital admissions related to exacerbations average 10-day stays, at a cost of $10,000/stay Total cost for COPD hospitalization estimated at 1.5 billion / year https://secure.cihi.ca/free_products/hospch-hosp-2016-2017-snapshot_en.pdf 12 https://secure.cihi.ca/free_products/Readmission_to_acutecare_en.pdf http://www.lung.ca/media-medias/news-nouvelles_e.php?id=213  Epidemiology http://www.respiratoryguidelines.ca/the-human-and-economic-burden-of-copd- a-leading-cause-of-hospital-admission-in-canada Hospitalizations by condition, 2006-2007 13 Pathogenesis  What is COPD? COPD (Chronic Obstructive Pulmonary Disease) is: - A common, preventable and treatable disease - Characterized by - Persistent respiratory symptoms - Airflow limitation usually caused by airway and/or alveolar abnormalities, typically as a result of significant exposure to noxious particles or gases - May be influenced by host factors - Mix of small airway disease (e.g., obstructive bronchiolitis) and parenchymal destruction (e.g., emphysema) 15 16  What is COPD? Most common symptoms include dyspnea, cough and sputum production Main risk factors: – Tobacco smoking – Environmental exposures – Host factors (genetics, abnormal lung development etc) Acute exacerbations are common with progression in disease Associated with significant concomitant illnesses, increased morbidity and mortality 17  Factors Influencing Development and Progression of COPD Cumulative Exposure Tobacco smoking (cigarette, pipe, Lungs cigar, environmental) Occupational dust / chemicals / fumes Biomass and coal cooking / heating Environmental / air pollution Biomass fuel for cooking and heating in poorly vented dwellings Genetics (alpha-1-antitrypsin deficiency) Lung growth and development Age and female sex 18  Factors Influencing Development and Progression of COPD Socioeconomic status Could be a reflection of increased Lungs exposure to other risk factors Asthma Airway hyper-reactivity Chronic bronchitis Infections Severe childhood respiratory infection 19  Mechanisms underlying airflow limitation Small airway disease Parenchymal Airway inflammation destruction Airway fibrosis, Loss of alveolar luminal plugs attachments Increased airway Decrease of elastic resistance recoil Decreased Decreased gas FEV1 transfer 20  How does this happen? Parenchymal Gas trapping Inhalation of tissue and Modified lung noxious destruction progressive inflammation particles and disrupted airflow defense limitation 21  Pathogenesis Increased oxidative stress: Oxidants generated by irritants and released from inflammatory cells such as macrophages and neutrophils. There may also be reduction in endogenous antioxidants due to reduced transcription factor Nrf2 that regulates antioxidant genes. Protease / antiprotease imbalance: Proteases that break down connective tissue are increased and antiproteases that protect connective tissue are decreased. 22  Pathogenesis Inflammatory cells: – Increased number of macrophages in peripheral airways, lung parenchyma and pulmonary vessels – Increased activated neutrophils, lymphocytes – Increased eosinophils particularly in concomitant asthma Inflammatory mediators: – Increased inflammatory mediators attract more inflammatory cells, amplify the inflammatory process and induce structural changes within the lungs 23  Pathogenesis Peribronchiolar and interstitial fibrosis: – Excess growth factors, preceded by inflammation – Repeated injury of the airway can lead to excessive production of muscle and fibrous tissue – Contributes to small airways limitation and eventually emphysema GOLD update 2020 24  Pathogenesis Diaz PT, Knoell DL. Chronic Obstructive Pulmonary Disease. In: Koda-Kimble MA, Young LY, et al, eds. Applied Therapeutics: The Clinical Use of Drugs, 10th Edition. Philadelphia, PA:Lippincott Williams & Wilkins, 2012:601-618. 25  Pathophysiology Airflow limitation / air trapping: – Progressive gas trapping during expiration → hyperinflation → reduced inspiratory capacity → increased dyspnea and reduced exercise capacity – Develops early in the disease – Relieved by bronchodilators – Extent of inflammation, fibrosis, luminal exudates in small airways correlates with reduction in FEV1 and FEV1/FVC ratio, and accelerated decline in FEV1 26  Pathophysiology Gas exchange abnormalities: – Result in hypoxemia and hypercapnia (CO2 retention) – Reduced ventilation due to reduced ventilatory drive, ventilatory muscle impairment and airway limitation – Worsen VA/Q abnormalities (ventilation/perfusion ratio) Mucus hypersecretion: – Inflammatory mediators and proteases can stimulate hypersecretion – Increased goblet cells and enlarged submucosal glands due to airway irritation – Results in chronic productive cough (chronic bronchitis) – Does not always lead to airway limitation 27 Airway Changes in COPD New Engl J Med 2004;350:2635-37. 28 Changes in Flow Rates and Lung Volumes Adapted from: New Engl J Med 2010;362:1407 Normal COPD 29  Pathophysiology Pulmonary hypertension: – Hypoxic vasoconstriction of small pulmonary arteries results in structural changes and smooth muscle hypertrophy – Loss of pulmonary capillary bed in emphysema – Inflammatory response in vessels – Abnormal pulmonary blood flow can be observed in mild disease and worsen with progression – Can lead to right ventricular hypertrophy and right side cardiac failure (cor pulmonale) 30  Pathophysiology Exacerbations: – Can be triggered by respiratory infections, environmental factors, or unknown factors – Increased inflammation, hyperinflation, gas trapping, reduced expiratory flow → dyspnea – Worsened VA / Q → hypoxemia Systemic features: – Concomitant diseases linked to smoking, aging and inactivity – Airflow limitation and hyperinflation will affect cardiac function – Inflammatory mediators can contribute to muscle wasting and cachexia – Worsened ischemic heart disease, heart failure, osteoporosis, anemia, diabetes, metabolic syndrome, depression – QoL and survival 31  COPD vs Asthma Diaz PT, Knoell DL. Chronic Obstructive Pulmonary Disease. In: Koda-Kimble MA, Young LY, et al, eds. Applied Therapeutics: The Clinical Use of Drugs, 10th Edition. Philadelphia, PA:Lippincott Williams & Wilkins, 2012:601-618. COPD Asthma Inflammation (neutrophils) Small airway fibrosis Inflammation (eosinophils) Luminal mucous plugs Increased airway resistance Bronchoconstriction Loss of alveolar elasticity Airway Hyperresponsiveness Loss of alveolar attachments not fully reversible reversible Airflow Limitation 32  COPD vs Asthma Diaz PT, Knoell DL. Chronic Obstructive Pulmonary Disease. In: Koda-Kimble MA, Young LY, et al, eds. Applied Therapeutics: The Clinical Use of Drugs, 10th Edition. Philadelphia, PA:Lippincott Williams & Wilkins, 2012:601-618. 33  For the Patient COPD Asthma Onset in mid-life Onset in early life Persistent Fluctuation in Slowly progressive presentation from day History of exposure to to day, or daytime to irritant(s) night-time Presence of allergy, rhinitis, eczema 34 Diagnosis and Assessment PFT: Spirometry 36  Assessment of Airflow Limitation: Spirometry Spirometry is the most reproducible and objective measurement of airflow limitation Should be performed before and after the administration of an adequate dose of a short-acting inhaled bronchodilator to minimize variability Evaluated by comparisons with appropriate reference values based on age, height, sex, and race – Values should be compared to age-related normal values to avoid over-diagnosis of COPD in the elderly 37  Diagnosis and Assessment COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and / or a history of exposure to risk factors Spirometry is required for diagnosis: – Post-bronchodilator FEV1/FVC < 0.70 confirms persistent airflow limitation and thus COPD Assess: – Level of airflow limitation – Impact of disease on patient – Risk of complications 38 Spirometry: Normal Trace Showing FEV1 and FVC 5 FVC 4 Volume, liters FEV1 = 4L 3 FVC = 5L 2 FEV1/FVC = 0.8 1 1 2 3 4 5 6 Time, sec 39 Spirometry: Obstructive Disease 5 Normal 4 Volume, liters 3 FEV1 = 1.8L 2 FVC = 3.2L Obstructive 1 FEV1/FVC = 0.56 1 2 3 4 5 6 Time, seconds 40  Key Indicators in COPD Dyspnea that is: – Progressive (worsens over time) – Usually worse with exercise – Persistent (present every day) – Described by the patient as “increased effort to breathe,” “heaviness,” “air hunger,” or “gasping.” Chronic cough: – May be intermittent and may be unproductive – Recurrent wheeze 41  Key Indicators in COPD Chronic sputum production: – Any pattern of chronic sputum production may indicate COPD History of exposure to risk factors, especially: – Tobacco smoke – Occupational dusts and chemicals – Smoke from home cooking and heating fuels – Host factors Family history / childhood factors Recurrent lower respiratory infections Systemic features in severe disease 42  Additional Investigations Imaging – X-ray / CT (for differential) Oximetry and Arterial Blood Gas – Oxygen saturation Alpha-1-antitrypsin deficiency – Younger age (