OBSTRUCTIVE AIRWAY DISEASE Airways - obstructive disease Lungs - restrictive disease Obstructive airway syndrome  Asthma  Chronic bronchitis  Emphysema

OBSTRUCTIVE AIRWAY DISEASE Terminology Early onset / late onset Atopic / non-atopic Extrinsic / Intrinsic

The asthma triad Asthma Reversible Airflow Obstruction Airway Inflammation Asthma Airway Hyperresponsiveness

Dynamic evolution of asthma Chronic airway inflammation Broncho- constriction Airway remodeling fixed airway obstruction Brief symptoms exacerbations BHR

Hallmarks of Remodeling in asthma Basement Membrane Submucosa Smooth Muscle Thickening Collagen Deposition Hypertrophy

THE INFLAMMATORY CASCADE Genetic predisposition + Trigger factor • Avoidance (e.g. viral, allergen, chemicals) Airway inflammation • Anti-inflammatory - corticosteroid Mediators • Anti-leukotriene (e.g. histamine, leukotriene) Antihistamine Twitchy smooth muscle • Bronchodilators (Hyper-reactivity) - 2-agonists

The “Tip” of the Iceberg Symptoms/ Exacerbations TITANIC TITANIC Airflow obstruction Bronchial hyperresponsiveness Airway inflammation

SLIDE 1.3 The photomicrograph on the left shows normal human airway mucosa, with the airspace above, pseudostratified respiratory epithelium, and rather bland sub-epithelial tissue. On the right, this photomicrograph shows infiltration of numerous eosinophils and other inflammatory cells into the submucosal tissue. Thickening at the basement membrane (BM) is apparent, but most striking is the desquamation of airway epithelium, with numerous eosinophils within the denuded epithelium. This epithelial damage may predispose the patient with asthma to a greater sensitivity to airway triggers (i.e. airway hyperresponsiveness).

Severe asthma –alive Epithelial shedding Severe asthma –autopsy Mucus plugging Normal

Ask about triggers Allergens animal dander dust mites pollen fungi Symptoms can occur or worsen in the presence of: Allergens animal dander dust mites pollen fungi Others exercise viral infection smoke changes in temperature chemicals drugs (NSAIDs, ß-blockers) Anyone suspected of suffering from asthma should be asked whether any specific triggers bring on or aggravate their respiratory symptoms Drug therapy should always be considered as a possible cause of asthma symptoms. The most important drugs to check for are NSAIDs (such as acetylsalicylic acid) and ß-blockers

ASTHMA - THE CLINICAL SYNDROME Episodic symptoms and signs Diurinal variability – nocturnal/early morning Non-productive cough, wheeze Triggers Associated atopy ( rhinitis , conjunctivitis, eczema) Family history of asthma Wheezing due to turbulent airflow

DIAGNOSIS OF ASTHMA History and examination Diurinal variation of peak flow rate Reduced forced expiratory ratio (FEV1/FVC < 75%) Reversibility to inh. salbutamol (>15%) Provocation testing  bronchospasm - exercise - histamine/allergen inhalation

High socioeconomic impact of COPD 1.5 million GP consultations in the UK per year 24 million lost working days in the UK per year Economic impact per year Direct NHS costs – £486 million2 Additional indirect costs – £1.5 billion (1995)2 In general practice, annual consultation rates for COPD per 10,000 population, rise from 417 at ages 45–64 to 886 at ages 65–74 and 1032 at ages 75–84; values that are up to four times the equivalent rates for angina.1 COPD places a heavy burden on society, industry and the health services. Although the direct costs of the disease are estimated at £486 million, once the effects on productivity, social security and disability payments are taken into account, the wider impact on the economy is estimated at more than £1.5 billion each year.2 References: 1. Royal College of General Practitioners, Office of Population, Census and Surveys, Department of Health. Mortality statistics from general practice. Fourth National Study, 1991–1992. London: HMSO, 1995. 2. Calverley PMA, Sondhi S. The burden of obstructive lung disease in the UK – COPD and asthma. Thorax 1998; 52 (suppl 4): A83 and poster presented at the BTS meeting, 1998.

COPD -A multicomponent disease process Noxious particles or gases, e.g. smoking Inflammation Mucociliary dysfunction Tissue Damage Development of obstruction and ongoing disease progression The disease process in COPD has a number of components which can be summarised under the following headings - muco-ciliary dysfunction, tissue damage and inflammation.1 These components are associated with an ongoing disease process which leads to obstruction of airflow and symptoms of COPD ( e.g.. Breathlessness and worsening quality of life) as well as a decline in exacerbations and lung function. These factors are all linked to the decline in health status seen in COPD Characteristics of the disease: Exacerbations Reduced lung function Symptoms: Breathlessness Worsening quality of life

Disease processes in COPD Cigarette smoke CD8+ lymphocyte ? Alveolar macrophage Neutrophil chemotatic factors, cytokines (IL-8), mediators (LTB4), oxygen radicals Neutrophil Exposure to inhaled noxious particles and gases causes inflammation of the lungs that can lead to COPD if the normal protective and/or repair mechanisms are overwhelmed or defective Cigarette smoke and other irritants activate macrophages and airway epithelial cells in the respiratory tract which release neutrophil chemotactic factors, including interleukin 8 (IL-8)and leukotriene B4. Neutrophils and macrophages then release proteases that break down connective tissues in the lung parenchyma and also stimulate mucus hypersecretion. Proteases are normally counteracted by protease inhibitors such as a1-antitrypsin, secretory leukoprotease inhibitor (SLPI) and tissue inhibitors of matrix metalloproteinases. Cytotoxic T cells (CD8+ lymphocytes) may also be involved in the inflammatory cascade, possibly through involvement in the destruction of alveolar wall epithelial cells. In COPD there appears to be an imbalance between proteases and antiproteases (either an increase in proteases, or a deficiency of antiproteases) which lead to inflammatory changes in the airways including damage of the respiratory mucosa. Reference: 1. Barnes PJ. Chronic Obstructive Pulmonary Disease. New Engl J Med 2000; 343(4): 269-280. - Protease inhibitors Proteases mucus hypersecretion (chronic bronchitis) Alveolar wall destruction (emphysema) Progressive airflow limitation

Mucociliary function in the healthy state mucus Mucociliary transport is the process by which mucus and the particles trapped in the mucus are moved out of the airways to be swallowed. Co-ordinated beating of the cilia in the healthy state is essential in clearing mucus from the airways Damage to the cilia can occur due to the activity of enzymes such as neutrophil elastase. Neutrophil elastase is released from neutrophils which are attracted into the airways by e.g. tobacco smoke, bacterial toxins etc. This damage compromises the ability of the cilia to perform the function of mucociliary transport

Damage to the respiratory mucosa due to bacterial infection Healthy COPD patients have recurrent respiratory tract infections (a common pathogen being H. influenzae) The bacteria damage the airway tissue (for example, breaking down the epithelial cell walls) leading to loss of ciliated cells H. influenzae

Destruction of the Alveoli Normal Emphysema In the normal state there are large numbers of alveoli which is where gas exchange occurs In emphysema many of the alveoli have been destroyed leading to increased air spaces - this is due to the action of proteases such as neutrophil elastase and relates to an imbalance between proteases and anti-proteases

COPD Chronic Bronchitis Emphysema Chronic neutrophilic inflammation Mucus hypersecretion Smooth muscle spasm and hypertrophy Partially reversible Alveolar destruction Impaired gas exchange Loss of bronchial support Irreversible

PROTEASE IMBALANCE IN EMPHYSEMA Smoking Genetic Protease Antiprotease Alveolar Destruction Emphysema

COPD -THE CLINICAL SYNDROME Chronic symptoms - not episodic Smoking Non-atopic Daily productive cough Progressive breathlessness Frequent infective exacerbations Chronic bronchitis- wheezing Emphysema- reduced breath sounds

CHRONIC CASCADE IN COPD Progressive fixed airflow obstruction Impaired alveolar gas exchange Respiratory failure: PaO2 PaCO2 Pulmonary hypertension Right ventricular hypertrophy/failure (i.e. cor pulmonale) Death Stopping smoking arrests further decline in lung volume

Asthma vs COPD Non smokers Allergic Early or late onset Intermittent symptoms Non productive cough Non progressive Eosinophilic inflammation Diurnal variability Good corticosteroid response Good bronchodilator response Preserved FVC and TLCO Normal gas exchange Smokers Non allergic Late onset Chronic symptoms Productive cough Progressive decline Neutrophilic inflammation No diurnal variability Poor corticosteroid response Poor bronchodilator response Reduced FVC and TLCO Impaired gas exchange