Pathology of common Respiratory condition( Part2) ( OBSTRUCTIVE AIRWAY DISEASE)

Objective:-To discuss,the definition,types,pathogenesis,morphology& clinical correlation of ch. Bronchitis,Emphysema,bronchiectasis and bronchial Asthma Learning Outcome. Define emphysema.List and compare types of Emphysema Explain the Pathogenesis of Emphysema.Describe gross and microscopic morphology of Empysema.Outline clinical course and prognosis of Empysema. Define Chronic Bronchitis.List predisposing condition of chronic bronchitis.Explain pathogenesis of ch bronchitis.Describe the morphology,outline the clinical course and prognosis of ch. Bronchitis. List the types of Bronchial Asthma.Explain its pathogenesis. Descibe gross and microscopic morphology of Br. Asthma Outline clinical course of Br. Asthma.

COPD Chronic bronchitis Asthma Bronchiectasis emphysema

COPD ConditionSiteCauseSigns Chronic bronchitis Bronchus Smoking, pollution Cough & sputum Bronchi- ectasis Bronchus Persistent or severe infection Cough, fever, sputum AsthmaBronchus Immunologic or unknown Wheezing cough dyspnea EmphysemaAcinus Tobacco smoke Dypnea Small airway disease bronchiole Smoking, pollution Cough, dyspnea

Chronic Bronchitis Is defined clinically as persistent cough with sputum production for at least 3 months out of the year and for 2 successive years, in the absence of another specific underlying pulmonary disease

Types of chronic bronchitis Simple chronic bronchitis – Have productive cough but no evidence of airway obstruction Chronic asthmatic bronchitis – Hyperreactive airways with intermittent bronchospasm & wheezing Obstructive chronic bronchitis – Chronic airflow obstruction with emphysema (in chronic smokers)

Chronic Bronchitis Pathogenesis Hypersecetion of mucus is characteristic. Etiology-:-1)Chronic irritation by inhaled substances (cigarette smoking single most important factor) and inhaled pollutants. – 4 – 10 times more common in smokers – Most frequent in middle-aged male smokers 2)Microbiologic factors

Bronchiolar & Bronchial injury Reversible obstruction in Bronchioles & small bronchi Chronic Bronchitis Destruction of Alveolar walls emphysema Chronic bronchitis & emphysema infection bronchospasm Hypersecretion Continued injury Continued infection Destruction of Alveolar walls Continued injury Continued infection Occasional Respiratory infection

Hypertrophy of mucus glands in trachea and main bronchi. Increased mucin secreting goblet cells in small bronchi and broncioles. Inflammation by irritants –infiltration by chronic and acute inflammatory cells but no eosinophils.

Hypersecretion of mucus is reflection of large bronchial mucosa Airflow obstrucion is peripheral-small airway obstruction by mucus plugging of broncioles and Inflammation of and bronchiolar wall fibrosis and coexistent emphysema. Epithelial cell effects are mediated by local release of T cell cytokines such as IL-13

Morphology Gross:- large airway-mucosal lining hyperaemia and swelling by oedema Mucinous or mucopurulent secretion on surface. Small bronchi and bronchioles filled by similar secretion MICRO:-diagnostic feature- Enlargement of mucus secreting glands. Assessed by Reid Index. Normal <.4 Inflammatory cells infiltrate-chronic and acute

chronic bronchiolitis(small airway disease) characterised by goblet cell metaplasia.mucus plugging, ch.inflammation and fibrosis is also present. Peribronciolar fibrosis and luminal narrowing =results in airway obstruction

Chronic Bronchitis

Chronic Bronchitis Acute exacerbation Bacterial infections – H. Influenza and Strep. Pneumonia Viral infections – Adenovirus and Respiratory Syncytial Virus

Emphysema Is defined as permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destructive changes without obvious fibrosis If there is no destruction, it is called overinflation

Emphysema (Anatomicall y Defined) Chronic Bronchitis (clinically defined) Emphysema Chronic Bronchitis COPD (physiologic Definition)

Emphysema More common and severe in males Clear association with cigarette smoking Generally does not become disabling until the 5 th -8 th decades

Types of emphysema Centriacinar (centilobular) Panacinar (panlobular) Paraseptal (distal acinar) Irregular

Centrilobular(Centriacinar) Emphysema Most common type More frequent in males and smokers Predominantly involves upper lobes Coal – workers’ pnemoconiosis closely resembles centriacinar emphysema

Centrilobular Emphysema Is enlargement with destruction of central or proximal part of the acini formed by the respiratory bronchioles, with sparing of the distal portion of the acinus More severe in the upper lobes (apical segments)

Centrilobular Emphysema

centracinar and panacinar emphysema

Panlobular (Panacinar) Emphysema Is uniform unselective enlargement of the acinus accompanied by destructive changes (entire lobule is involved)

Panlobular Emphysema Predominantly involves lower lung zones Often occurs together with centrilobular emphysema Associated with alpha 1 antitrypsin deficiency

Panlobular Emphysema

Distal acinar Emphysema (Paraseptal Emphysema) Is enlargement with destruction of the distal portion of the acinus More strikingly adjacent to pleura, lobular connective tissue, areas of fibrosis & collapse More severe in the upper zones of lungs

Localized Emphysema (Paraseptal Emphysema) Multiple, continuous, enlarged airspaces from 2.0 cm in diameter Associated with spontaneous pneumothorax and bullous disease of the lung in young adults

Irregular Emphysema Acinus is irregularly involved Associated with scarring (also called paracicatricial emphysema) May be the most common type but it is usually asymptomatic

Other types of emphysema Compensatory Senile Obstructive overinflation Bullous Interstitial

Bullous Emphysema Defined as subpleural emphysematous spaces >1-2 cm in diameter Usually associated with other types of emphysema

Bullous Emphysema

Pathogenesis

Pathogenesis of emphysema Protease – antiprotease theory Alpha 1 antitrypsin Elastase (PMN, macrophage) Elastic damage Emphysema Smoking

Pathogenesis of Emphysema

Smoking & emphysema Smokers have greater numbers of neutrophils & macrophages in their alveoli Smoking stimulate release of elastase from neutrophils Smoking enhances elastolytic activity in macrophages Oxidants in smoke & free radicals released by neutrophils inhibit alpha 1 antitrypsin

Alpha 1 antitrypsin deficiency Geno Type % of Population Normal Pi MM 95% - 97% Heterozygote Pi MZ 3% - 5% Homozygote Pi ZZ 0.07% - 0.2% More than 80% of PiZZ phenotype develop symptomatic emphysema

ASTHMA Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning.

This clinical picture is caused by repeated immediate hypersensitivity and late-phase reactions in the lung that give rise to the triad of 1) intermittent and reversible airway obstruction, 2)chronic bronchial inflammation with eosinophils, 3)bronchial smooth muscle cell hypertrophy and hyper-reactivity

Asthma Affects 10% of children; 5% of adults Half the cases develop in patients <10 years of age

Asthma-TYPES 1.Extrinsic (allergic)or Atopic – affects children and young adults with atopic history,  IgE, eosinophilia 2.Intrinsic (non-immune) – affects adults with no apparent allergic diathesis

Types of Asthma Drug induced – Aspirin sensitive asthma (occurring in patients with allergic rhinitis & nasal polyps) Occupational – fumes, organic & chemical dusts, gases, other chemicals Drug induced – Aspirin sensitive asthma (occurring in patients with allergic rhinitis & nasal polyps) Occupational – fumes, organic & chemical dusts, gases, other chemicals

Pathogenesis Genetic predisposition to Type -1 hypersensitivity reaction(Atopy). Inflmmatory response is mediated by Th2 helper cells.Cytokines produced by Th2 cells IL-4 stimulates IgE production IL-5 activate eosinophils IL-13 stimulate mucus production

Structural changes in bronchial wall (Airway Remodelling ) - Hypertrophy of bronchial smooth muscless muscles - Depositon of subepithelial collagen Etiology not clear but inherited predisposition asociated with polymorphism in gene associated with gene that resulst in proliferation of bronchial smooth muscles and collagen. Role of mast cells-secret growth factors that stimulate smooth muscle proliferation

Atopic Asthma(Pathogenesis) This most common type of asthma usually begins in childhood. A positive family history of atopy is common, Asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema. The disease is triggered by environmental antigens, such as dusts, pollen, animal dander, and foods A skin test with the offending antigen results in an immediate wheal-and-flare reaction, a classic example of the type I IgE-mediated hypersensitivity reaction

Initial sensitization of airway to the inhaled inciting antigens, which stimulates induction of T H 2-type cells and release of interleukins IL-4 and IL-5 and IL-13 This leads to synthesis of IgE that binds to mucosal mast cells. Subsequent IgE-mediated reaction to inhaled allergens elicits an immediate response and a late-phase reaction (Exposure of IgE-coated mast cells to the same antigen causes cross-linking of IgE and the release of chemical mediators)

Asthma Inhaled allergen reacts with IgE coated mast cells releasing: – Histamine – Bradykinin – Leukotrienes – Prostaglandins – Thromboxane A2 – Platelet activating factor (PAF) – Chemotactic factors

Immediate or acute phase response -which consists of bronchoconstriction, edema (due to increased vascular permeability), and mucus secretion. A variety of inflammatory mediators have been implicated in the acute-phase response – histamine,acetyle choline,leukotrienes,Prostaglandine D2,Platelet activating factors Late phase reaction-Eosinophils products-major basic protein,eosinophil cation protein and eosinophil peroxidase cause tissue damage. Leukotriene 4 =bronchospasm

Nature of Allergens They are usually soluble proteins They are usually soluble proteins Most have enzymatic function Most have enzymatic function This allows greater access to dendritic cells and enhances sensitisation by disrupting tight junctions of epithelial cells Major allergens for asthma are derived from dust mites, cats & cockroaches Major allergens for asthma are derived from dust mites, cats & cockroaches They are usually soluble proteins They are usually soluble proteins Most have enzymatic function Most have enzymatic function This allows greater access to dendritic cells and enhances sensitisation by disrupting tight junctions of epithelial cells Major allergens for asthma are derived from dust mites, cats & cockroaches Major allergens for asthma are derived from dust mites, cats & cockroaches

Non-atopic Asthma No role for IgE No role for IgE Lack of skin sensitivity to common allergens Lack of skin sensitivity to common allergens Family history is lacking Family history is lacking Probably due to hyperirritability of the bronchial tree Probably due to hyperirritability of the bronchial tree Triggered by infection Triggered by infection No role for IgE No role for IgE Lack of skin sensitivity to common allergens Lack of skin sensitivity to common allergens Family history is lacking Family history is lacking Probably due to hyperirritability of the bronchial tree Probably due to hyperirritability of the bronchial tree Triggered by infection Triggered by infection

It is thought that inflammation causes an increase in airway responsiveness (bronchospasm) to a variety of stimuli, which would cause no ill effects in the normal airways of nonasthmatic individuals. The underlying genetic basis for hyper-responsive airways is not entirely clear, In some cases, the attacks are triggered by exposure to an allergen to which the person has been previously sensitized, but often no trigger can be identified.

Asthma Microscopic Features 1.Thickened basement membrane 2.Edema and inflammation (eosinophils) 3.Hypertrophy of bronchial smooth muscle 4.Mucous plugs 5.Desquamation of bronchial epithelium 6.Goblet cell metaplasia, squamous metaplasia

Mucus Cast Of Bronchial Tree (asthma)

Bronchial Epithelium

Asthma

Asthma Treatment Beta-adrenergic agonists Inhaled corticosteroids Cromolyn sodium Methylxanthines Anticholinergic agents Systemic corticosteroids

Bronchiectasis Irreversible dilation of bronchi due to destruction of elastic and muscular elements in the wall

Bronchiectasis Obstructive – Tumor – Foreign body – Concretions/secretions Non-obstructive – Post-infective – Inherited disorders – cystic fibrosis, immunodeficiency, and immotile cilia syndrome

Kartagener Syndrome Defect in ciliary motility due to structural abnormality in the cilia (absence of dynein arms) Dextrocardia Bronchiectasis Sinusitis

Kartagener Syndrome

Bronchiectasis

Bronchiectasis - c linical Features Chronic productive cough Hemoptysis Dyspnea and wheezing Pneumonia, abscess Systemic: fever, weight loss, weakness

THE SPECTRUM OF COPD ClinicalTerm Anatomic Site Major Pathologic Changes EtiologySigns/Symptoms ChronicbronchitisBronchus Mucous gland hyperplasia, hypersecretion Tobacco smoke, air pollutants Cough, Sputum production BronchiectasisBronchus Airway dilation and scarring Persistent or severe infections Cough; purulent sputum; fever AsthmaBronchus Smooth muscle hyperplasia, excess mucus, inflammation Immunologic or undefined causes Episodic wheezing, cough, dyspnea EmphysemaAcinus Airspace enlargement; wall destruction Tobacco smoke Dyspnea Small airway disease, bronchiolitis Bronchiole Inflammatory scarring/obliteration Tobacco smoke, air pollutants, miscellaneous Cough, dyspnea

Obstructive vs. Restrictive Lung Disease Obstructive – increased resistance to airflow due to partial or complete obstruction from trachea to respiratory bronchioles (e.g. emphysema, chronic bronchitis) Restrictive – reduced expansion of lung parenchma with decreased TLC – Chest wall disorders with normal lungs (e.g. Kyphoscoliosis) – Acute or chronic interstitial and infiltrative lung disease (e.g. DAD, UIP, pneumoconiosis)

Diagnosis of Ventilatory Defect ObstructiveRestrictive VC Normal or Decrease Decrease FEV1Decrease FEV1/FVCDecrease Normal or Increase Optional RV Decrease TLC Decrease