Session 25: Chronic Obstructive Pulmonary disorders (COPD)

Session 25: Chronic Obstructive Pulmonary disorders (COPD)

• Alex Simon (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Explain pathogenesis of emphysema.

Explain pathogenesis of chronic bronchitis.

Explain pathogenesis of bronchiectasis.

Explain pathogenesis of bronchial asthma.

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Introduction

Introduction

Obstructive (airway) disease characterized by limitation of airflow.

Usually resulting from an increase in resistance caused by partial or complete obstruction at any level.

The major diffuse obstructive disorders are

Emphysema.

Chronic bronchitis.

Bronchiectasis.

Bronchial asthma.

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Emphysema

Emphysema

Emphysema is the presence of air in the lung tissues characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without significant fibrosis.

There are four (4) major types of emphysema

Centriacinar emphysema (most common).

Panacinar emphysema.

Distal acinar emphysema.

Irregular emphysema.

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Centriacinar (Centrilobular) emphysema

Centriacinar (Centrilobular) emphysema

Central or proximal parts of the acini are affected while distal alveoli are spared.

Thus, both emphysematous and normal air spaces exist within the same acinus and lobule.

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Centriacinar (Centrilobular) emphysema cont…

Centriacinar (Centrilobular) emphysema cont…

The lesions are more common and severe in the upper lobes, particularly in the apical segments.

In severe centriacinar emphysema the distal acinus also becomes involved, and thus, the differentiation from panacinar emphysema becomes difficult.

This type of emphysema is most commonly seen as a consequence of cigarette smoking in people who do not have congenital deficiency of α1-antitrypsin.

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Panacinar (Panlobular) emphysema

Panacinar (Panlobular) emphysema

Acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli.

Occur more commonly in the lower lung zones.

It is the type of emphysema that occurs in α1-antitrypsin deficiency.

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Distal acinar (Paraseptal) emphysema

Distal acinar (Paraseptal) emphysema

Proximal portion of the acinus is normal but the distal part is primarily involved.

The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules.

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Distal acinar (Paraseptal) emphysema cont…

Distal acinar (Paraseptal) emphysema cont…

It occurs adjacent to areas of fibrosis, scarring, or atelectasis.

Usually more severe in the upper half of the lungs.

Characteristic finding is the presence of multiple, contiguous, enlarged air spaces, sometimes forming cystic structures, with progressive enlargement, are referred to as bullae.

The cause of this type of emphysema is unknown.

It is seen most often in cases of spontaneous pneumothorax in young adults.

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Irregular emphysema

Irregular emphysema

Acinus is irregularly involved.

It is almost invariably associated with scarring, such as that resulting from healed inflammatory diseases.

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Pathogenesis of Emphysema cont…

Pathogenesis of Emphysema cont…

Exposure to toxic substances such as tobacco smoke and inhaled pollutants induces ongoing inflammation with accumulation of neutrophils, macrophages and lymphocytes in the lung.

Elastases, cytokines (including IL-8) and oxidants are released causing epithelial injury and proteolysis of the extracellular matrix (ECM).

Elastin degradation products further increase the inflammation.

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Pathogenesis of Emphysema cont…

Pathogenesis of Emphysema cont…

Unless checked by antielastases (e.g., α1-antitrypsin) and antioxidants, the cycle of inflammation and ECM proteolysis continues.

Destruction of respiratory tissue leads to a loss of elastic recoil in the lungs and a decreased area available for gaseous exchange.

Emphysema arising as a consequence of two critical imbalances

The protease- antiprotease imbalance.

Oxidant-antioxidant imbalance.

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Pathogenesis of Emphysema cont…

Pathogenesis of Emphysema cont…

Neutrophils (the principal source of cellular proteases) are normally sequestered in peripheral capillaries, including those in the lung, and a few gain accesses to the alveolar spaces.

Any stimulus that increases either the number of leukocytes (neutrophils and macrophages) in the lung or the release of their protease-containing granules increases proteolytic activity.

With low levels of serum α1-antitrypsin, elastic tissue destruction is unchecked and emphysema results.

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Pathogenesis of Emphysema cont…

Pathogenesis of Emphysema cont…

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Chronic bronchitis

Chronic bronchitis

Chronic bronchitis is defined by the presence of a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.

The diagnosis of chronic bronchitis is made on clinical grounds.

Cigarette smoking is the most important underlying risk factor.

Environmental irritants (air pollutants, such as sulfur dioxide and nitrogen dioxide) also contribute.

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Pathogenesis of Chronic bronchitis

Pathogenesis of Chronic bronchitis

Constant irritation by cigarette smoke causes chronic inflammation and hypersecretion of mucus, beginning in the large airways.

Environmental irritants induce hypertrophy of mucous glands in the trachea and main bronchi.

Increase in mucin-secreting goblet cells in the surface epithelium of smaller bronchi and bronchioles.

In addition, these irritants cause inflammation with infiltration of CD8+ lymphocytes, macrophages, and neutrophils.

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Pathogenesis of Chronic bronchitis cont…

Pathogenesis of Chronic bronchitis cont…

The morphologic basis of airflow obstruction in chronic bronchitis is more peripheral and results from:

Small airway disease, induced by goblet cell metaplasia with mucous plugging of the bronchiolar lumen, inflammation, and bronchiolar wall fibrosis, and

Coexistent emphysema.

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Morphology of Chronic bronchitis

Morphology of Chronic bronchitis

Gross

Mucosal lining of the larger airways usually is hyperemic and swollen by edema fluid.

Covered by a layer of mucinous or mucopurulent secretions.

The smaller bronchi and bronchioles also may be filled with similar secretions.

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Morphology of Chronic bronchitis cont…

Morphology of Chronic bronchitis cont…

Histologic examination

Enlargement of the mucus-secreting glands.

The magnitude of the increase in size is assessed by the ratio of the thickness of the submucosal gland layer to that of the bronchial wall.

Inflammatory cells, largely mononuclear but sometimes admixed with neutrophils, are frequently present in variable density in the bronchial mucosa.

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Morphology of Chronic bronchitis cont…

Morphology of Chronic bronchitis cont…

Chronic bronchiolitis (small airway disease) is also present.

Characterized by goblet cell metaplasia, mucous plugging, inflammation, and fibrosis is also present.

In the most severe cases of chronic bronchiolitis, there may be complete obliteration of the lumen as a consequence of fibrosis (bronchiolitis obliterans).

It is the submucosal fibrosis that leads to luminal narrowing and airway obstruction.

Changes of emphysema often co-exist.

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Bronchiectasis

Bronchiectasis

Bronchiectasis is the permanent dilation of bronchi and bronchioles caused by destruction of the muscle and the supporting elastic tissue, resulting from or associated with chronic necrotizing infections.

It is not a primary disease but rather secondary to persisting infection or obstruction caused by a variety of conditions.

Present with cough and expectoration of copious amounts of purulent sputum.

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Conditions that predispose to Bronchiectasis

Conditions that predispose to Bronchiectasis

Bronchial obstruction.

Common causes are tumors, foreign bodies, and occasionally impaction of mucus.

Congenital or hereditary conditions

In cystic fibrosis

In primary immunodeficiency states

Kartagener syndrome

Necrotizing or suppurative pneumonia

Staphylococcus aureus or Klebsiella spp.,

Post tuberculosis bronchiectasis

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Pathogenesis of Bronchiectasis

Pathogenesis of Bronchiectasis

Two (2) processes are crucial and intertwined in the pathogenesis of bronchiectasis

Obstruction

Chronic persistent infection.

Either of these may come first.

Normal clearance mechanisms are hampered by obstruction so secondary infection soon follows.

Conversely, chronic infection over time causes damage to bronchial walls, leading to weakening and dilation.

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Morphology of Bronchiectasis

Morphology of Bronchiectasis

Bronchiectasis usually affects lower lobes bilaterally.

When bronchiectasis caused by tumors or aspiration of foreign bodies, the involvement may be sharply localized to a single segment of the lungs.

Usually, the most severe involvement is found in the more distal bronchi and bronchioles.

The airways may be dilated to as much as four times than usual diameter and on gross examination of the lung can be followed almost to the pleural surfaces.

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Morphology of Bronchiectasis cont…

Morphology of Bronchiectasis cont…

In the full-blown active case, an intense acute and chronic inflammatory exudate and desquamation of lining epithelium cause extensive areas of ulceration.

Fibrosis of the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in chronic cases.

In some instances, the necrosis destroys the bronchial or bronchiolar walls resulting in the formation of an abscess cavity.

A fungus ball may develop.

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Bronchial asthma

Bronchial 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.

The hallmarks of bronchial asthma are

Intermittent and reversible airway obstruction.

Chronic bronchial inflammation with eosinophils.

Bronchial smooth muscle cell hypertrophy and hyperreactivity.

Increased mucus secretion.

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Bronchial asthma cont…

Bronchial asthma cont…

Some of the stimuli that trigger attacks in patients would have little or no effect in persons with normal airways.

Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells.

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Types of Asthma

Types of Asthma

Based on the stimuli initiating bronchial asthma, three (3) broad etiologic types are traditionally described:

Extrinsic (allergic, atopic) asthma.

Intrinsic (idiosyncratic, non-atopic) asthma.

Mixed pattern in which the features do not fit clearly into either of the two main types.

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Pathogenesis of Asthma

Pathogenesis of Asthma

The major etiologic factors of asthma are

Genetic predisposition to type I hypersensitivity (atopy).

Acute and chronic airway inflammation.

Bronchial hyperresponsiveness to a variety of stimuli.

The inflammation involves many cell types and numerous inflammatory mediators.

Role of CD4+ helper T cells 2 (TH2) cells may be critical to the pathogenesis of asthma.

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Pathogenesis of Asthma cont…

Pathogenesis of Asthma cont…

The classic atopic form of asthma is associated with an excessive CD4+ helper T cells 2 (TH2) reaction against environmental antigens.

Cytokines produced by CD4+ helper T cells 2 (TH2) cells account for most of the features of asthma:

IL-4 stimulates IgE production.

IL-5 activates eosinophils.

IL-13 stimulates mucus production and also promotes IgE production by B cells.

IgE coats submucosal mast cells, which, on exposure to allergen, release granule contents.

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Pathogenesis of Asthma cont…

Pathogenesis of Asthma cont…

This induces two (2) waves of reaction

An early (immediate) phase.

A late phase..

The early reactions are bronchoconstriction, increased mucus production and variable vasodilation.

Bronchoconstriction is triggered by direct stimulation of subepithelial vagal receptors.

The late-phase reaction consists of inflammation, with activation of eosinophils, neutrophils, and T cells.

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Pathogenesis of Asthma cont…

Pathogenesis of Asthma cont…

In addition, epithelial cells are activated to produce chemokines that promote recruitment of:

More CD4+ helper T cells 2 (TH2) cells.

Eosinophils (including eotaxin, a potent chemoattractant and activator of eosinophils).

Other leukocytes, thus amplifying the inflammatory reaction.

Refer to Handout 25.1 for additional information on sequences involved in the pathogenesis of asthma.

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Structural changes in Asthma

Structural changes in Asthma

Repeated bouts of inflammation lead to structural changes in the bronchial wall, collectively referred to as airway remodeling.

These changes include

Thickening of airway wall

Sub-basement membrane fibrosis

Increased vascularity in submucosa

An increase in size of the submucosal glands and goblet cell metaplasia of the airway epithelium

Hypertrophy and/or hyperplasia of the bronchial muscle

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Morphology of Asthma

Morphology of Asthma

Gross

Lungs are overdistended because of overinflation, and there may be small areas of atelectasis.

Occlusion of bronchi and bronchioles by thick, tenacious mucous plugs (most striking finding).

Histological findings

The mucous plugs contain whorls of shed epithelium (Curschmann spirals).

Numerous eosinophils and Charcot Leyden crystals (collections of crystalloids made up of eosinophil proteins) also are present.

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Key points

Key points

Emphysema is characterized by abnormal permanent enlargement of the airspaces distal to the terminal bronchioles.

The distinctive feature of chronic bronchitis is hypersecretion of mucus.

Bronchiectasis is a permanent dilation of bronchi and bronchioles caused by destruction of the muscle and elastic supporting tissue.

Expectoration of copious amounts of purulent sputum is commonly seen in bronchiectasis.

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Key points cont…

Key points cont…

Chronic bronchitis and emphysema often co-exist.

Asthma is characterized by reversible bronchoconstriction caused by airway hyperresponsiveness to a variety of stimuli.

Atopic asthma is caused by a CD4+ helper T cells 2 (TH2) cells and IgE-mediated immunologic reaction to environmental allergens.

The CD4+ helper T cells 2 (TH2) cells cytokines IL-4, IL-5, and IL-13 are important mediators in atopic asthma.

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Review questions

Review questions

Outline four (4) types of emphysema.

Define chronic bronchitis.

Explain pathogenesis of bronchiectasis.

Explain pathophysiology of bronchial asthma.

List five (5) structural changes seen in bronchial asthma.

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References

References

Goljan E.;(2007): Rapid Review Pathology (2th Ed.) Elsevier Saunders, USA. Pg. 312-314.

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 463-472.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 477-485.

Xiu P.;(2012): Crash Course Pathology (4th Ed.) Elsevier Saunders, USA. Pg. 90-95.

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