Chapter 20: Pathology of Obstructive Pulmonary Diseases

Obstructive lung diseases are characterized by reductions in airflow due to increased resistance from partial or complete airway obstructions at any level. Such obstructions can arise from direct narrowing of the airway lumen or by decreased elastic recoil of the pulmonary parenchyma surrounding the airways, which has the effect of reducing lumen caliber. The many causes of obstructive disease include tumors, aspirated foreign bodies, asthma, emphysema, chronic bronchitis, cystic fibrosis, and bronchiolitis. This chapter will focus on the pathology of emphysema, chronic bronchitis, asthma, and bronchiectasis. Bronchiectasis is included here although it occurs as a result of airway obstruction, rather than being a cause in itself. The chronic obstructive pulmonary diseases (COPDs) comprise emphysema and chronic bronchitis. Though it is possible to have emphysema without chronic bronchitis or the converse, most patients have some degree of both, though one may dominate the clinical scenario. They share common etiologies, the most significant of which is tobacco smoking. Despite this significant association, most smokers do not develop COPD.

Emphysema is defined morphologically as the irreversible enlargement of airspaces distal to the terminal bronchioles, due to destruction of airspace walls and without obvious fibrosis. Emphysema is present in approximately one-half of adults at autopsy, most of whom were asymptomatic. Emphysema is further subdivided into four subtypes based on the anatomic distribution of the airspace enlargement: centriacinar (centrilobular), panacinar (panlobular), distal acinar (paraseptal), and irregular.

Centriacinar emphysema (Figs. 20.1 and 20.2) is characterized by airspace enlargement at the level of the respiratory bronchioles, sparing the distal alveoli. Anatomically, the several acini that comprise a lobule (Chap. 2) are arranged such that their respiratory bronchioles are grouped in the center of the lobule. This anatomic arrangement underlies the alternate name, centrilobular emphysema. Centriacinar emphysema accounts for more than 95% of those cases of emphysema with clinically significant airway obstruction. It is more pronounced in the upper lobes and is the type of emphysema most strongly associated with smoking.

Panacinar emphysema (Figs. 20.1, 20.2, 20.3) is characterized by airspace enlargement at the level of the alveolar ducts and more distally. At the gross level, airspace enlargement appears to affect the entire lobule, giving rise to the alternate name, panlobular emphysema. Panacinar emphysema accounts for less than 5% of cases of emphysema with clinically significant airway obstruction and is more pronounced in the lower lung zones. It is the type of emphysema most strongly associated with α₁-antiprotease (α₁-PI) deficiency (Chap. 22).

Distal acinar emphysema (Fig. 20.4) involves distal airspaces and is most prominent adjacent to the visceral pleura and to the connective tissue septa that define the lobules. Distal acinar emphysema typically does not result in clinically significant airway obstruction. It is more severe in the upper half of the lungs and likely represents the underlying lesion resulting in spontaneous pneumothorax in young adults.

Emphysema that does not show centriacinar, panacinar, or distal acinar distribution is called irregular emphysema. Irregular emphysema is very common adjacent to foci of scarring and does not typically cause significant airway obstruction. In any form of emphysema, large, distended sacs of air or bullae can form. Any subtype of emphysema with bullae is likely to be referred to as bullous emphysema (Fig. 20.5). In its most severe forms, emphysema is difficult to subclassify (Fig. 20.6).

The pathogenesis of emphysema is generally considered to involve excess protease and/or elastase activity that is insufficiently opposed by antiprotease regulation (Fig. 20.7). The probable sequence begins with neutrophil sequestration in capillaries, migration into airways and alveoli, and their stimulation to release elastase-containing granules that degrade elastic tissue in the absence of sufficient antiprotease activity (Chap. 10). Such antiprotease insufficiency can be due to α₁-PI deficiency and/or the functional impairment of it and other antiproteases (Chap. 22).

Given that emphysema involves tissue destruction and enlargement of airspaces, it may seem counterintuitive that affected individuals exhibit significant airflow obstruction by PFT (Chaps. 16 and 22). This obstructive pattern emerges in emphysema due to the loss of lung parenchyma, whose elastic recoil normally tethers the airways open by radial traction forces (Chaps. 5 and 6). In the absence of such radial tethering, the airways open less widely during inspiration, and they also collapse more readily during expiration.

Rather unfortunately, the term "emphysema" has been applied to other medical conditions that technically do not satisfy the definition used here of irreversible airspace enlargement caused by tissue destruction. By example, compensatory emphysema is used to describe the excessive dilatation of residual alveoli following loss of lung volume as by lobectomy. In that setting, since there has been no destruction of airspace walls, the preferred term is compensatory hyperinflation. The terms mediastinal emphysema, interstitial emphysema, and subcutaneous emphysema all can refer to the presence of air within connective tissue spaces that normally contain none. In the chest and neck, this is most typically due to a perforated airway lining, as can occur by faulty intubation for mechanical ventilation (Chap. 30), with subsequent dissection or insufflation of air through the adjacent adventitial layers. Obstructive overinflation can mimic emphysema on gross examination and is occasionally called emphysema, again despite the absence of airspace wall destruction. Obstructive overinflation of airways occurs when obstructions such as mucus or tumor mass act as a ball-valve, allowing airflow during inspiration but not on expiration. With severe or total airway obstruction, air may move through collateral septal pathways (pores of Kohn and canals of Lambert) more readily during inspiration than expiration, causing alveolar overinflation. A classic form of such obstructive overinflation occurs in congenital lobar emphysema (also termed infantile lobar overinflation) as discussed in Chap. 37.

In contrast to emphysema, chronic bronchitis is defined not morphologically but clinically as a persistent, productive cough for at least three consecutive months in at least two consecutive years and without another identifiable cause (Chap. 22). Among the 5%-15% of smokers who develop physiological evidence of COPD by PFT work-ups, many of those have an initial clinical presentation that includes chronic bronchitis. As such, chronic bronchitis is subdivided into three subtypes: simple chronic bronchitis, in which there is no PFT-based evidence of obstruction; obstructive chronic bronchitis, in which there is physiological evidence of obstruction; and chronic asthmatic bronchitis, in which a patient's hyper-responsiveness to allergens or other stimuli contributes to the airway obstruction (Chaps. 21 and 22).

The pathogenesis of chronic bronchitis begins with inhalation of smoke and/or other air pollutants, resulting in hypersecretion of mucus by bronchial mucous glands, hyperplasia of mucous glands, and goblet cell metaplasia (Chap. 2). Excessive mucus worsens airway obstruction and increases the susceptibility to infection, resulting in inflammation, fibrosis, and subsequent narrowing of bronchioles. Further increasing the likelihood of infection is the impairment of mucociliary clearance (Chap. 10) caused by smoke-induced ciliary dysfunction and/or by squamous metaplasia of the airway lining.

In COPD patients with simple chronic bronchitis, obstruction is mainly within respiratory bronchioles. In patients with moderate or severe obstruction, most of their diminished flow by PFT is due to superimposed emphysema. Grossly, chronic bronchitis shows mucosal hyperemia, edema of large airways, and mucinous or mucopurulent intraluminal secretions in large and small airways. Microscopically, mucous gland hyperplasia in the trachea and large bronchi is frequently accompanied by goblet cell hyperplasia and/or loss of cilia. Collectively these thicken the mucous gland layer.

Chronic bronchitis, despite its suffix, does not always show severe inflammation. In the absence of superimposed infection, the inflammatory infiltrate is predominantly mononuclear (Fig. 20.9) as would be expected based on normal lung host defense mechanisms (Chap. 10). When superimposed infection is present, variable numbers of neutrophils are likely. In the setting of chronic bronchitis, there is typically small airway disease (chronic bronchiolitis) featuring goblet cell metaplasia, inflammation, smooth muscle hyperplasia, thickened basement membranes, and fibrosis. In the most severe forms, the fibrosis occludes the bronchiolar lumen to cause bronchiolitis obliterans.

Asthma is a chronic inflammatory airway disease characterized by episodic bronchospasm which is clinically manifest as an asthma attack comprising dyspnea, chest tightness, cough, and wheezing (Chap. 21). The airway luminal narrowing is partially reversible, and inflammation likely plays a role in causing exaggerated bronchoconstriction. Asthma affects approximately 5% of adults and 7%-10% of children in the United States. There are several approaches to classifying asthma (Table 20.1); regardless of the system used, many patients will have features overlapping two or more categories (Chap. 21). Asthma can be complicated by Aspergillus ssp. colonization of the bronchial mucosa which, in a patient with allergy to the fungus, is called allergic bronchopulmonary aspergillosis.

Main factors underlying the pathogenesis of asthma are a genetic predisposition to type I hypersensitivity reactions, airway inflammation, and bronchial hyperresponsiveness. Many inflammatory cells play roles in the pathogenesis of asthma: eosinophils, mast cells, macrophages, neutrophils, and lymphocytes. Among these lymphocytes, the CD4⁺ T-cells include T_H1 and T_H2 phenotypes. A number of T_H1-derived cytokines (eg, IFN-γ, IL-2) activate macrophages and CD8⁺ cytotoxic T-cells to kill viruses and other intracellular pathogens. T_H1 cells also inhibit the action of T_H2 cells. In contrast, the T_H2-derived mediators promote allergic inflammation and stimulate production of IgE by B-cells. Additionally, T_H2 cells inhibit T_H1 cells. In asthma, it appears that this mutual inhibition of T_H1 cells and T_H2 cells is altered to favor T_H2 cell-mediated effects. The transcription factor T-bet that is required for T_H1 cell differentiation has been found to be diminished or lacking in pulmonary lymphocytes in the setting of asthma. Thus, a future approach to asthma may be to up-regulate T-bet expression (Chap. 21). Despite the role of lymphocytes in the pathogenesis of asthma, the inflammatory infiltrate in asthma is typically rich in eosinophils.

Morphologically, asthma is characterized by airway remodeling, including bronchial smooth muscle hypertrophy and subepithelial collagen deposition. Recently, the gene ADAM-33 that encodes a metalloproteinase has been linked to asthma. Polymorphisms in ADAM-33 accelerate bronchial smooth muscle cell proliferation, resulting in bronchial hyperreactivity, and accelerate fibroblast proliferation, leading to subepithelial fibrosis.

Pathogenetically, asthma can be subdivided into extrinsic and intrinsic categories. All forms of extrinsic asthma involve initiation of an asthmatic crisis by a type I hypersensitivity reaction to an extrinsic antigen, which in this setting can be called an allergen. The most common form of extrinsic asthma is atopic asthma; other forms of extrinsic asthma include some types of occupational asthma as well as allergic bronchopulmonary aspergillosis. Sensitization occurs when inhaled allergens stimulate an inflammatory response dominated by T_H2 cells, favoring the production of IgE and recruiting eosinophils. The IgE released by B-cells attaches to the surface of resident mast cells. Once sensitized, reexposure to the allergen can trigger the asthma attack, classically described as having an early phase and late phase. The early phase occurs 30-60 minutes after exposure as the inhaled antigen binds to IgE on mast cells, stimulating release of their mediators that cause bronchoconstriction, edema, mucus secretion, and recruitment of granulocytes, especially eosinophils. The late phase begins 4-8 hours after the early phase and is dominated by eosinophil release of mediators that activate mast cells. During the late phase, these eosinophil-derived mediators increase and sustain the inflammatory response that damages airway epithelia, even in the absence of additional allergen exposure. If exposure persists, the epithelial injury facilitates translocation of inhaled allergen from the airway lumen into the subepithelial connective tissue, where more inflammatory cells reside.

Intrinsic asthma involves nonimmune triggers of an asthma attack. Its subtypes include non-atopic asthma that is usually initiated by viral respiratory infections. The ensuing infectious inflammation stimulates subepithelial vagus receptors, causing bronchospasm. A classic example of drug-induced asthma is initiated by aspirin, in which cyclooxygenase inhibition leads to leukotriene synthesis that stimulates bronchoconstriction.

Morphologically, asthma is characterized by bronchial wall edema, erythema due to hyperemia, and inflammation, with 5%-50% eosinophils. These are accompanied by patchy epithelial necrosis and cell shedding, with basement membrane thickening due to subepithelial deposition of collagen. Hyperplasia of submucosal mucous glands and goblet cells is evident, as well as hypertrophy and hyperplasia of bronchial smooth muscle (Fig. 20.10).

Microscopic features of asthma overlap with those of chronic bronchitis. Clues that help distinguish asthma from chronic bronchitis morphologically include whorls of shed epithelium termed Curschmann spirals, and eosinophil-dominant inflammation that produces Charcot-Leyden crystals composed of eosinophil proteins (Fig. 20.11).

Clinically, the asthma attack includes wheezing and dyspnea, with more difficult expiration. Symptoms can last several hours and are followed by prolonged coughing. Though the asthma attack can spontaneously resolve, medical therapy with bronchodilators and/or corticosteroids can expedite resolution (Chap. 21). In some patients, a severe and treatment-resistant asthma attack can persist for days to weeks, resulting in status asthmaticus and leading to hypoxemia, acidosis, and death. In the event of such a death, autopsy would show plugging of airways by viscous mucus.

Bronchiectasis is defined as the permanent dilatation of airways due to the destruction of tissue caused by chronic necrotizing inflammation and obstruction (Fig. 20.12). Bronchiectasis is not a primary disease but rather occurs secondarily to chronic infection and/or chronic obstruction. There are many predispositions to the development of bronchiectasis: bronchial obstruction; congenital and hereditary conditions such as cystic fibrosis, immunodeficiency, ciliary dyskinesia, and intralobar sequestration; necrotizing or suppurative pneumonia; and allergic bronchopulmonary aspergillosis. The pathogenesis of bronchiectasis involves obstruction and persistent infection, occurring in either order and frequently overlapping. The infection usually involves mixed flora.

Morphologically, there is by definition bronchial dilatation up to fourfold normal airway diameters. Such bronchial dilatation is usually more prominent in lower lung lobes and can be cylindroid, fusiform, or saccular. In the setting of active infection, there is typically a dense mixed inflammatory exudate with epithelial ulceration. The chronic nature of the inflammation is reflected in bronchial, bronchiolar, and peribronchial fibrosis. Bronchiectasis can be complicated by abscess formation. Clinically, the patient with bronchiectasis presents with severe, persistent cough and mucopurulent sputum that is occasionally bloody. Additional clinical findings may include frank hemoptysis, digital clubbing, and the blood gas sequelae expected with pulmonary obstruction as well as disseminated infection and reactive amyloidosis.