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.

Table 20.1Various approaches to the classification of asthmaa

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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 TH1 and TH2 phenotypes. A number of TH1-derived cytokines (eg, IFN-, IL-2) activate
macrophages and CD8+ cytotoxic T-cells to kill viruses and other intracellular pathogens. TH1
cells also inhibit the action of TH2 cells. In contrast, the TH2-derived mediators promote allergic
inflammation and stimulate production of IgE by B-cells. Additionally, TH2 cells inhibit TH1 cells.
In asthma, it appears that this mutual inhibition of TH1 cells and TH2 cells is altered to favor TH2
cell-mediated effects. The transcription factor T-bet that is required for TH1 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-33that
encodes a metalloproteinase has been linked to asthma. Polymorphisms in ADAM-
33accelerate 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
TH2 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.

CLINICAL CORRELATION 20.3

Intrinsic asthma can be triggered by aspirin, viral infection, inhalation of cold air or chemical
irritants, psychological stimuli including stress, and exercise. Notably, triggers of intrinsic
asthma also cause bronchospasm in non-asthmatics, and bronchospasms in intrinsic asthma
are more pronounced and persistent than those associated with extrinsic asthma.

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).

FIGURE 20.10
Atopic asthma, showing a mucous plug obscuring the airway lumen (left). Also seen are numerous epithelial
goblet cells, thickened basement membrane, an eosinophilic inflammatory infiltrate, and smooth muscle
hyperplasia (right). From Kemp WL, Pathology: the Big Picture, McGraw-Hill, 2008.
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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).

FIGURE 20.11
(a) The eosinophil-rich inflammatory infiltrate that typifies atopic asthma. Although thickening of the basement
membrane, hyperplasia of submucosal glands, increase in goblet cells and smooth muscle hyperplasia all
mimic findings in chronic bronchitis, the inflammatory infiltrate in chronic bronchitis is not eosinophil-rich. (b)
While Charcot-Leyden crystals (arrow) are frequently seen in asthma, they are not specific for asthma but
rather are common in many inflammatory disorders with prominent eosinophilia. The crystals are composed
of major basic protein from degranulated eosinophils. (a): From Robbins and Cotran Atlas of Pathology, 2nd
ed. 2010. (b): From Kemp WL, Pathology: the Big Picture, McGraw-Hill, 2008.
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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.