Asthma PDF

# Asthma Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of bronchospasm characterized by wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning. The hallmarks of asthma are the following: * Intermittent, reve...

# Asthma Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of bronchospasm characterized by wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning. The hallmarks of asthma are the following: * Intermittent, reversible airway obstruction * Chronic bronchial inflammation with eosinophils * Bronchial smooth muscle cell hypertrophy and hyperreactivity * Increased mucus secretion In patients with severe airway hyperreactivity, trivial stimuli may be sufficient to trigger attacks. Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells. Of note, asthma has increased in incidence significantly in more affluent countries over the past four decades. One proposed explanation for this trend is the **hygiene hypothesis**, according to which a lack of exposure to microbes and potential allergens in early childhood results in hyperreactivity to immune stimuli later in life. Attractive as it seems, there is no mechanistic basis for this hypothesis. ## Pathogenesis Major factors contributing to the development of asthma include genetic predisposition to type I hypersensitivity (atopy), acute and chronic airway inflammation, and bronchial hyperresponsiveness to a variety of stimuli. Asthma may be subclassified as atopic (marked by evidence of allergen sensitization) or nonatopic. In both types, episodes of bronchospasm are triggered by diverse exposures, such as respiratory infections (especially viral), airborne irritants (e.g., smoke, fumes), and environmental stresses. There are varying patterns of inflammation—eosinophilic (most common), neutrophilic, mixed inflammatory, and pauci-granulocytic—that are associated with differing etiologies, immunopathologies, and responses to treatment. ### Atopic Asthma This is the most common type of asthma and is a classic example of type I IgE-mediated hypersensitivity reaction. It usually begins in childhood. A positive family history of atopy and/or asthma is common, and the onset of asthmatic attacks is often preceded by allergic rhinitis, urticaria, or eczema. Attacks may be triggered by allergens in dust, pollen, animal dander, or food, or by infections. The diagnosis depends on the presence of typical episodic symptoms and documentation of airflow limitation that is corrected by treatment with bronchodilators. Skin testing with the offending antigen results in an immediate wheal-and-flare reaction. In addition, immunoassays can be used to identify the presence of IgE antibodies that recognize specific allergens. The classic atopic form is associated with activation of type 2 helper T (Th2) cells, which release cytokines that account for most of the observed features—specifically, increased production of IgE from B cells (stimulated by IL-4 and IL-13); increased recruitment and activation of eosinophils (stimulated by IL-5); and increased mucus production (stimulated by IL-13). IgE binds to Fc receptors on submucosal mast cells, sensitizing these cells to allergens that cross-link IgE molecules and stimulate the release of mast cell granule contents and the secretion of cytokines and other mediators. These mediators set in motion events that lead to two waves of reaction, an early (immediate) phase and a late phase. * **The early phase reaction** is dominated by bronchoconstriction, increased mucus production, and vasodilation. Bronchoconstriction is triggered by mediators released from mast cells, including histamine, prostaglandin D2, and leukotrienes C4, D4, and E4, and also by reflex neural pathways. * **The late-phase reaction** is inflammatory in nature. Inflammatory mediators stimulate epithelial cells to produce chemokines (including eotaxin, a potent chemoattractant of eosinophils) that promote the recruitment of Th2 cells, eosinophils, and other leukocytes, thus amplifying an inflammatory reaction that is initiated by resident immune cells. * Repeated bouts of inflammation lead to structural changes in the bronchial wall that are collectively referred to as airway remodeling. These changes include hypertrophy of bronchial smooth muscle and mucus glands and increased vascularity and deposition of sub-epithelial collagen, which may occur several years before symptoms begin. * In addition, recent experimental work has shown that Charcot-Leyden crystals, derived from a protein produced by eosinophils called galectin-10 and frequently seen in the airway mucous of patients with asthma, may be an important proinflammatory factor. ## Nonatopic Asthma Patients with nonatopic forms of asthma do not have evidence of allergen sensitization, and skin test results are usually negative. A positive family history of asthma is less common. Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) and inhaled air pollutants (e.g., sulfur dioxide, ozone, nitrogen dioxide) are common triggers. Also important are other environmental triggers, such as cold air, stress, and exercise. It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Although the connections are not well understood, the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and nonatopic variants of asthma, so treatment is similar. ### Drug-Induced Asthma Several pharmacologic agents provoke asthma, aspirin being the most striking example. Patients with aspirin sensitivity present with recurrent rhinitis, nasal polyps, urticaria, and bronchospasm. The precise pathogenesis is unknown but is likely to involve some abnormality in prostaglandin metabolism stemming from inhibition of cyclooxygenase by aspirin. ### Occupational Asthma Occupational asthma may be triggered by fumes (e.g., epoxy resins, plastics), organic and chemical dusts (e.g., wood, cotton, platinum), gases (e.g., toluene), and other chemicals. Asthma attacks usually develop after repeated exposure to the inciting antigen(s). ## Morphology The morphologic changes in asthma have been described in individuals who die due to severe attacks and in mucosal biopsy specimens of individuals challenged with allergens. In fatal cases, the lungs are distended due to air trapping (overinflation), and there may be small areas of atelectasis. The most striking finding is occlusion of bronchi and bronchioles by thick, tenacious mucous plugs containing whorls of shed epithelium (Curschmann spirals). Numerous eosinophils and Charcot-Leyden crystals are also present. Other characteristic morphologic changes in asthma (Fig. 11.10B), collectively called airway remodeling, include * Thickening of airway wall * Subbasement membrane fibrosis (Fig. 11.11) * Increased submucosal vascularity * An increase in size of the submucosal glands and goblet cell metaplasia of the airway epithelium * Hypertrophy and/or hyperplasia of bronchial muscle ## Clinical Features An attack of asthma is characterized by severe dyspnea and wheezing due to bronchoconstriction and mucus plugging, which leads to trapping of air in distal air spaces and progressive hyperinflation of the lungs. In the usual case, attacks last from 1 to several hours and subside either spontaneously or with therapy. Intervals between attacks are characteristically free from overt respiratory difficulties, but persistent subtle deficits can be detected by pulmonary function tests. Occasionally a severe paroxysm occurs that does not respond to therapy and persists for days and even weeks (status asthmaticus). The associated hypercapnia, acidosis, and severe hypoxia may be fatal, although in most cases the condition is more disabling than lethal. ## Treatment Patients with relatively mild episodic disease are usually treated symptomatically with bronchodilators (such as beta-agonist drugs) and glucocorticoids, sometimes in combination with leukotriene inhibitors (recall that leukotrienes are potent bronchoconstrictors). In patients with more severe disease who have elevated eosinophil counts, high IgE levels, and other evidence of a heightened Th2 response, antibodies that block the action of specific immune mediators (such as IL-4, IL-5, and IgE) are beneficial.