Until recently, the entire range of asthma severity was regarded as eminently treatable, because treatments for quick relief of symptoms of acute bronchoconstriction (“short-term relievers”) and treatments for reduction in symptoms and prevention of attacks, especially using inhaled corticosteroids (“long-term controllers”), had been shown to be effective in many large, well-designed randomized clinical trials, pragmatic clinical trials, observational studies, and evidence-based reviews. The persistence of high medical costs for asthma, driven largely by the costs of emergency department and hospital treatment of asthma exacerbations, was thus believed to reflect underutilization of the treatments available. Reconsideration of this view was driven by recognition that the term “asthma” is applied to a variety of different disorders sharing common clinical features but fundamentally different pathophysiologic mechanisms. Attention has thus turned to the possibility that there are different asthma phenotypes, some of which are less responsive to the current mainstays of asthma controller therapy. The current view of asthma treatment may be summarized as follows: that the treatments commonly used at present are indeed effective for the most common form of the disease, as it presents in children and young adults with allergic asthma, but that there are other phenotypes of asthma for which these therapies are less effective, and that represent an unmet medical need. Accordingly, this chapter first reviews the pathophysiology of the most common form of asthma (classic allergic asthma) and the basic pharmacology of the agents used in its treatment. This is followed by a discussion of different forms or phenotypes of asthma and the efforts to develop effective therapies for them.
Classic allergic asthma is regarded as mediated by immune globulin (IgE), produced in response to exposure to foreign proteins, like those from house dust mite, cockroach, animal danders, molds, and pollens. These qualify as allergens on the basis of their induction of IgE antibody production in people exposed to them. The tendency to produce IgE is at least in part genetically determined, and asthma clusters with other allergic diseases (allergic rhinitis, eczema, food allergy) in family groups. Once produced, IgE binds to high-affinity receptors (FCεR-1) on mast cells in the airway mucosa (Figure 20–1), so that re-exposure to the allergen triggers the release of mediators stored in the mast cells’ granules and the synthesis and release of other mediators. The histamine, tryptase, leukotrienes C4 and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction of the “early asthmatic response.” This response is often followed in 3–6 hours by a second, more sustained phase of bronchoconstriction, the “late asthmatic response,” associated with an influx of inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity. This late response is thought to be due to cytokines characteristically produced by T2 lymphocytes, especially interleukins (IL) 5, 9, and 13. These cytokines are thought to attract and activate eosinophils, stimulate IgE production by B lymphocytes, and stimulate mucus production by bronchial epithelial cells. It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response, but the benefits of corticosteroid therapy are attributed to their inhibition of the production of proinflammatory cytokines in the airways and of the response of airway epithelial cells to them.