A major limitation to this classic conception of asthma as an allergic disease is that it applies only to a subgroup of patients with asthma, those with evidence of allergy. Allergic asthma accounts for a great proportion of asthma that develops in childhood, but a smaller proportion of adult-onset asthma. This is implied by the use of modifying terms to describe asthma in different patients, such as “extrinsic” versus “intrinsic,” “aspirin-sensitive,” “adult-onset,” “postviral,” and “obesity-related.” The allergen challenge model fails to account for all the features of the condition even in allergic asthmatics. Many pathways and mechanisms other than production of IgE and activation of mast cell degranulation are involved in asthma’s pathogenesis (Figure 20–2), and most asthma attacks are not triggered by inhalation of allergens, but instead by viral respiratory infections. Asthmatic bronchospasm can also be provoked by nonallergenic stimuli such as distilled water aerosol, exercise, cold air, cigarette smoke, and sulfur dioxide. This tendency to develop bronchospasm on encountering nonallergenic stimuli—assessed by measuring the fall in maximal expiratory flow provoked by inhaling serially increasing concentrations of the aerosolized cholinergic agonist methacholine—is described as “bronchial hyperreactivity.” It is considered fundamental to asthma’s pathogenesis because it is nearly ubiquitous in patients with asthma, and its degree roughly correlates with the clinical severity of the disease.
The mechanisms underlying bronchial hyperreactivity are incompletely understood but appear to be related to inflammation of the airway mucosa. The anti-inflammatory activity of inhaled corticosteroid (ICS) treatment is credited with preventing the increase in bronchial reactivity associated with the late asthmatic response (Figure 20–1).
Whatever the mechanisms responsible for bronchial hyperreactivity, bronchoconstriction itself results not simply from the direct effect of the released mediators but also from their activation of neural pathways. This is suggested by the effectiveness of muscarinic receptor antagonists, which have no direct effect on smooth muscle contractility, in inhibiting the bronchoconstriction caused by inhalation of allergens and airway irritants.
The hypothesis suggested by this conceptual model—that asthmatic bronchospasm results from a combination of release of mediators and an exaggeration of responsiveness to their effects— predicts that drugs with different modes of action may effectively treat asthma. The bronchospasm provoked by exposure to allergens might be reversed or prevented, for example, by drugs that reduce the amount of IgE bound to mast cells (anti-IgE antibody), reduce the number and activity of eosinophils in the airway mucosa (antiIL-5 antibody), block the receptor for IL-4 and IL-13 (anti-IL-4α receptor antibody), prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers), block the action of the products released (antihistamines and