Asthma is a disease whose ability to cause episodic symptomatology has been appreciated since antiquity. Although the fine points of the definition can be debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized reversible obstruction of airflow and to define reversibility as a greater than 12% increase in the patient’s forced expiratory volume in 1 second (FEV1) that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as methacholine and histamine or specific antigens, is the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of recurrent wheeze, cough, or shortness of breath, reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating airway hyperresponsiveness. It has long been assumed that patients with asthma experience intermittent attacks and have relatively normal lung function during intervening periods. More recent studies have demonstrated that asthma can cause progressive lung impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.
Any discussion of asthma must take into account the recent increase in its prevalence. Since approximately 1980, the frequency of this disorder has almost doubled. As a result of this “epidemic,” asthma now affects approximately 8–10% of the population in the US, is the leading cause of hospitalization among children less than 15 years of age, and costs society billions of dollars annually. This increase in prevalence is not simply due to diagnostic transference or increased diagnostic awareness, since asthma mortality rates have also increased during this interval.
An aerosol antigen challenge of an appropriately sensitized asthmatic patient can induce two types of airway responses. The early response is an acute bronchospastic event that occurs 15–30 minutes after exposure and resolves over time. The late-phase response peaks 4–6 hours after exposure and can cause prolonged symptomatology. Over the years, a variety of concepts of pathogenesis have been put forth in an attempt to explain one or both of these responses (Table (Table1).1). Early investigators postulated that there was an intrinsic airway smooth muscle abnormality at the root of the asthmatic diathesis. However, many studies with airway myocytes in culture have not corroborated this contention. This was followed by the contention that asthma is an autonomic dysfunction syndrome characterized by excess cholinergic and/or tachykinin pathway activity. This was never proven or disproven. Instead, IgE-mediated mast cell and/or basophil degranulation with the release of leukotrienes, histamine, prostaglandins, tryptase, cytokines (such as IL-4 and IL-5), and other mediators was appreciated to be a key event in the acute response. The prominent eosinophil-, macrophage-, and lymphocyte-rich inflammatory response in the airways of patients with asthma (Figure (Figure1)1) and the efficacy of steroids in the majority of patients with asthma then led to the present-day concept that asthma is a chronic inflammatory disorder of the airway and that T cells are pivotal initiators and regulators of this response. Structural alterations including airway wall thickening, fibrosis in the lamina reticularis and adventitia of the airway, mucus metaplasia, myocyte hypertrophy and hyperplasia, and neovascularization are all readily appreciated in the asthmatic airway (Figure (Figure1).1). This led to the hypothesis that the inflammatory response in the asthmatic airway causes these remodeling events, and to the belief that these events contribute to disease pathogenesis. Studies using new immunologic and molecular approaches have provided impressive insights into the nature of this inflammatory response and the relationship between this response and the remodeling and physiologic alterations characteristic of the disorder.