Asthma

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Asthma

Chapter 4 discussed the normal structure of airways and considered several aspects of airway function. The most common disorders disrupting the normal structure and function of the airways—asthma and chronic obstructive pulmonary disease—are discussed here and in Chapter 6, respectively. Several other miscellaneous diseases affecting airways are covered in Chapter 7.

Asthma is a condition characterized by episodes of reversible airway narrowing associated with contraction of smooth muscle within the airway wall. It is a common disorder that affects approximately 7% to 10% of the population. Although asthma can occur in any age group, it is particularly common in children and young adults and probably is the most common chronic disease in these age groups.

The primary feature patients with asthma appear to have in common is hyperresponsiveness of the airways, that is, an exaggerated response of airway smooth muscle to a wide variety of stimuli. The hyperresponsiveness is likely due in part to underlying airway inflammation with a variety of types of inflammatory cells, especially eosinophils. The particular constellation of stimuli triggering attacks often varies among patients, but the net effect (bronchoconstriction) is qualitatively similar. Because asthma is by definition a disease with at least some reversibility, the patient experiences exacerbations (attacks) interspersed between intervals of diminished symptoms or symptom-free periods. During an attack, the diagnosis usually is straightforward. During a symptom-free period, the diagnosis may be more difficult to make and may require provocation or challenge tests to induce airway constriction.

Asthma is characterized by hyperreactivity of the airways and reversible episodes of bronchoconstriction.

Etiology and Pathogenesis

Despite the high prevalence of asthma in the general population and the many advances that have been made in treating the manifestations of the disease, a great deal about its etiology and pathogenesis remains speculative. This section focuses on two major questions: (1) What causes certain people to have airways that hyperreact to various stimuli? (2) What is the sequence of events from the time of exposure to the stimulus until the time of clinical response?

Predisposition to Asthma

Potential factors that may predispose an individual to developing asthma are either inherited or acquired. There has been significant interest in and investigation of genetic and environmental factors that may contribute to the development of asthma, but the roles of these factors and their possible interactions have not been fully elucidated.

Genetics

A substantial proportion of patients with asthma have an underlying history of allergies (allergic rhinitis and eczema) along with accompanying markers for allergic disease, such as positive skin tests and elevated immunoglobulin E (IgE) levels. In these patients, the asthma frequently is exacerbated by exposure to various allergens to which the patients have been previously sensitized. Patients with an allergic component to their asthma often have a strong family history of asthma or other allergies, suggesting that genetic factors may play a role in the development of asthma as well as the underlying allergic diathesis (often called atopy). However, no simple pattern of mendelian inheritance suggesting a single gene as responsible for either atopy or asthma has been identified.

Epidemiologic studies have confirmed an increased frequency of asthma and atopy in first-degree relatives of asthmatic subjects compared with control subjects, and studies in twins indicate a much higher concordance for asthma in monozygotic than in dizygotic twins. Attempts to identify chromosomal regions carrying genes associated with asthma have found a number of such regions, particularly on the long arm of chromosomes 5, 11, and 12 (5q, 11q, and 12q, respectively) and on the short arm of chromosome 6 (6p). Examples of candidate genes proposed to be involved in the predisposition to asthma include the β-subunit gene of the high-affinity receptor for IgE (on chromosome 11q), a gene cluster for production of various cytokines (on chromosome 5q), and the gene encoding the β2-adrenergic receptor (on chromosome 5q). More recently, a disintegrin and matrix metalloproteinase gene called ADAM33 on the short arm of chromosome 20 (20p) has attracted interest as a major candidate gene for asthma and bronchial hyperresponsiveness. Despite these intriguing associations, there is general agreement that the genetic influences in asthma are complex, varying according to the population being studied, and that multiple genes, gene products, and environmental exposures likely interact in the pathogenesis of the disease.

Acquired (Environmental) Factors

A variety of environmental factors that might predispose an individual to develop asthma, most likely interacting with one or more genetic factors, have been proposed. Exposure to allergens, possibly at a critical time during childhood, may be an important environmental factor. Some of these exposures are to common environmental allergens, such as those derived from house dust mites, domestic animals, and cockroaches. These allergens are found indoors, often concentrated in bedding and carpets, and are present throughout the year. Another potential environmental factor is maternal cigarette smoking. An increased risk for early-onset asthma is found in children whose mothers smoke, possibly related to increasing the immune responsiveness of the child.

Viral respiratory tract infections precipitate airway inflammation and trigger acute exacerbations of asthma, but their potential role as an inducer or cause of asthma in the absence of other factors is controversial. One theory suggests that early childhood viral infections are causally associated with later development of asthma. A contrary view (the so-called hygiene hypothesis) suggests that exposure to microbes and microbial byproducts (e.g., endotoxin) during childhood protects against development of asthma by shifting the immunologic profile of helper T (TH) cells toward a TH1 response (responsible for cellular defense) and away from a TH2 response (which mediates allergic inflammation). It is also possible some infections increase the chance of developing asthma, whereas others decrease the risk.

Finally, a recent line of inquiry to explain the increasing prevalence of asthma throughout industrialized parts of the world has turned to a possible role for vitamin D deficiency among pregnant women. Vitamin D is believed to have an immunoregulatory role, and it has been hypothesized that deficiency of vitamin D during pregnancy may predispose to asthma in the offspring.

The relative contribution of these different factors to the development of asthma is unknown. It is possible each of the factors discussed contributes to disease in at least a subset of asthma patients.

Airway Inflammation and Bronchial Hyperresponsiveness

The association between asthma and allergies is significant but not universal. Many individuals with asthma have no other evidence of atopy and do not experience exacerbations as a result of antigen exposure. In this group, asthma attacks often are precipitated by other stimuli, as will be described later. However, the feature both groups of patients—those with and those without an allergic background, sometimes referred to as “extrinsic” (atopic) and “intrinsic” (non-atopic) asthmatic patients, respectively—have in common is hyperresponsiveness of their airways to a variety of stimuli. When exposed to such stimuli, the airways often demonstrate bronchoconstriction, which can be measured as an increase in airway resistance or a decrease in forced expiratory flow rates.

Although many asthmatic patients have allergies, some do not, and the overall relationship between allergies and asthma is not clear.

The histologic feature that accompanies this hyperresponsiveness and is thought to be a critical component of its pathogenesis is airway inflammation. Airway inflammation, especially with eosinophils and lymphocytes, has been found on both postmortem examination in persons with asthma who died of their disease and on bronchial biopsy specimens obtained from patients with mild asthma. Another typical finding is evidence of what has been called airway remodeling, which likely results from chronic airway inflammation and the associated production and release of a multitude of mediators including growth factors. Such remodeling changes include epithelial damage, airway fibrosis, and smooth muscle hyperplasia. These histologic findings, particularly the increase in airway smooth muscle, may be partly responsible for the hyperresponsiveness that can be documented in such persons with asthma, even when they are free of obvious bronchospasm.

Airway inflammation and remodeling are believed to contribute to nonspecific bronchial hyperresponsiveness.

No single factor or cell appears to be responsible for asthma; rather, a complex and interrelated series of events, including cellular infiltration, cytokine release, and airway remodeling, likely culminates in airway hyperresponsiveness and episodes of airflow obstruction (Fig. 5-1). A variety of mediators released from inflammatory cells can alter the extracellular milieu of bronchial smooth muscle, increasing its responsiveness to bronchoconstrictive stimuli. Mediators that have been proposed to play such a role include prostaglandin and leukotriene products of arachidonic acid metabolism. Some cytokine mediators released from inflammatory cells have various effects on other inflammatory cells, thus perpetuating the inflammatory response. For example, lymphocytes of the TH2 phenotype, which are thought to be a prominent component of the inflammatory response in asthma, release interleukin (IL)-5, which has a chemoattractant effect for eosinophils. IL-5 also stimulates growth, activation, and degranulation of eosinophils. IL-4, another cytokine released from TH2 lymphocytes, exerts a different type of proinflammatory effect by activating B lymphocytes, enhancing synthesis of IgE and promoting differentiation of TH2 cells.

Mediators released from inflammatory cells may produce tissue damage that contributes to asthma pathogenesis. For example, when eosinophils degranulate, they release several toxic proteins from their granules, such as major basic protein and eosinophil cationic protein. These and other eosinophil products may contribute to the epithelial damage found in the asthmatic airway. Once the epithelium is injured or denuded, its barrier function is disrupted, allowing access of inhaled material to deeper layers of the mucosa. Additionally, the epithelial cells themselves may become actively involved in amplifying the inflammatory process (through production of cytokine and chemokine mediators) and in perpetuating airway edema (through vasodilation mediated by release of nitric oxide, leukotrienes, and prostaglandins). Finally, sensory nerve endings in the airway epithelial layer may become exposed, triggering a reflex arc and release of tachykinin mediators (e.g., substance P, neurokinin A), as shown in pathway 4 of Figure 4-3. These peptide mediators, released at bronchial smooth muscle, submucosal glands, and blood vessels, are capable of causing bronchoconstriction and airway edema.

Mediators from inflammatory cells may recruit and activate other inflammatory cells and promote epithelial injury.

Common Provocative Stimuli

A substantial amount is known about the sequence of events from the time of exposure to a stimulus until the clinical response of bronchoconstriction in asthmatic persons. Four specific types of stimuli that can result in bronchoconstriction are considered here: (1) allergen (antigen) exposure, (2) inhaled irritants, (3) respiratory tract infection, and (4) exercise.

Common stimuli that precipitate bronchoconstriction in the asthmatic patient are:

Allergen Exposure

The pathogenetic mechanisms leading to bronchoconstriction are best defined for allergen-induced asthma. Allergens to which an asthmatic person may be sensitized are widespread throughout nature. Although patients and clinicians often first consider seasonal outdoor allergens such as pollen, many indoor allergens may play a more critical role. These allergens include antigens from house dust mites (Dermatophagoides and others), domestic animals, and cockroaches. Inhaled antigens are initially identified and processed by antigen-presenting cells called dendritic cells, which in turn present the antigenic material to T lymphocytes. Chemicals released by TH2 cells, especially IL-4 and IL-13, signal B lymphocytes to produce antigen-specific IgE antibodies. When an asthmatic person has IgE antibody against a particular antigen, the antibody binds to high-affinity IgE receptors on the surface of tissue mast cells and circulating basophils (see Fig. 5-1). If that particular antigen is inhaled, it binds to and cross-links IgE antibody (against the antigen) bound to the surface of mast cells in the bronchial lumen. The mast cell then is activated, leading to release of both preformed and newly synthesized mediators. Mediators released from the mast cell induce bronchoconstriction and increase airway epithelial permeability, allowing the antigen access to the much larger population of specific IgE-containing mast cells deeper within the epithelium. Binding of antigen to antibody on this larger population of mast cells again initiates a sequence of events leading to release of chemical mediators capable of inducing bronchoconstriction and inflammation. Several mediators have been recognized (Table 5-1), but the discussion here is limited to the few that have been primarily implicated in the pathogenesis of allergic asthma; major mediators include histamine and leukotrienes.

Leukotrienes: The leukotrienes include a series of compounds (LTC4, LTD4, and LTE4) that formerly were called slow-reacting substance of anaphylaxis (SRS-A). Unlike histamine, leukotrienes are not preformed in the mast cell but synthesized after antigen exposure and then released. To some extent, their actions are similar to those of histamine; they also have a direct bronchoconstrictor action on smooth muscle, increase vascular permeability, and stimulate excess production of airway mucus. Leukotrienes are synthesized from arachidonic acid (also the precursor for prostaglandins) but along a different pathway involving a lipoxygenase enzyme, as opposed to the cyclooxygenase enzyme used for prostaglandin synthesis (Fig. 5-2). LTC4 and LTD4 in particular are extraordinarily potent bronchoconstrictors and may have an important role in the pathogenesis of bronchial asthma. An interesting sidelight is provided by knowledge that some persons with asthma experience exacerbations of their disease after taking aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). These drugs are known inhibitors of the cyclooxygenase enzyme and may result in preferential shifting of the pathway shown in Figure 5-2 toward production of the bronchoconstrictor leukotrienes.

The role of other mediators listed in Table 5-1 in asthma pathogenesis is less clear. Platelet-activating factor has been proposed to play a role in recruiting eosinophils to the lung, and platelet-activating factor activates eosinophils, stimulating them to release proteins toxic to airway epithelial cells.

Late-Phase Asthmatic Response: The airway response to antigen challenge, as measured by changes in forced expiratory volume in 1 second (FEV1), appears to be more complicated and involves more than just the rapid mediator-induced bronchoconstriction seen within the first half hour following exposure. In many patients, the return of FEV1 to normal is followed by a secondary delayed fall in FEV1 occurring hours after antigen exposure (Fig. 5-3). This delayed fall in FEV1 is accompanied histologically by inflammatory changes in the airway wall. At the same time, increased bronchial hyperresponsiveness to nonspecific stimuli, such as histamine or methacholine, can be demonstrated and can last for days.

It now appears that this “late-phase response,” as it has been called, depends on the presence of antigen-specific IgE. Presumably, release of mediators after allergen binding to IgE-coated mast cells results in an influx of inflammatory cells, especially eosinophils, into the airway wall. Experimental data suggest that this heightened airway inflammation is responsible for the increased nonspecific bronchial hyperresponsiveness seen at the time of the late-phase response.

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