5: Asthma

OUTLINE

Etiology and Pathogenesis, 69

Predisposition to Asthma, 70

Airway Inflammation, Cytokine Mediators, and Bronchial Hyperresponsiveness, 71

Asthma Phenotypes, 72

Common Provocative Stimuli, 73

Pathology, 75

Pathophysiology, 76

Clinical Features, 77

Diagnostic Approach, 78

Treatment, 80

Bronchodilators, 80

Anti-inflammatory Drugs, 82

Agents With Specific Targeted Action, 83

Bronchial Thermoplasty, 84

Management Strategy, 84

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 (COPD)—are discussed here and in Chapter 6, respectively. Several other miscellaneous diseases affecting airways are covered in Chapter 7.

Asthma is an inflammatory condition characterized by episodes of reversible airway narrowing due to 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 constriction of airway smooth muscle and consequent narrowing of

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airways in response to a wide variety of stimuli. The hyperresponsiveness is likely due in part to underlying airway inflammation with several types of inflammatory cells, especially lymphocytes and 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 is usually straightforward. During a symptom-free period, the diagnosis may be more difficult to establish 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 uncertain. In fact, it is likely that what we call asthma may not represent a single disease process, but rather may encompass several pathogenetic pathways (endotypes) that have somewhat different expressions (phenotypes) despite common features of airway inflammation and episodic bronchoconstriction. While recognizing the difficulty of presenting a unifying framework for understanding asthma, this section focuses on two major questions that are relevant across the spectrum of what we call asthma: (1) What causes certain people to have airways that hyperreact to various stimuli?

(2) What factors appear to be important 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 both inherited and 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, particularly children and young adults, have a history of 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 is frequently exacerbated by exposure to allergens to which the patients have been previously sensitized. Patients who have an allergic phenotype 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 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 subjects with asthma compared with control subjects, and studies in twins indicate a much higher concordance for asthma in monozygotic than in dizygotic twins. Attempts to identify genes associated with asthma have found over 128 independently associated genetic loci, most of which represent single nucleotide polymorphisms. Nevertheless, variations in any of these single genes appear to explain only a small portion of the overall heritability. This may be in part because any genetic

influence involves multiple genes, and in part because genetic studies often combine individuals with different phenotypes and presumably different endotypes, thus potentially diluting the effect of a genetic variant that may play a strong role only in a specific subset of the total asthma population. The latter issue is illustrated by the fact that variants at the 17q21 locus appear associated with childhood asthma, but not with adult-onset asthma. Despite whatever intriguing genetic associations are found with asthma, 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 altering the normal development of the child’s immune system.

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. On the other hand, the so-called hygiene hypothesis suggests that exposure to microbes and microbial byproducts (e.g., endotoxin) during childhood may protect 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 likely that some infections increase the chance of developing asthma, whereas others decrease the risk, and that timing of the infection and other factors may play a role in this interaction.

Finally, one 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.

Airway inflammation, cytokine mediators, and bronchial hyperresponsiveness

No single factor or cell appears to be responsible for asthma. Instead, a complex and interrelated series of events, including cellular infiltration, epithelial injury, cytokine release, and airway remodeling, likely culminates in airway hyperresponsiveness and episodes of airflow obstruction (Fig. 5.1). A further complication is the recognition that specific mechanistic pathways and the role of various cells and mediators differ depending on the particular asthma phenotype. The explosion of research relating to pathogenetic mechanisms and potential chemical mediators means that we can only scratch the surface in this discussion. However, the interested reader can find more detailed information in the Suggested Readings at the end of this chapter.

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FIGURE 5.1 Schematic Diagram of Events in Pathogenesis of Antigen-Induced

Asthma. A hypothetical series of complex interactions is shown, focusing on

bronchoconstriction, mucus secretion, and airway inflammation. Ag, antigen; IgE,

immunoglobulin E.

As noted, a feature that is common to patients with asthma, independent of their age at presentation or their specific phenotype, is hyperresponsiveness of the 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.

A myriad of cytokine mediators, produced and released by inflammatory cells and by the airway epithelium, are responsible for recruitment and activation of other inflammatory cells and amplification of cytokine production, 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 many patients with 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 naïve TH lymphocytes (TH0) to TH2 cells. These and several other of the many cytokine mediators thought to be of particular importance in asthma are summarized in Table 5.1.

TABLE 5.1

Important Cytokines in Asthma Pathogenesis

Cytokine	Origin	Effect
IL-4	TH2 cells	Differentiation of naïve TH0 cells to TH2 cells; differentiation of B cells to
		IgE-producing plasma cells
IL-5	TH2 cells	Eosinophil recruitment
IL-13	TH2 cells	Similar to IL-4; airway remodeling
IL-17	TH17 cells	Neutrophil recruitment
IL-25	Epithelial	Stimulation of TH2 cytokine production
	cells
IL-33	Epithelial	Activation of group 2 innate lymphoid cells (ILC2) and production of IL-5
	cells	and IL-13 by ILC2
TSLP	Epithelial	Activation and mobilization of antigen-processing dendritic cells
	cells

IL, interleukin; TSLP, thymic stromal lymphopoietin.

Another typical finding in many patients with asthma is 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 disruption, airway fibrosis, and smooth muscle hyperplasia. These histologic findings, particularly the increase in airway smooth muscle, also likely contribute to the hyperresponsiveness that can be documented in individuals with asthma, even when they are free of obvious bronchospasm.

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

A variety of other 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. Mediators released from inflammatory cells may also 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 into deeper layers of the mucosa. The epithelial cells 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 Fig. 4.3. These peptide mediators, released at bronchial smooth muscle, submucosal glands,

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and blood vessels, can cause bronchoconstriction and airway edema.

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

Asthma phenotypes

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. A common framework used in the past has distinguished two “types” of asthma: (1) “extrinsic” (atopic) asthma, typically seen in younger patients and having a significant allergic component; and (2) “intrinsic” (nonatopic) asthma, typically in adults and lacking a significant allergic component.

Although many patients with asthma have allergies, heterogeneity in asthma presentation (phenotypes) has been increasingly recognized and suggests multiple underlying mechanistic pathways.

More recently, the recognition of differences in asthma presentation has led to an evolution of this framework and a number of proposed asthma phenotypes, potentially with different underlying pathogenetic mechanisms (endotypes). However, whether these phenotypes are truly distinct and have different endotypes or whether they represent different manifestations of a continuous spectrum of disease is uncertain. A particularly common phenotype is an “allergic” phenotype, roughly corresponding to what was previously described as extrinsic asthma. The allergic phenotype is typically associated with atopy and asthma developing early in life. Another phenotype, which describes severe asthma presenting during adulthood, accompanied by tissue and often peripheral eosinophilia as well as sinusitis, but not identifiable allergies or atopy, has been called an “eosinophilic” phenotype. An association of obesity with asthma, particularly in women and developing during adulthood, has defined an “obesity-related” phenotype. These and other asthma phenotypes are described in more detail in the Suggested Readings at the end of this chapter.

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 persons with asthma. 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 a patient with asthma are as follows:

1.Exposure to an allergen

2.Inhaled irritants

3.Respiratory tract infection

4.Exercise

Allergen exposure

The pathogenetic mechanisms leading to bronchoconstriction are best defined for allergen-induced asthma. Allergens to which a person with asthma 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. Chemical mediators released by TH2 cells, especially IL-4 and IL13, signal B lymphocytes to produce antigen-specific IgE antibodies. When a person with asthma has the 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 the IgE antibody (against the antigen) bound to the surface of mast cells in the bronchial lumen. The mast cell is then 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 IgEcontaining 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 mediators which induce bronchoconstriction and inflammation. Several mediators have been recognized (Table 5.2), 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.

TABLE 5.2

Additional Potential Chemical Mediators in Asthma

Histamine

Leukotrienes (LTC4, LTD4, LTE4)

Platelet-activating factor

Prostaglandins (PGD2)

Eosinophil chemotactic factor of anaphylaxis

Neutrophil chemotactic factor of anaphylaxis

Bradykinin

Serotonin

Kallikrein

Histamine.

This relatively small (molecular weight 111) compound is found preformed within the mast cell and is released on exposure to specific antigens. Histamine has several effects that are important in asthma, including contraction of bronchial smooth muscle, augmentation of vascular permeability with formation of airway edema, and stimulation of irritant receptors (which can trigger a reflex neurogenic pathway via the vagus nerve, causing secondary bronchoconstriction). Despite these varied effects, the fact that the clinical manifestations of asthma do not respond to antihistamines suggests that histamine is not the most important chemical mediator involved.

Leukotrienes.

The leukotrienes include a series of compounds (LTC4, LTD4, and LTE4) that formerly were called slowreacting substance of anaphylaxis (SRS-A). Unlike histamine, leukotrienes are not preformed in the mast cell but are synthesized after antigen exposure and then released. To some extent, their actions are similar

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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 have an important role in the pathogenesis of some cases of bronchial asthma. A noteworthy insight is provided by knowledge that some persons with asthma experience exacerbations of their disease after taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are known inhibitors of the cyclooxygenase enzyme and may result in preferential shifting of the pathway shown in Fig. 5.2 toward production of the bronchoconstrictor leukotrienes.

FIGURE 5.2 Outline of the pathway for formation of leukotrienes (slow-reacting

substance of anaphylaxis [SRS-A]) and prostaglandins. Aspirin and other

nonsteroidal anti-inflammatory drugs are inhibitors of the enzyme cyclooxygenase.

The role of other mediators listed in Table 5.2 in asthma pathogenesis is less clear. Platelet-activating factor has been proposed to play a role in recruiting eosinophils to the lung, activating them, and 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), is 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.

FIGURE 5.3 Response of forced expiratory volume in 1 second (FEV1) after antigen challenge in a patient who demonstrates a biphasic response. Early

bronchoconstrictive response is at point A. Slower onset late-phase asthmatic

response is at point B.

This “late-phase response,” as it has been called, depends on the presence of antigen-specific IgE. 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.

Inhaled irritants

Inhaled irritants such as cigarette smoke, inorganic dusts, and environmental pollutants are common precipitants of bronchoconstriction in persons with asthma. These airborne irritants appear to stimulate irritant receptors located primarily in the walls of the larynx, trachea, and large bronchi. Stimulation of the receptors initiates a reflex arc that travels to the central nervous system and back to the bronchi via the vagus nerve. This efferent vagal stimulation of the bronchi completes the reflex arc and induces bronchoconstriction. As mentioned in the discussion about chemical mediators, histamine can stimulate irritant receptors, and at least part of its bronchoconstrictive effect may be mediated indirectly via

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