Introduction

Asthma is a common chronic disorder of the airways that involves a complex interaction of airflow obstruction, bronchial hyperresponsiveness and an underlying inflammation. This interaction can be highly variable among patients and within patients over time. This section presents a definition of asthma, a description of the processes on which that definition is based—the pathophysiology and pathogenesis of asthma, and the natural history of asthma.

Definition of Asthma

Asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation (box 2-1). The interaction of these features of asthma determines the clinical manifestations and severity of asthma (figure 2-1) and the response to treatment.

Box 2-1

CHARACTERISTICS OF CLINICAL ASTHMA. ▪ Symptoms ▪ Airway obstruction ▪ Inflammation ▪ Hyperresponsiveness ▪ Symptoms

Figure 2-1

THE INTERPLAY AND INTERACTION BETWEEN AIRWAY INFLAMMATION AND THE CLINICAL SYMPTOMS AND PATHOPHYSIOLOGY OF ASTHMA

The concepts underlying asthma pathogenesis have evolved dramatically in the past 25 years and are still undergoing evaluation as various phenotypes of this disease are defined and greater insight links clinical features of asthma with genetic patterns (Busse and Lemanske 2001; EPR—2 1997). Central to the various phenotypic patterns of asthma is the presence of underlying airway inflammation, which is variable and has distinct but overlapping patterns that reflect different aspects of the disease, such as intermittent versus persistent or acute versus chronic manifestations. Acute symptoms of asthma usually arise from bronchospasm and require and respond to bronchodilator therapy. Acute and chronic inflammation can affect not only the airway caliber and airflow but also underlying bronchial hyperresponsiveness, which enhances susceptibility to bronchospasm (Cohn et al. 2004).

Treatment with anti-inflammatory drugs can, to a large extent, reverse some of these processes; however, the successful response to therapy often requires weeks to achieve and, in some situations, may be incomplete (Bateman et al. 2004; O'Byrne and Parameswaran 2006). For some patients, the development of chronic inflammation may be associated with permanent alterations in the airway structure—referred to as airway remodeling—that are not prevented by or fully responsive to currently available treatments (Holgate and Polosa 2006). Therefore, the paradigm of asthma has been expanded over the last 10 years from bronchospasm and airway inflammation to include airway remodeling in some persons (Busse and Lemanske 2001).

The concept that asthma may be a continuum of these processes that can lead to moderate and severe persistent disease is of critical importance to understanding the pathogenesis, pathophysiology, and natural history of this disease (Martinez 2006). Although research since the first NAEPP guidelines in 1991 (EPR 1991) has confirmed the important role of inflammation in asthma, the specific processes related to the transmission of airway inflammation to specific pathophysiologic consequences of airway dysfunction and the clinical manifestations of asthma have yet to be fully defined. Similarly, much has been learned about the host–environment factors that determine airways' susceptibility to these processes, but the relative contributions of either and the precise interactions between them that leads to the initiation or persistence of disease have yet to be fully established. Nonetheless, current science regarding the mechanisms of asthma and findings from clinical trials have led to therapeutic approaches that allow most people who have asthma to participate fully in activities they choose. As we learn more about the pathophysiology, phenotypes, and genetics of asthma, treatments will become available to ensure adequate asthma control for all persons and, ideally, to reverse and even prevent the asthma processes.

As a guide to describing asthma and identifying treatment directions, a working definition of asthma put forth in the previous Guidelines remains valid: Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma (EPR 1991; EPR—2 1997).

This working definition and its recognition of key features of asthma have been derived from studying how airway changes in asthma relate to the various factors associated with the development of airway inflammation (e.g., allergens, respiratory viruses, and some occupational exposures) and recognition of genetic regulation of these processes. From these descriptive approaches has evolved a more comprehensive understanding of asthma pathogenesis, the processes involved in the development of persistent airway inflammation, and the significant implications that these immunological events have for the development, diagnosis, treatment, and possible prevention of asthma.

Pathophysiology and Pathogenesis of Asthma

Airflow limitation in asthma is recurrent and caused by a variety of changes in the airway. These include:

• ▪ Bronchoconstriction. In asthma, the dominant physiological event leading to clinical symptoms is airway narrowing and a subsequent interference with airflow. In acute exacerbations of asthma, bronchial smooth muscle contraction (bronchoconstriction) occurs quickly to narrow the airways in response to exposure to a variety of stimuli including allergens or irritants. Allergen-induced acute bronchoconstriction results from an IgE-dependent release of mediators from mast cells that includes histamine, tryptase, leukotrienes, and prostaglandins that directly contract airway smooth muscle (Busse and Lemanske 2001). Aspirin and other nonsteroidal anti-inflammatory drugs (see section 3, component 3) can also cause acute airflow obstruction in some patients, and evidence indicates that this non-IgE-dependent response also involves mediator release from airway cells (Stevenson and Szczeklik 2006). In addition, other stimuli (including exercise, cold air, and irritants) can cause acute airflow obstruction. The mechanisms regulating the airway response to these factors are less well defined, but the intensity of the response appears related to underlying airway inflammation. Stress may also play a role in precipitating asthma exacerbations. The mechanisms involved have yet to be established and may include enhanced generation of pro-inflammatory cytokines.
• ▪ Airway edema. As the disease becomes more persistent and inflammation more progressive, other factors further limit airflow (figure 2-2). These include edema, inflammation, mucus hypersecretion and the formation of inspissated mucus plugs, as well as structural changes including hypertrophy and hyperplasia of the airway smooth muscle. These latter changes may not respond to usual treatment.
• ▪ Airway hyperresponsiveness. Airway hyperresponsiveness—an exaggerated bronchoconstrictor response to a wide variety of stimuli—is a major, but not necessarily unique, feature of asthma. The degree to which airway hyperresponsiveness can be defined by contractile responses to challenges with methacholine correlates with the clinical severity of asthma. The mechanisms influencing airway hyperresponsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyperresponsiveness. Treatment directed toward reducing inflammation can reduce airway hyperresponsiveness and improve asthma control.
• ▪ Airway remodeling. In some persons who have asthma, airflow limitation may be only partially reversible. Permanent structural changes can occur in the airway (figure 2-2); these are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy. Airway remodeling involves an activation of many of the structural cells, with consequent permanent changes in the airway that increase airflow obstruction and airway responsiveness and render the patient less responsive to therapy (Holgate and Polosa 2006). These structural changes can include thickening of the sub-basement membrane, subepithelial fibrosis, airway smooth muscle hypertrophy and hyperplasia, blood vessel proliferation and dilation, and mucous gland hyperplasia and hypersecretion (box 2-2). Regulation of the repair and remodeling process is not well established, but both the process of repair and its regulation are likely to be key events in explaining the persistent nature of the disease and limitations to a therapeutic response.

Figure 2-2

FACTORS LIMITING AIRFLOW IN ACUTE AND PERSISTENT ASTHMA Source: Adapted and reprinted from The Lancet, 368, Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults, 780–93. Copyright (2006), with permission from (more...)

Box 2-2

FEATURES OF AIRWAY REMODELING. ▪ Inflammation ▪ Mucus hypersecretion ▪ Subepithelial fibrosis ▪ Airway smooth muscle hypertrophy ▪ Angiogenesis ▪ Inflammation

PATHOPHYSIOLOGIC MECHANISMS IN THE DEVELOPMENT OF AIRWAY INFLAMMATION

Inflammation has a central role in the pathophysiology of asthma. As noted in the definition of asthma, airway inflammation involves an interaction of many cell types and multiple mediators with the airways that eventually results in the characteristic pathophysiological features of the disease: bronchial inflammation and airflow limitation that result in recurrent episodes of cough, wheeze, and shortness of breath. The processes by which these interactive events occur and lead to clinical asthma are still under investigation. Moreover, although distinct phenotypes of asthma exist (e.g., intermittent, persistent, exercise-associated, aspirin-sensitive, or severe asthma), airway inflammation remains a consistent pattern. The pattern of airway inflammation in asthma, however, does not necessarily vary depending upon disease severity, persistence, and duration of disease. The cellular profile and the response of the structural cells in asthma are quite consistent.

Inflammatory Cells

Lymphocytes

An increased understanding of the development and regulation of airway inflammation in asthma followed the discovery and description of subpopulations of lymphocytes, T helper 1 cells and T helper 2 cells (Th1 and Th2), with distinct inflammatory mediator profiles and effects on airway function (figure 2-3). After the discovery of these distinct lymphocyte subpopulations in animal models of allergic inflammation, evidence emerged that, in human asthma, a shift, or predilection, toward the Th2-cytokine profile resulted in the eosinophilic inflammation characteristic of asthma (Cohn et al. 2004). In addition, generation of Th2 cytokines (e.g., interleukin-4 (IL-4), IL-5, and IL-13) could also explain the overproduction of IgE, presence of eosinophils, and development of airway hyperresponsiveness. There also may be a reduction in a subgroup of lymphocytes, regulatory T cells, which normally inhibit Th2 cells, as well as an increase in natural killer (NK) cells that release large amounts of Th1 and Th2 cytokines (Akbari et al. 2006; Larche et al. 2003). T lymphocytes, along with other airway resident cells, also can determine the development and degree of airway remodeling. Although it is an oversimplification of a complex process to describe asthma as a Th2 disease, recognizing the importance of n families of cytokines and chemokines has advanced our understanding of the development of airway inflammation (Barnes 2002; Zimmermann et al. 2003).

Figure 2-3

AIRWAY INFLAMMATION Inhaled antigen activates mast cells and Th2 cells in the airway. They in turn induce the production of mediators of inflammation (such as histamine and leukotrienes) and cytokines including interleukin-4 and interleukin-5. Interleukin-5 (more...)

Mast cells

Activation of mucosal mast cells releases bronchoconstrictor mediators (histamine, cysteinyl-leukotrienes, prostaglandin D₂) (Boyce 2003; Galli et al. 2005; Robinson 2004). Although allergen activation occurs through high-affinity IgE receptors and is likely the most relevant reaction, sensitized mast cells also may be activated by osmotic stimuli to account for exercise-induced bronchospasm (EIB). Increased numbers of mast cells in airway smooth muscle may be linked to airway hyperresponsiveness (Brightling et al. 2002). Mast cells also can release a large number of cytokines to change the airway environment and promote inflammation even though exposure to allergens is limited.

Eosinophils

Increased numbers of eosinophils exist in the airways of most, but not all, persons who have asthma (Chu and Martin 2001; Sampson 2000; Williams 2004). These cells contain inflammatory enzymes, generate leukotrienes, and express a wide variety of pro-inflammatory cytokines. Increases in eosinophils often correlate with greater asthma severity. In addition, numerous studies show that treating asthma with corticosteroids reduces circulating and airway eosinophils in parallel with clinical improvement. However, the role and contribution of eosinophils to asthma is undergoing a reevaluation based on studies with an anti-IL-5 treatment that has significantly reduced eosinophils but did not affect asthma control (Leckie et al. 2000). Therefore, although the eosinophil may not be the only primary effector cell in asthma, it likely has a distinct role in different phases of the disease.

Neutrophils

Neutrophils are increased in the airways and sputum of persons who have severe asthma, during acute exacerbations, and in the presence of smoking. Their pathophysiological role remains uncertain; they may be a determinant of a lack of response to corticosteroid treatment (Fahy et al. 1995). The regulation of neutrophil recruitment, activation, and alteration in lung function is still under study, but leukotriene B₄ may contribute to these processes (Jatakanon et al. 1999; Wenzel et al. 1997; Wenzel 2006).

Dendritic cells

These cells function as key antigen-presenting cells that interact with allergens from the airway surface and then migrate to regional lymph nodes to interact with regulatory cells and ultimately to stimulate Th2 cell production from naïve T cells (Kuipers and Lambrecht 2004).

Macrophages

Macrophages are the most numerous cells in the airways and also can be activated by allergens through low-affinity IgE receptors to release inflammatory mediators and cytokines that amplify the inflammatory response (Peters-Golden 2004).

Resident cells of the airway

Airway smooth muscle is not only a target of the asthma response (by undergoing contraction to produce airflow obstruction) but also contributes to it (via the production of its own family of pro-inflammatory mediators). As a consequence of airway inflammation and the generation of growth factors, the airway smooth muscle cell can undergo proliferation, activation, contraction, and hypertrophy—events that can influence airway dysfunction of asthma.

Epithelial cells

Airway epithelium is another airway lining cell critically involved in asthma (Polito and Proud 1998). The generation of inflammatory mediators, recruitment and activation of inflammatory cells, and infection by respiratory viruses can cause epithelial cells to produce more inflammatory mediators or to injure the epithelium itself. The repair process, following injury to the epithelium, may be abnormal in asthma, thus furthering the obstructive lesions that occur in asthma.

Inflammatory Mediators

Chemokines are important in recruitment of inflammatory cells into the airways and are mainly expressed in airway epithelial cells (Zimmermann et al. 2003). Eotaxin is relatively selective for eosinophils, whereas thymus and activation-regulated chemokines (TARCs) and macrophage-derived chemokines (MDCs) recruit Th2 cells. There is an increasing appreciation for the role this family of mediators has in orchestrating injury, repair, and many aspects of asthma.

Cytokines direct and modify the inflammatory response in asthma and likely determine its severity. Th2-derived cytokines include IL-5, which is needed for eosinophil differentiation and survival, and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for IgE formation. Key cytokines include IL-1β and tumor necrosis factor-α (TNF-α), which amplify the inflammatory response, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which prolongs eosinophil survival in airways. Recent studies of treatments directed toward single cytokines (e.g., monoclonal antibodies against IL-5 or soluble IL-4 receptor) have not shown benefits in improving asthma outcomes.

Cysteinyl-leukotrienes are potent bronchoconstrictors derived mainly from mast cells. They are the only mediator whose inhibition has been specifically associated with an improvement in lung function and asthma symptoms (Busse 1996; Leff 2001). Recent studies have also shown leukotriene B₄ can contribute to the inflammatory process by recruitment of neutrophils (Gelfand and Dakhama 2006).

Nitric oxide (NO) is produced predominantly from the action of inducible NO synthase in airway epithelial cells; it is a potent vasodilator (Deykin et al. 2002; Strunk et al. 2003). Measurements of fractional exhaled NO (FeNO) may be useful for monitoring response to asthma treatment because of the purported association between FeNO and the presence of inflammation in asthma (Green et al. 2002).

Immunoglobulin E

IgE is the antibody responsible for activation of allergic reactions and is important to the pathogenesis of allergic diseases and the development and persistence of inflammation. IgE attaches to cell surfaces via a specific high-affinity receptor. The mast cell has large numbers of IgE receptors; these, when activated by interaction with antigen, release a wide variety of mediators to initiate acute bronchospasm and also to release pro-inflammatory cytokines to perpetuate underlying airway inflammation (Boyce 2003; Sporik et al. 1995). Other cells, basophils, dendritic cells, and lymphocytes also have high-affinity IgE receptors.

The development of monoclonal antibodies against IgE has shown that the reduction of IgE is effective in asthma treatment (Busse et al. 2001; Holgate et al. 2005). These clinical observations further support the importance of IgE to asthma.

Implications of Inflammation for Therapy

Recent scientific investigations have focused on translating the increased understanding of the inflammatory processes in asthma into therapies targeted at interrupting these processes (Barnes 2002). Some investigations have yielded promising results, such as the development leukotriene modifiers and anti-IgE monoclonal antibody therapy. Other studies, such as those directed at IL-4 or IL-5 cytokines, underscore the relevance of multiple factors regulating inflammation in asthma and the redundancy of these processes. All of these clinical studies also indicate that phenotypes of asthma exist, and these phenotypes may have very specific patterns of inflammation that require different treatment approaches. Current studies are investigating novel therapies targeted at the cytokines, chemokines, and inflammatory cells farther upstream in the inflammatory process. For example, drugs designed to inhibit the Th2 inflammatory pathway may cause a broad spectrum of effects such as airway hyperresponsiveness and mucus hypersecretion. Further research into the mechanisms responsible for the varying asthma phenotypes and appropriately targeted therapy may enable improved control for all manifestations of asthma, and, perhaps, prevention of disease progression.

PATHOGENESIS

What initiates the inflammatory process in the first place and makes some persons susceptible to its effects is an area of active investigation. There is not yet a definitive answer to this question, but new observations suggest that the origins of asthma primarily occur early in life. The expression of asthma is a complex, interactive process that depends on the interplay between two major factors—host factors (particularly genetics) and environmental exposures that occur at a crucial time in the development of the immune system (figure 2-4).

Figure 2-4

HOST FACTORS AND ENVIRONMENTAL EXPOSURES

Host Factors

Innate immunity

There is considerable interest in the role of innate and adaptive immune responses associated with both the development and regulation of inflammation (Eder et al. 2006). In particular, research has focused on an imbalance between Th1 and Th2 cytokine profiles and evidence that allergic diseases, and possibly asthma, are characterized by a shift toward a Th2 cytokine-like disease, either as overexpression of Th2 or underexpression of Th1 (figure 2-5). Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of Th lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce IL-2 and interferon-γ (IFN-γ), which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, -5, -6, -9, and -13) that can mediate allergic inflammation. The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in westernized countries. This hypothesis is based on the assumption that the immune system of the newly born is skewed toward Th2 cytokine generation. Following birth, environmental stimuli such as infections will activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance. Evidence indicates that the incidence of asthma is reduced in association with certain infections (M. tuberculosis, measles, or hepatitis A), exposure to other children (e.g., presence of older siblings and early enrollment in childcare), and less frequent use of antibiotics (Eder et al. 2006; Gern et al. 1999; Gern and Busse 2002; Horwood et al. 1985; Sears et al. 2003). Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern. Under these conditions, the genetic background of the child who has a cytokine imbalance toward Th2 will set the stage to promote the production of IgE antibodies to key environmental antigens, such as house-dust mite, cockroach, Alternaria, and possibly cat. Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating IgE, and sensitization occurs. Precisely why the airways of some individuals are susceptible to these allergic events has not been established.

Figure 2-5

CYTOKINE BALANCE Numerous factors, including alterations in the number or type of infections early in life, the widespread use of antibiotics, adoption of the Western lifestyle, and repeated exposure to allergens, may affect the balance between Th1-type (more...)

There also appears to be a reciprocal interaction between the two subpopulations in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternatively, recent studies have suggested the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished. The focus on actions of cytokines and chemokines to regulate and activate the inflammatory profile in asthma has provided ongoing and new insight into the pattern of airway injury that may lead to new therapeutic targets.

Genetics

It is well recognized that asthma has an inheritable component to its expression, but the genetics involved in the eventual development of asthma remain a complex and incomplete picture (Holgate 1999; Ober 2005). To date, many genes have been found that either are involved in or linked to the presence of asthma and certain of its features. The complexity of their involvement in clinical asthma is noted by linkages to certain phenotypic characteristics, but not necessarily the pathophysiologic disease process or clinical picture itself. The role of genetics in IgE production, airway hyperresponsiveness, and dysfunctional regulation of the generation of inflammatory mediators (such as cytokines, chemokines, and growth factors) has appropriately captured much attention. In addition, studies are investigating genetic variations that may determine the response to therapy. The relevance of polymorphisms in the beta-adrenergic and corticosteroid receptors in determining responsiveness to therapies is of increasing interest, but the widespread application of these genetic factors remains to be fully established.

Sex

In early life, the prevalence of asthma is higher in boys. At puberty, however, the sex ratio shifts, and asthma appears predominantly in women (Horwood et al. 1985). How specifically sex and sex hormones, or related hormone generation, are linked to asthma has not been established, but they may contribute to the onset and persistence of the disease.

Environmental Factors

Two major environmental factors have emerged as the most important in the development, persistence, and possibly severity of asthma: airborne allergens and viral respiratory infections. In the susceptible host, and at a critical time of development (e.g., immunological and physiological), both respiratory infections and allergens have a major influence on asthma development and its likely persistence. It is also apparent that allergen exposure, allergic sensitization, and respiratory infections are not separate entities but function interactively in the eventual development of asthma.

Allergens

The role of allergens in the development of asthma has yet to be fully defined or resolved, but it is obviously important. Sensitization and exposure to house-dust mite and Alternaria are important factors in the development of asthma in children. Early studies showed that animal danders, particularly dog and cat, were associated with the development of asthma. Recent data suggest that, under some circumstances, dog and cat exposure in early life may actually protect against the development of asthma. The determinant of these diverse outcomes has not been established. Studies to evaluate house-dust mite and cockroach exposure have shown that the prevalence of sensitization and subsequent development of asthma are linked (Huss et al. 2001; Sporik et al. 1990; Wahn et al. 1997). Exposure to cockroach allergen, for example, a major allergen in inner-city dwellings, is an important cause of allergen sensitization, a risk factor for the development of asthma (Rosenstreich et al. 1997). In addition, allergen exposure can promote the persistence of airway inflammation and likelihood of an exacerbation.

Respiratory infections

During infancy, a number of respiratory viruses have been associated with the inception or development of the asthma. In early life, respiratory syncytial virus (RSV) and parainfluenza virus in particular, cause bronchiolitis that parallels many features of childhood asthma (Gern and Busse 2002; Sigurs et al. 2000). A number of long-term prospective studies of children admitted to hospital with documented RSV have shown that approximately 40 percent of these infants will continue to wheeze or have asthma in later childhood (Sigurs et al. 2000). Symptomatic rhinovirus infections in early life also are emerging as risk factors for recurrent wheezing. On the other hand, evidence also indicates that certain respiratory infections early in life—including measles and even RSV (Stein et al. 1999) or repeated viral infections (other than lower respiratory tract infections) (Illi et al. 2001; Shaheen et al. 1996)—can protect against the development of asthma. The "hygiene hypothesis" of asthma suggests that exposure to infections early in life influences the development of a child's immune system along a "nonallergic" pathway, leading to a reduced risk of asthma and other allergic diseases. Although the hygiene hypothesis continues to be investigated, this association may explain observed associations between large family size, later birth order, daycare attendance, and a reduced risk of asthma (Eder et al. 2006; Illi et al. 2001).

The influence of viral respiratory infections on the development of asthma may depend on an interaction with atopy. The atopic state can influence the lower airway response to viral infections, and viral infections may then influence the development of allergic sensitization. The airway interactions that may occur when individuals are exposed simultaneously to both allergens and viruses are of interest but are not defined at present.

Other environmental exposures

Tobacco smoke, air pollution, occupations, and diet have also been associated with an increased risk for the onset of asthma, although the association has not been as clearly established as with allergens and respiratory infections (Malo et al. 2004; Strachan and Cook 1998a; Strachan and Cook 1998b).

In utero exposure to environmental tobacco smoke increases the likelihood for wheezing in the infant, although the subsequent development of asthma has not been well defined. In adults who have asthma, cigarette smoking has been associated with an increase in asthma severity and decreased responsiveness to inhaled corticosteroids (ICSs) (Dezateux et al. 1999).

The role of air pollution in the development of asthma remains controversial and may be related to allergic sensitization (American Thoracic Society 2000). One recent epidemiologic study showed that heavy exercise (three or more team sports) outdoors in communities with high concentration of ozone was associated with a higher risk of asthma among school-age children (McConnell et al. 2002). The relationship between increased levels of pollution and increases in asthma exacerbations and emergency care visits has been well documented.

An association of low intake of antioxidants and omega-3 fatty acids has been noted in observational studies, but a direct link as a causative factor has not been established.

Increasing rates of obesity have paralleled increasing rates in asthma prevalence, but the interrelation is uncertain (Ford 2005). Obesity may be a risk factor for asthma due to the generation of unique inflammatory mediators that lead to airway dysfunction.

In summary, our understanding of asthma pathogenesis and underlying mechanisms now includes the concept that gene-by-environmental interactions are critical factors in the development of airway inflammation and eventual alteration in the pulmonary physiology that is characteristic of clinical asthma.

Natural History of Asthma

If the persistence and severity of asthma involves a progression of airway inflammation to airway remodeling and some eventual irreversible airway obstruction, then an important question is whether anti-inflammatory medication (i.e., ICSs), given early in the course of disease might interrupt this process and prevent permanent declines in lung function. For early initiation of ICSs to be more beneficial than delayed initiation, two assumptions must be valid: (1) as a group, people who have mild or moderate persistent asthma experience a progressive decline in lung function that is measurable and clinically significant, and (2) treatment with ICSs prevents or slows this decline, in addition to providing long-term control of asthma. Reviews were conducted in 2002 (EPR—Update 2002) and for the current report to evaluate the literature on the effect of intervention with ICSs in altering the progression of disease.

Implications of Current Information about Pathophysiology and Pathogenesis, and Natural History for Asthma Management

Airway inflammation is a major factor in the pathogenesis and pathophysiology of asthma. The importance of inflammation to central features of asthma continues to expand and underscore this characteristic as a primary target of treatment. It has also become apparent, however, that airway inflammation is variable in many aspects including intensity, cellular/mediator pattern, and response to therapy. As knowledge of the various phenotypes of inflammation become apparent, it is likely that treatment also will also have greater specificity and, presumably, effectiveness.

It is also apparent that asthma, and its persistence, begin early in life. Although the factors that determine persistent versus intermittent asthma have yet to be ascertained, this information will become important in determining the type of treatment, its duration, and its effect on various outcomes of asthma. Early studies have indicated that although current treatment is effective in controlling symptoms, reducing airflow limitations, and preventing exacerbations, present treatment does not appear to prevent the underlying severity of asthma.

Despite these unknowns, the current understanding of basic mechanisms in asthma has greatly improved appreciation of the role of treatment. The Expert Panel's recommendations for asthma treatment, which are directed by knowledge of basic mechanisms, should result in improved control of asthma and a greater understanding of therapeutic effectiveness.

References

1. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med. 1994;88(5):373–81. [PubMed: 8036306]
2. Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, Kronenberg M, DeKruyff RH, Umetsu DT. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med. 2006;354(11):1117–29. [PubMed: 16540612]
3. American Thoracic Society. What constitutes an adverse health effect of air pollution? Official statement of the American Thoracic Society. Am J Respir Crit Care Med. 2000;161(2 Pt 1):665–73. [PubMed: 10673213]
4. Barnes PJ. Cytokine modulators as novel therapies for asthma. Annu Rev Pharmacol Toxicol. 2002;42:81–98. [PubMed: 11807165]
5. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE. GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836–44. [PubMed: 15256389]
6. Boyce JA. Mast cells: beyond IgE. J Allergy Clin Immunol. 2003;111(1):24–32. quiz 33. Review. [PubMed: 12532090]
7. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002;346(22):1699–1705. [PubMed: 12037149]
8. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A, Gupta N. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108(2):184–90. [PubMed: 11496232]
9. Busse WW. The role of leukotrienes in asthma and allergic rhinitis. Clin Exp Allergy. 1996;26(8):868–79. Review. [PubMed: 9011329]
10. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;344(5):350–62. [PubMed: 11172168]
11. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403–06. [PubMed: 11029352]
12. Childhood Asthma Management Program Research Group (CAMP). Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343(15):1054–63. [PubMed: 11027739]
13. Chu HW, Martin RJ. Are eosinophils still important in asthma? Clin Exp Allergy. 2001;31(4):525–28. [PubMed: 11359418]
14. Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol. 2004;22:789–815. Review. [PubMed: 15032597]
15. Covar RA, Spahn JD, Murphy JR, Szefler SJ. Childhood Asthma Management Program Research Group. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004;170(3):234–41. Epub March 2004. [PubMed: 15028558]
16. Deykin A, Massaro AF, Drazen JM, Israel E. Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med. 2002;165(12):1597–1601. [PubMed: 12070059]
17. Dezateux C, Stocks J, Dundas I, Fletcher ME. Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma. Am J Respir Crit Care Med. 1999;159(2):403–10. [PubMed: 9927350]
18. Dijkstra A, Vonk JM, Jongepier H, Koppelman GH, Schouten JP, ten Hacken NH, Timens W, Postma DS. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax. 2006;61(2):105–10. Epub November 2005. [PMC free article: PMC2104585] [PubMed: 16308336]
19. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355(21):2226–2235. Review. [PubMed: 17124020]
20. EPR. "Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma (EPR 1991)". NIH Publication No. 91-3642. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program, 1991.
21. EPR—2. "Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR—2 1997)". NIH Publication No. 97-4051. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program, 1997.
22. EPR—Update 2002. "Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. Update on Selected Topics 2002 (EPR—Update 2002)". NIH Publication No. 02-5074. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program, June 2003.
23. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol. 1995;95(4):843–52. [PubMed: 7722165]
24. Finucane KE, Greville HW, Brown PJ. Irreversible airflow obstruction. Evolution in asthma. Med J Aust. 1985;142(11):602–4. [PubMed: 4000023]
25. Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol. 2005;115(5):897–909. quiz 910. Review. [PubMed: 15867841]
26. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as "tunable" effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005;23:749–86. Review. [PubMed: 15771585]
27. Gelfand EW, Dakhama A. CD8+ T lymphocytes and leukotriene B4: novel interactions in the persistence and progression of asthma. J Allergy Clin Immunol. 2006;117(3):577–82. [PubMed: 16522456]
28. Gern JE, Busse WW. Relationship of viral infections to wheezing illnesses and asthma. Nat Rev Immunol. 2002;2(2):132–8. Review. [PMC free article: PMC7096896] [PubMed: 11910895]
29. Gern JE, Lemanske RF Jr, Busse WW. Early life origins of asthma. J Clin Invest. 1999;104(7):837–43. Review. [PMC free article: PMC408565] [PubMed: 10510321]
30. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21. [PubMed: 12480423]
31. Griffith KA, Sherrill DL, Siegel EM, Manolio TA, Bonekat HW, Enright PL. Predictors of loss of lung function in the elderly: the Cardiovascular Health Study. Am J Respir Crit Care Med. 2001;163(1):61–68. [PubMed: 11208627]
32. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF Jr,, Strunk RC, Allen DB. et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–97. [PubMed: 16687711]
33. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459–65. Review. [PubMed: 15753888]
34. Holgate ST. Genetic and environmental interaction in allergy and asthma. J Allergy Clin Immunol. 1999;104(6):1139–46. Review. [PMC free article: PMC7172426] [PubMed: 10588993]
35. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006;368(9537):780–93. Review. [PubMed: 16935689]
36. Horwood LJ, Fergusson DM, Shannon FT. Social and familial factors in the development of early childhood asthma. Pediatrics. 1985;75(5):859–68. [PubMed: 3991272]
37. Huss K, Adkinson NF Jr,, Eggleston PA, Dawson C, Van Natta ML, Hamilton RG. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol. 2001;107(1):48–54. [PubMed: 11149990]
38. Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, Sommerfeld C, Wahn U. MAS Group. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001;322(7283):390–5. [PMC free article: PMC26566] [PubMed: 11179155]
39. James AL, Palmer LJ, Kicic E, Maxwell PS, Lagan SE, Ryan GF, Musk AW. Am J Respir Crit Care Med. 2005. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking;171(2):109–14. Epub 2004. [PubMed: 15486340]
40. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1532–9. [PubMed: 10556116]
41. Kuipers H, Lambrecht BN. Curr Opin Immunol. 2004. The interplay of dendritic cells, Th2 cells and regulatory T cells in asthma;16(6):702–8. Review. [PubMed: 15511661]
42. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194–200. [PubMed: 9780339]
43. Lange P, Scharling H, Ulrik CS, Vestbo J. Inhaled corticosteroids and decline of lung function in community residents with asthma. Thorax. 2006;61(2):100–4. [PMC free article: PMC2104582] [PubMed: 16443705]
44. Larche M, Robinson DS, Kay AB. J Allergy Clin Immunol. 2003. The role of T lymphocytes in the pathogenesis of asthma. ;111(3):450–63. quiz 464. Review. [PubMed: 12642820]
45. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356(9248):2144–8. [PubMed: 11191542]
46. Leff AR. Annu Rev Med. 2001. Regulation of leukotrienes in the management of asthma: biology and clinical therapy;52:1–14. Review. [PubMed: 11160764]
47. Malo JL, Lemiere C, Gautrin D, Labrecque M. Curr Opin Pulm Med. 2004. Occupational asthma;10(1):57–61. Review. [PubMed: 14749607]
48. Martinez FD. Inhaled corticosteroids and asthma prevention. Lancet. 2006;368(9537):708–710. [PubMed: 16935667]
49. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3):133–8. [PubMed: 7800004]
50. McConnell R, Berhane K, Gilliland F, London SJ, Islam T, Gauderman WJ, Avol E, Margolis HG, Peters JM. Asthma in exercising children exposed to ozone: a cohort study. Lancet. 2002;359(9304):386–91. [PubMed: 11844508]
51. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, Taussig LM, Wright AL, Martinez FD. Am J Respir Crit Care Med. 2005. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence;172(10):1253–8. Epub August 2005. [PMC free article: PMC2718414] [PubMed: 16109980]
52. Ober C. Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol. 2005;116(2):274–8. [PubMed: 16083779]
53. O'Byrne PM, Parameswaran K. Lancet. 2006. Pharmacological management of mild or moderate persistent asthma;368(9537):794–803. Review. [PubMed: 16935690]
54. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, Lamm CJ, O'Byrne PM. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–6. [PubMed: 12672309]
55. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis. 1987;70(3):171–9. [PubMed: 3569449]
56. Peters-Golden M. Am J Respir Cell Mol Biol. 2004. The alveolar macrophage: the forgotten cell in asthma;31(1):3–7. Review. [PubMed: 15208096]
57. Polito AJ, Proud D. J Allergy Clin Immunol. 1998. Epithelia cells as regulators of airway inflammation;102(5):714–8. Review. [PubMed: 9867498]
58. Robinson DS. J Allergy Clin Immunol. 2004. The role of the mast cell in asthma: induction of airway hyperresponsiveness by interaction with smooth muscle?;114(1):58–65. Review. [PubMed: 15241345]
59. Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D. et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med. 1997;336(19):1356–63. [PubMed: 9134876]
60. Sampson AP. Clin Exp Allergy. 2000. The role of eosinophils and neutrophils in inflammation;30(Suppl 1):22–7. Review. [PubMed: 10849470]
61. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349(15):1414–22. [PubMed: 14534334]
62. Selroos O, Lofroos AB, Pietinalho A, Riska H. Asthma control and steroid doses 5 years after early or delayed introduction of inhaled corticosteroids in asthma: a real-life study. Respir Med. 2004;98(3):254–62. [PubMed: 15002762]
63. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell AW, Goudiaby A. Measles and atopy in Guinea-Bissau. Lancet. 1996;347(9018):1792–6. [PubMed: 8667923]
64. Sherrill D, Guerra S, Bobadilla A, Barbee R. The role of concomitant respiratory diseases on the rate of decline in FEV₁ among adult asthmatics. Eur Respir J. 2003;21(1):95–100. [PubMed: 12570115]
65. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000;161(5):1501–7. [PubMed: 10806145]
66. Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med. 1990;323(8):502–7. [PubMed: 2377175]
67. Sporik R, Ingram JM, Price W, Sussman JH, Honsinger RW, Platts-Mills TA. Association of asthma with serum IgE and skin test reactivity to allergens among children living at high altitude. Tickling the dragon's breath. Am J Respir Crit Care Med. 1995;151(5):1388–92. [PubMed: 7735590]
68. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, Wright AL, Martinez FD. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354(9178):541–5. [PubMed: 10470697]
69. Stevenson DD, Szczeklik A. J Allergy Clin Immunol. 2006. Clinical and pathologic perspectives on aspirin sensitivity and asthma;118(4):773–86. quiz 787–8. Epub September 2006. Review. [PubMed: 17030227]
70. Strachan DP, Cook DG. Health effects of passive smoking. 5. Parental smoking and allergic sensitisation in children. Thorax 1998a;53(2):117–23. Review. Erratum in: Thorax. 1999;54(4):366. [PMC free article: PMC1758719] [PubMed: 9624297]
71. Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental smoking and childhood asthma: longitudinal and case-control studies. Thorax. 1998b;53(3):204–12. [PMC free article: PMC1745164] [PubMed: 9659358]
72. Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G, Hodgdon K, Morgan W, Sorkness CA, Lemanske RF Jr. J Allergy Clin Immunol. 2003. Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood Institute. Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children;112(5):883–92. [PubMed: 14610474]
73. Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ. for the CAMP Research Group. J Allergy Clin Immunol. 2006. Mild to moderate asthma affects lung growth in children and adolescents;118(5):1040–7. [PubMed: 17088127]
74. Wahn U, Lau S, Bergmann R, Kulig M, Forster J, Bergmann K, Bauer CP, Guggenmoos-Holzmann I. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol. 1997;99(6 Pt 1):763–9. [PubMed: 9215243]
75. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368(9537):804–13. [PubMed: 16935691]
76. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med. 1997;156(3 Pt 1):737–43. [PubMed: 9309987]
77. Williams TJ. The eosinophil enigma. J Clin Invest. 2004;113(4):507–9. [PMC free article: PMC338272] [PubMed: 14966558]
78. Xuan W, Peat JK, Toelle BG, Marks GB, Berry G, Woolcock AJ. Lung function growth and its relation to airway hyperresponsiveness and recent wheeze. Results from a longitudinal population study. Am J Respir Crit Care Med. 2000;161(6):1820–4. [PubMed: 10852751]
79. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol. 1999;103(3 Pt 1):376–87. [PubMed: 10069869]
80. Zimmermann N, Hershey GK, Foster PS, Rothenberg ME. Chemokines in asthma: cooperative interaction between chemokines and IL-13. J Allergy Clin Immunol. 2003;111(2):227–42. [PubMed: 12589338]