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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.

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 (). The interaction of these features of asthma determines the clinical manifestations and severity of asthma () and the response to treatment. 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 (; ). 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 ().

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 (; ). 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 (). 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 ().

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 (). Although research since the first NAEPP guidelines in 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 (; ).

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.

▪ 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 (). 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 (). 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 (). 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 (); 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 (). 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 (). 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.

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.

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 (). 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 (). 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 (; ). 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 (; ).

Activation of mucosal mast cells releases bronchoconstrictor mediators (histamine, cysteinyl-leukotrienes, prostaglandin D 2 ) (; ; ). 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 (). 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.

Increased numbers of eosinophils exist in the airways of most, but not all, persons who have asthma (; ; ). 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 (). 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 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 (). The regulation of neutrophil recruitment, activation, and alteration in lung function is still under study, but leukotriene B 4 may contribute to these processes (; ; ).

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 ().

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 ().

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.

Airway epithelium is another airway lining cell critically involved in asthma (). 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.

Chemokines are important in recruitment of inflammatory cells into the airways and are mainly expressed in airway epithelial cells (). 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 (; ). Recent studies have also shown leukotriene B 4 can contribute to the inflammatory process by recruitment of neutrophils (). Nitric oxide (NO) is produced predominantly from the action of inducible NO synthase in airway epithelial cells; it is a potent vasodilator (; ). 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 ().

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 (; ). 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 (; ). These clinical observations further support the importance of IgE to asthma.

Recent scientific investigations have focused on translating the increased understanding of the inflammatory processes in asthma into therapies targeted at interrupting these processes (). 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.

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 ().

There is considerable interest in the role of innate and adaptive immune responses associated with both the development and regulation of inflammation (). 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 (). 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 (; ; ; ; ). 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.

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.

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 (; ). 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.

In early life, the prevalence of asthma is higher in boys. At puberty, however, the sex ratio shifts, and asthma appears predominantly in women (). 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.

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.

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 (; ; ). 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 (). In addition, allergen exposure can promote the persistence of airway inflammation and likelihood of an exacerbation.

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 (; ). 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 (). 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 () or repeated viral infections (other than lower respiratory tract infections) (; )—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 (; ).