Asthma is a major public health issue. It affects nearly 5% of the United States population and is the reason for approximately two million emergency department visits, 470,000 hospitalizations, and 4,500 deaths annually.1 Mortality has declined over the past 10 years, but rates remain 2.5 to 3 times higher in blacks than in whites.2 Some evidence indicates that the quality of life of patients with asthma has improved with the development of new medications; however, inappropriate use of medications in the treatment of this disease is widespread. To address these issues, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and the World Health Organization (WHO) generated several expert panel reports on the diagnosis and treatment of asthma, including the National Asthma Education Prevention Program (NAEPP).1 This topic reviews the current understanding of asthma pathogenesis, diagnosis, and treatment.
Pathogenesis
Asthma has been defined as a chronic inflammatory disorder of the airways that is associated with recruitment of inflammatory cells and the clinical development of wheezing, shortness of breath, chest tightness, and cough. There is widespread but variable airflow obstruction that is often reversible, either spontaneously or as a result of treatment. In addition, asthmatic patients exhibit airway hyperreactivity that can be assessed by measuring the increased bronchoconstrictor response to inhaled agents such as histamine or methacholine. It has been proposed that airway hyperreactivity, as well as the clinical signs and symptoms of asthma, is driven by persistent airway inflammation.
Allergic response
The precise basis for the development of airway inflammation in patients with asthma is not fully defined. One traditional scheme postulates the development of an allergic response in the airways. In this case, the inflammatory cascade may begin when an antigen is inhaled into the airway and is taken up and processed by an antigen-presenting cell, usually a dendritic cell. The dendritic cell then migrates from the airway mucosa to the regional lymph nodes. Upon arrival at the lymph node, the dendritic cell, which has matured along the journey, presents the processed antigenic peptides to T cells. Rare antigen-specific T cells sample the peptides being presented in the lymph node; when an antigen-specific T cell finds a dendritic cell that presents the peptides for which the T cell is specific, it begins to proliferate [see Figure 1]. Simultaneously, the dendritic cell, through various signals, attempts to skew the cytokine profile of the developing T cells to cause them to become T helper type 1 (Th1) cells (which primarily produce interferon gamma [IFN-y]) and interleukin 12 [IL-12]) or Th2 cells (which produce IL-4, IL-5, and IL-13). These cytokine profiles may be found in both CD4+ and CD8+ T cells; both types of T cells have been implicated in causing asthma.
The allergic response in general and the asthmatic allergic response in particular depend on a Th2 response to an antigen.3 Th2 cells produce IL-4, which causes B cells to switch from usual production of IgM or IgG antibody to production of IgE antibody. Once produced, IgE antibodies bind to the surface of mast cells and basophils, where subsequent antigen cross-linking causes the generation and release of mediators that drive the asthma phenotype.
In an experimental model of the allergic response to inhaled antigen, Th2 cells alone were not sufficient to cause the asthma phenotype, because Th2 cell recruitment to the allergic site depends on help from Th1 cells.4 Th1 cells are more readily recruited to the airway tissue and are responsible for tumor necrosis factor (TNF)-dependent expression of vascular cell adhesion molecules; the presence of Th1 cells in the airway tissue in turn allows Th2 cells to enter the tissue. The Th1 cells do not need to be of the same antigenic specificity as the Th2 cells.5 This finding may help explain why inflammatory stimuli, such as respiratory viral infections, may facilitate the allergic response and contribute to flares of allergic asthma.
Allergen itself may also be sufficient to produce airway inflammation. When a sensitized individual is reexposed to allergen, the subsequent cross-linking of IgE on the surface of the mast cells and basophils can lead to the release of immediate-phase reactants such as histamine and TNF. Within 4 to 6 hours after exposure, the activated immune cells produce chemokines and cytokines, proteinases, enzymes, and lipid mediators such as the cysteinyl leukotrienes. Chemokines recruit and help activate additional Th2 cells and eosinophils in the airway. Pro-teinases and other enzymes may lead to airway damage, which promotes collagen deposition in the subepithelial basement membrane region. Cysteinyl leukotrienes can cause airway smooth muscle constriction and mucous cell secretion that further obstruct the airway lumen.
Leukotrienes in concert with chemokines (e.g., eotaxin) and cytokines (e.g., IL-5) may also recruit and activate eosinophils in the airway. Eosinophils are granulocytes that have a very short life span in the periphery and do not appear in large amounts in the circulation. These cells are produced in the bone marrow under the influence of Th2 cell production of IL-5. Newly produced eosinophils are released into the circulation and home in on the lung tissue, guided by a similar set of cell adhesion molecules that direct Th2 cell traffic. Upon entry into airway tissue, eosinophils and Th2 cells secrete their products, which, in addition to the mast cell/basophil products, are thought to lead to mucous cell metaplasia and smooth muscle hyperplasia. These changes in cellular behavior are the basis for the hypersecretion and hyperresponsiveness that is characteristic of the asthma phenotype. The Th2 cytokines IL-9 and IL-13 are especially effective in driving differentiation of mucous cells. Eosinophil granule constituents such as myelin basic protein, eosinophilic cationic protein, and eosinophil-derived neurotoxin may also contribute to airway inflammation, damage, and remodeling, although recent findings in mouse models and human subjects suggest that the contribution of the eosinophil may not be necessary for the asthma phenotype, at least under some conditions.6-9 Recently, an additional type of T cell, the regulatory T cell (Tr), was identified. Tr cells produce IL-10 and transforming growth factor-| (TGF-|), which may downregulate the immune response. Studies in experimental models suggest that an inhibition of the Tr function may also drive the asthma phenotype,10 but whether this phenomenon occurs in humans still needs to be determined.
Figure 1 Pathogenesis of allergic asthma. Inhaled antigen is processed by dendritic cells and presented to Th2 CD4+ T cells. B cells are stimulated to produce IgE, which binds to mast cells. Inhaled antigen binds to IgE, stimulating the mast cell to degranulate, which in turn leads to the release of mediators of the immediate response and the late response. Histamine and the leukotrienes produce bronchospasm and airway edema. Released chemotactic factors, along with factors from the Th2 CD4+ T cells, facilitate eosinophil traffic from the bone marrow to the airway walls. These late responses are proposed to lead to excessive mucus production, airway wall inflammation, injury, and hyperresponsiveness. (GM-CSF—granulocyte-macrophage colony-stimulating factor; IFN-y—interferon gamma; IL—interleukin)
Genetic influence
Family and twin studies have clearly shown that asthma is a heritable disease; however, it has proved difficult to identify specific linkage to individual genes. This difficulty likely rests on the fact that asthma is a complex genetic disorder in which multiple genes contribute to the development of the disease. In addition, asthma is a multifactorial disease in which a variety of environmental factors can influence the development of the disease phenotype. Nonetheless, several candidate genes have been linked to the development of asthma, at least in some populations. Genome-wide screens have shown associations between asthma and regions on chromosomes 2p, 4q, 5q23-31, 6p24-21,11q13-21, 12q21-24, 13q12-14, 16q21-23, and 19q.n These chromosomal regions encode genes involved in antigen presentation and activation of T cells (i.e., CTLA-4 HLA) and cytokines such as IFN-a, IL-4, IL-5, IL-9, and IL-13, as well as components of the IgE receptor (i.e., FcsRIp) and the beta agonist receptor.
Through use of a candidate-gene approach, IL-13 and associated proteins (i.e., the a chains of the IL-13 and IL-4 receptors and STAT-6) were also found to exhibit linkage to asthma.12-14 Other investigators have identified novel genes that are associated with asthma. ADAM33 encodes a metalloproteinase found in airway smooth muscle and fibroblasts and is presumably involved in airway remodeling.15 The B isoform of GPRA, a G protein-coupled receptor, is found in airway smooth muscle cells of asthmatic patients but not in those of nonasthmatic persons.16 Two additional genes associated with asthma are the dipeptidyl peptidase family member DPP10 and PHF11, which is a member of the family of proteins containing zinc fingers.17,18 The function of these gene products is unknown. Future studies are likely to provide additional insight into the genetic basis of asthma.
Viral influence
The cascade of events that surround the generation and activation of allergen-specific Th2 cells is best demonstrated in persons with allergy. However, many patients with allergy do not develop asthma, and some asthma patients have no demonstrable allergic component. Other than the generation of Th1 cells early in the allergic response, the Th2 hypothesis for asthma does not offer a useful explanation for how certain viral infections may not only exacerbate but initiate the development of asthma. Severe viral infections of the epithelium appear to generate a cascade of events that ultimately leads to the development of both an acute and a chronic asthma phenotype [see Figure 2]. Moreover, nearly 25% of children who develop a severe respiratory disease from infection with respiratory syncytial virus (RSV) before 3 years of age will subsequently develop asthma, whereas fewer than 5% of those who develop milder disease from RSV infection will manifest any long-term effects.19 The basis of the response to RSV infection and the relationship of this response to the development of asthma still need to be defined.
One line of research has focused on the behavior of viral host cells (especially airway epithelial cells).20 The findings have led to the proposal of an alternative paradigm for asthma pathogenesis that incorporates observed abnormalities in innate immune behavior of airway epithelial cells, viral capacity to initiate and sustain the asthma phenotype, and allergic predisposition of many asthma patients (the so-called Epi-Vir-All paradigm).21 The contribution of each of these abnormalities to asthma pathogenesis likely varies in different types of asthmatic patients and at different times in the same patients. Moreover, some of the same abnormalities in innate and adaptive airway immunity may also underlie the pathogenesis of other chronic inflammatory airway diseases (e.g., chronic bronchitis) that manifest similar disease traits (e.g., airway hyperreactivity and mucous cell metaplasia). A challenge of current asthma research is to more precisely define these abnormalities and to develop biomarkers that can be used clinically for more accurate diagnosis and treatment of this condition.
Diagnosis
Clinical manifestations
The classic symptoms of asthma are wheezing, cough, and shortness of breath. Because of the intermittent nature of asthma symptoms, patients may be entirely asymptomatic between attacks. However, studies suggest that even with essentially normal lung function and an absence of symptoms, patients may still have persistent airway inflammation that requires ongoing therapy.
Figure 2 Pathogenesis of viral-induced asthma. Inhaled virus infects epithelial cells and leads to apoptosis of some of them. The release of chemotactic factors promotes the recruitment of macrophages into the lung parenchyma, where they ingest the dead epithelium. An acute response consisting of bronchospasm occurs at this time. Similar to allergic asthma, the inhaled virus is processed by dendritic cells and presented to Th2 CD8+ T cells. These cells produce copious amounts of IFN-y. Perforin released from the T cells leads to apoptosis of infected cells. B cells produce IgG, which is capable of neutralizing the virus. These events are thought to be related to the chronic response, which consists of airway inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. (IFN-Y—interferon gamma; IL—interleukin; CCL—chemokine ligand)
Wheezing
Wheezing is the most common finding during acute airway obstruction, and the chest may be hyperresonant on percussion. As airflow obstruction becomes severe, a number of physical signs may become manifest and may offer clues to the severity of the attack. Tachypnea and tachycardia are common. A fall in systolic blood pressure of more than 10 to 12 mm Hg during inspiration (paradoxical pulse) is found in approximately one half of patients whose forced expiratory volume in one second (FEV1) is 1 L or less during acute exacerbations. Accessory muscle usage and paradoxical pulse with decreasing intensity of breath sounds also signify severe airway obstruction. The cessation of wheezing in the absence of therapy is an especially ominous sign that may reflect a marked decrease in airflow. Bron-choconstriction can be triggered by a variety of stimuli that have little or no impact on the airways of nonasthmatic persons; these responses can be helpful diagnostically. The stimulus need not be a specific allergen or chemical in the workplace; a nonspecific (i.e., nonantigenic) stimulus, such as strenuous exercise, especially while breathing dry air, may trigger the response.
Cough
The cough of patients with asthma can be nonproductive or can raise copious amounts of sputum. In the absence of infection, sputum is typically mucoid and often tenacious. Eosino-phils and their constituents may cause a yellow discoloration of sputum, even when infection is absent. Cough is occasionally the only manifestation of asthma; the term cough-varient asthma has sometimes been used to designate such cases.
Dyspnea
The level of dyspnea tends to vary greatly in individual patients over time, reflecting wide variations in the severity of airflow obstruction. At times, airflow obstruction prevents any significant physical exertion; at other times, strenuous exercise is possible but may trigger wheezing and shortness of breath [see Exercise-Induced Asthma, below]. During a severe attack, a desperate hunger for air is the overwhelming symptom. Chest tightness commonly occurs with dyspnea and may be confused with angina pectoris. Most patients associate their chest tightness with the sensation of being unable to take in a full and satisfying breath. Older patients are often less aware of airflow obstruction and may therefore require closer monitoring.
Stimuli that trigger attacks
The stimuli that trigger asthmatic attacks vary among individual patients. For some patients, attacks of asthma are triggered by allergens such as ragweed or animal dander, house dust containing antigens from dust mites and cockroaches, strong odors or fumes, or ingested substances such as certain foods, sulfite agents, aspirin, and tartrazine [see Specific Forms and Complications of Asthma, below]. Emotional stress may trigger symptoms in some patients, but the precise role of the central nervous system in regulating airway function is difficult to quantitate. Reflux of gastric acid into the lower esophagus may exacerbate asthmatic symptoms, presumably through vagally mediated parasympathetic nervous reflexes,23 but the role of gastroesophageal reflux in asthma remains controversial.24 Persistent posterior drainage of nasal mucus may also be an aggravating factor. Indirect evidence indicates that nasal and sinus disease increases airway responsiveness and thereby exacerbates asthma.25 Other stimuli are virtually universal precipitants of asthma symptoms. Such stimuli include strenuous exercise, particularly if it is performed in cold, dry air; respiratory infections, usually caused by community-acquired viruses; inhaled pollutants and irritants such as ozone, sulfur dioxide, and cigarette smoke; beta blockers, angiotensin-converting enzyme inhibitors, and, in some Asian patients, ingestion of ethanol.26 Specific antigen responsiveness may be more severe after exposure to environmental pollutants. Some women with asthma have been noted to have a significant increase in exacerbations during the preovulatory and perimenstrual periods.27 The exact hormonal contributions to asthma flares in these patients are not known; however, increases in progesterone levels have been implicated on the basis of temporal association.
Figure 3 The change in expiratory flow, as measured by forced expiratory volume in 1 second (FEVj), after administration of a given concentration of bronchoprovocative agonist is shown for a general population. A large decrease in expiratory flow implies a greater bronchial reactivity. Bronchial reactivity is normally distributed, with a skew toward increased reactivity. The figure indicates that asthmatic persons exhibit varying degrees of bronchial hyperreactivity and that some persons with increased bronchial responsiveness do not manifest clinical signs of asthma.
Asthma that is triggered by identifiable inhaled antigens (aeroallergens) is often associated with manifestations of atopic disease (i.e., seasonal allergic rhinitis or eczema). Exceptions to this association include cases of asthma caused by certain sensitizing antigens encountered in the workplace that may not elicit an IgE antibody response [see Occupational Asthma, below]. Laboratory tests can be used to support a diagnosis of atopic disease. These include increased levels of peripheral blood eosino-phils, total serum IgE levels, and specific IgE levels as determined by radioallergosorbent testing (RAST) directed at a particular antigen or by positive wheal-and-flare reactions to antigens pricked or injected into the skin.
Some experts make a distinction between asthma in which there are known allergic precipitants of bronchoconstriction (i.e., extrinsic asthma) and asthma in which there are no known preci-pants (i.e., intrinsic asthma). In asthma cases in which there is evidence of atopy, lung function may decline at a greater rate than in nonatopic cases.28 The distinction between extrinsic and intrinsic asthma has probably been overemphasized and may be misleading, because it implies a differentiation of etiology or pathogenesis that is not supported by current data. Categorization into extrinsic or intrinsic asthma groups is difficult: allergic precipitants may not be recognized, symptoms of other atopic diseases may create ambiguity, and laboratory test results may be inconclusive or falsely positive. As a result, it is probably best to avoid the use of the terms intrinsic and extrinsic asthma. Fortunately, the management of asthmatic patients is not dependent on this distinction.
Laboratory tests
No single laboratory test can establish a diagnosis of asthma, but a test for bronchodilator responsiveness can provide supportive evidence when asthma is suspected on clinical grounds. In patients with baseline airflow obstruction, a significant increase in expiratory airflow (e.g., > 12% increase in FEVj) after inhalation of a bronchodilator suggests asthma.29 Unfortunately, as a diagnostic test, bronchodilator responsiveness lacks both sensitivity and specificity. Negative results may be found in asthmatic patients who have near-normal baseline lung function, are tested shortly after self-administration of a bronchodilator, or have obstruction caused by increased mucus secretions. Significant bron-chodilator responses may also be observed in other types of chronic obstructive airway diseases, such as chronic bronchitis.
Because asthma is episodic, a diagnosis of asthma may be suspected on the basis of recurrent symptoms, even if there is normal pulmonary function. Measurement of airway reactivity may be a useful diagnostic test in this setting. In clinical practice, airway reactivity is defined by increased airway resistance or decreased maximal expiratory airflow (e.g., FEVj) after a challenge with an inhaled nonspecific stimulus, such as methacholine or histamine. In asthmatic patients, airflow obstruction occurs with nonspecific stimuli that do not alter the airway mechanics of patients without asthma. The degree of nonspecific reactivity is often expressed as the dose required to reduce the FEVj by 20% from the measured baseline. This variable, the PD20 FEVj, does not absolutely distinguish asthmatic patients from patients with other respiratory disorders (e.g., allergic rhinitis); however, as the degree of reactivity increases (with a decrease in the PD20 FEV1), the confidence that asthma is present increases.
Other, less frequently used stimuli for bronchoprovocation include cold air, exercise, eucapnic hyperventilation, and adenosine 5′-monophosphate. Although bronchoprovocation tests are very sensitive, they are not specific for asthma [see Figure 3]. An alternative approach for the diagnosis of asthma is to demonstrate lability of maximal airflow. This can be demonstrated by having the patient periodically monitor his or her condition with a self-operated peak flowmeter and by keeping a diary of the results or by using a device that electronically collects and stores the information. A diurnal variation in peak expiratory airflow (PEF) of 15% or more is highly suggestive of a diagnosis of asthma.30
In an adult with asthmatic symptoms of new onset, a chest radiograph is also warranted to exclude alternative diagnoses (e.g., pneumonia, congestive heart failure, and pulmonary fibrosis). In patients with asthma, the chest radiograph is usually normal; occasionally, subtle changes indicative of bronchial wall thickening are detected, and during an episode of severe airflow obstruction, radiographic signs of hyperinflation may be present. Chest radiographs of patients treated for asthma exacerbations reveal unsuspected pulmonary infiltrates, atelectasis, pneumothorax, or pneumomediastinum only 2% of the time; therefore, radiographs are not routinely indicated in patients with documented asthma who are experiencing a flare of disease.
