Asthma affects between 5% and 15% of the population in most countries where this has been evaluated. Asthma is a clinical syndrome characterized by variable airﬂow obstruction, increased responsiveness of the airway to constriction induced by nonspeciﬁc inhaled stimuli (airway hyperresponsiveness), and cellular inﬂammation. Asthmatic symptoms are characteristically epi- sodic and consist of dyspnea, wheezing, cough, and chest tightness caused by airﬂow obstruction because of airway smooth muscle constriction, airway wall edema, airway inﬂammation, and hypersecretion by mucous glands. A major feature of the airﬂow obstruction of asthma is that it is partially or fully reversible either spontaneously or as a result of treatment.
Clinical Forms of Bronchial Asthma
Asthma is a syndrome because, although the clinical presentation is often quite characteristic, its etiologic factors vary. Previous descriptors of asthma included the terms extrinsic asthma, implying that an external stimulus was responsible for causing the disease, and intrinsic asthma, in which no obvious external cause could be identiﬁed. It is now recognized that likely all asthma is initiated by some external stimulus, the most commonly identiﬁed of which are environmental allergens.
Allergic asthma most often affects children and young adults (Plate 4-14). A personal history of other allergic manifestations (atopy), such as allergic rhinitis, conjunctivitis, or eczema is common, as is a family history of atopy. Atopy is identiﬁed by positive dermal responses to environmental and occupational allergens and elevated serum immunoglobulin E (IgE) levels.
Nonallergic asthma is usually identiﬁed in patients who develop asthma symptoms as adults (see Plate 4-15). The symptoms may develop after a respiratory tract infection, and occasionally infective agents such as Chlamydia pneumoniae or Mycoplasma spp. are implicated. Occupational sensitizers are other important causes of nonallergic asthma, and a detailed occupational history is a critical component of the evaluation of the patient. Nonallergic asthma is also commonly associated with comorbidities such as chronic sinusitis, obesity, or gastroesophageal reﬂux.
Inducers and Inciters of Asthma
An important distinction needs to be made between stimuli that are inducers of asthma (cause the disease), such as environmental allergens and occupational sensitizers, and inciters of asthma, which are stimuli that cause exacerbations or transient symptoms (see Plate 4-16).
Respiratory Viral Infections
Viral infections are important inducers of asthma and have been associated with a number of important clinical consequences in people with asthma, including the development of wheezing-associated illnesses in infants and small children; the development of asthma in the ﬁrst decade of life; causing acute asthma exacerbations (particularly rhinovirus); and inducing changes in airway physiology, including increasing airway responsiveness.
Allergens are known to both induce asthma and be inciters of asthma symptoms. Indeed, some people with asthma only experience seasonal symptoms when they are exposed to allergens. Patients with allergen sensitivity can experience acute bronchoconstriction within 10 to 15 minutes after allergen inhalation, which usually resolves with 2 hours (the early asthmatic response); however, the bronchoconstriction can recur between 3 to 6 hours later (the late asthmatic response), which develops more slowly and is characterized by severe bronchoconstriction and dyspnea. The late response occurs because of progressively increasing inﬂux of inﬂammatory cells, particularly basophils and eosinophils, into the airways. The bronchoconstriction usually resolves within 24 hours, but patients are left with increased airway responsiveness, which may persist for more than 1 week.
Occupational Sensitizing Agents
Occupational asthma is a common cause of adult- onset asthma. More than 200 agents have been identiﬁed in the workplace, including allergens such as animal dander, wheat ﬂour, psyllium, and enzymes, which cause airway narrowing through IgE-mediated responses, and chemicals (often small molecular weight, e.g., toluene diisocyanate), which cause asthma through non–IgE-mediated mechanisms. Work-related exposures and inhalation accidents are a signiﬁcant risk for new-onset asthma. When occupational chemical sensitizers are inhaled by a sensitized subject in the laboratory, an early asthmatic response can often be elicited, similar to that induced by allergen. This can be followed by a late asthmatic response. The airway inﬂammatory responses caused by occupational sensitizers do not appear to differ substantially from other causes of asthma, such as environmental allergens.
Exercise is a very commonly experienced asthma inciter. Bronchoconstriction occurs after exercise, becoming maximal 10 to 20 minutes after the end of exertion, and generally resolves within 1 hour. Bronchoconstriction very rarely occurs during exercise. Bronchoconstriction is caused by the cooling and drying of the airways because the large volumes of air inhaled during exercise are conditioned to body temperature and are fully saturated. Similar symptoms can be experienced by people with asthma who inhale very cold, dry air. Exercise-induced bronchoconstriction can usually be prevented by pretreatment with inhaled β2-agonists 5 to 10 minutes before exercise.
A variety of atmospheric pollutants are asthma inciters. These include nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone, and inhaled particles smaller than 10 μm in diameter (PM10). Other environmental irritants that can incite asthma symptoms include strong smells, such as perfume, car exhaust fumes, and secondhand tobacco smoke.
A triad of aspirin sensitivity, asthma, and nasal polyposis (Samter triad) has been recognized in approximately 5% of individuals with asthma (although nasal polyposis is not invariably present in asthmatics with aspirin sensitivity). Symptoms of asthma develop within 20 minutes of ingestion of aspirin, which may be very severe and occasionally life threatening. This sensitivity exists to all drugs that are cyclo-oxygenase (COX-1) inhibitors and sometimes also to tartrazine. Acetaminophen and COX-2 inhibitors appear to be safe to use in most aspirin-sensitive individuals with asthma.
Symptoms and Clinical Findings
Symptoms and signs of asthma range from mild, discrete episodes of shortness of breath, wheezing, and cough, which are very intermittent, usually after exposure to an asthma trigger, followed by signiﬁcant remission, to continuous, chronic symptoms that wax and wane in severity. For any patient, symptoms may be mild, moderate, or severe at any given time, and even patients with mild, intermittent asthma can have severe life-threatening exacerbations. An asthmatic exacerbation can be a terrifying experience, especially for patients who are aware of its potentially progressive nature.
Symptoms of an asthmatic exacerbation most often develop gradually but occasionally can be sudden in onset. Most often asthma exacerbations are preceded by viral upper respiratory tract infections. Many patients complain of a sensation of retrosternal chest tightness. Expiratory and often inspiratory wheezing is audible and is associated with variable degrees of dyspnea. Cough is likely to be present and may be productive of purulent sputum.
In severe asthma exacerbations, the patient prefers to sit upright; visible nasal alar ﬂaring and use of the accessory respiratory muscles reﬂect the increased work of breathing. Anxiety and apprehension generally relate to the intensity of the exacerbation. Tachypnea may be the result of fear, airway obstruction, or changes in blood and tissue gas tensions or pH. Hypertension and tachy- cardia both reﬂect increased catecholamine output, although a pulse rate greater than 110 to 130 beats/min may indicate signiﬁcant hypoxemia (PaO2 <60 mm Hg) and the seriousness of the episode. Pulsus paradoxus (<10 mm Hg) accompanies pulmonary hyperinﬂation, occurring when the forced expiratory volume in 1 second (FEV1) is usually below 30% of predicted normal. If severe hypoxemia and hypercapnia with respiratory acidosis occur, the patient is usually cyanotic, fatigued, confused, and agitated. Chest examination reveals a hyperresonant percussion note, a low-lying diaphragm, and other evidence of hyperinﬂation. Expiration is prolonged. The patient has generalized inspiratory and expiratory wheezing. With low-grade obstruction, wheezing may be slight or even absent but may be accentuated by rapid, deep breathing. When airflow is severely reduced, the chest may become paradoxically silent. This ominous finding may be inadvertently induced or worsened by administration of hypnotics, tranquilizers, or sedatives, which depress respiration. At the point where airflow is so decreased that the chest becomes silent, cough becomes ineffective, and ventilatory failure supervenes. This requires immediate and intensive therapy.
DIAGNOSIS OF ASTHMA
Because asthma is a lifelong disease in most patients, it is important to make the correct diagnosis when symptoms first present. Unfortunately, this is sometimes not done, and patients are inappropriately treated. None of the symptoms of asthma are pathognomonic, and the adage “all that wheezes is not asthma” serves as a reminder that wheezing but also cough, chest tightness, and dyspnea are symptoms of other respiratory or cardiac diseases. The diagnosis of asthma must be made by the presence of the characteristic symptoms associated with the presence of variable airflow obstruction or airway hyperresponsiveness to inhaled bronchoconstrictor mediators.
Variable airﬂow obstruction is best measured using spirometry with a ﬂow-volume loop and demonstrating a reduced FEV1 and ratio of FEV1 to forced vital capacity (FVC), which improves after inhalation of β2-agonists (Plate 4-17). An improvement in FEV1 of more than 12%, with a minimal change of 200 mL, is usually accepted as documentation of reversible airﬂow obstruction. Some clinics may not have access to spirometry, so variability in peak expired ﬂow (PEF) measurements can also be used for both diagnosis and monitoring asthma. An improvement of more than 20% (or <60 L/min) after inhalation of a β2-agonist or diurnal variation in PEF of more than 20% over 2 weeks of measurements also conﬁrms variable airﬂow obstruction.
For patients with symptoms consistent with asthma but normal lung function, measurements of airway responsiveness to direct airway challenges (e.g., inhaled methacholine and histamine) or indirect airway challenges (e.g., inhaled mannitol or exercise challenge) may help establish a diagnosis of asthma (Plate 4-17). Measurements of airway responsiveness reflect the “sensitivity” of the airways to factors that can cause asthma symptoms, and the test results are usually expressed as the provocative concentration (or dose) of the agonist causing a given decrease in FEV1. These tests are sensitive for a diagnosis of asthma but have limited specificity. This means that a negative test result can be useful to exclude a diagnosis of persistent asthma in a patient who is not taking inhaled glucocorticosteroid treatment, but a positive test result does not always mean that a patient has asthma. This is because airway hyperresponsiveness has been described in patients with allergic rhinitis and in those with airflow limitation caused by conditions other than asthma, such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD).
The primary value of radiography is to exclude other diseases and to determine whether pneumonia, atelectasis, pneumothorax, pneumomediastinum, or bronchiectasis exists. In mild asthma, the chest radiograph shows no abnormalities. With severe obstruction, however, a characteristic reversible hyperlucency of the lung is evident, with widening of costal interspaces, depressed diaphragms, and increased retrosternal air. In contrast to pulmonary emphysema, in which vascular branching is attenuated and distorted, vascular caliber and distribution in asthma are generally undisturbed.
Focal atelectasis, a complication of asthma, is caused by impaction of mucus. In children, even complete collapse of a lobe may be observed. Atelectatic shadows may be transient as mucus impaction shifts from one lung zone to another. When sputum is mobilized, these patterns resolve.
Radiography is also useful in evaluating coexisting sinusitis. An upper gastrointestinal series may be indicated if gastroesophageal reﬂux is suspected. A lung ventilation-perfusion scan or computed tomography angiogram may be required if pulmonary emboli are believed to mimic asthma.
Spontaneously produced as well as induced sputum can be helpful in conﬁrming the diagnosis of asthma and in deciding treatment requirements (Plate 4-18). Spontaneously produced sputum may be mucoid, purulent, or a mixture of both. Importantly, purulent sputum does not always indicate the presence of a bacterial infection in asthmatic patients.
Thin spiral bronchiolar casts (Curschmann spirals) in sputum, measuring up to several centimeters in length, are strongly indicative of asthma. Ciliated columnar bronchial epithelial cells are frequently found. Creola bodies are clumps of such bronchial epithelial cells with moving cilia and are seen in severe asthma.
In asthma, both sputum eosinophils and neutrophils may be increased or the cellular inﬁltrate may be pre-dominantly eosinophilic or neutrophilic or occasionally paucigranulocytic. The importance of a sputum eosinophilia is that it indicates inadequate treatment with or poor adherence to inhaled corticosteroids (ICS). Acute exacerbations of asthma are usually associated with an increase in eosinophil or neutrophil cell numbers in sputum.
Skin Prick Tests
It is important to establish the presence of atopy in asthmatic subjects, particularly, whether environmental allergens are important triggers of asthma symptoms.
Preferably, skin tests are performed by a skin prick using aqueous extracts of common antigens, such as molds, pollens, fungi, house dusts, feathers, foods, or animal dander technique (Plate 4-19). If skin-sensitizing antibodies to the antigen are present, a wheal-and-ﬂare reaction develops within 15 to 30 minutes; a control test with saline diluent should show little or no reaction.
Optimally, both the history and dermal reactivity will give corresponding results. However, some patients have positive histories but negative skin test results. In other patients, negative histories and positive skin test results indicate immunologic reactivity that is clinically insigniﬁcant.
Blood tests are rarely of value in the diagnosis of asthma, but radioallergosorbent tests (RASTs) are used to identify the presence of allergy to speciﬁc allergens. Also, blood eosinophil counts may be increased in asthmatic patients, but they are neither sensitive nor speciﬁc for a diagnosis.
Exhaled Nitric Oxide
Elevated levels of exhaled nitric oxide (eNO) may indicate eosinophilic inﬂammation associated with asthma in the right clinical setting, but the clinical utility of this test is still uncertain.
Diseases to be considered in the differential evaluation are depicted in Plate 4-20. In children, diseases that may be misdiagnosed as asthma also include chronic rhinosinusitis, gastroesophageal reﬂux, cystic ﬁbrosis, bronchopulmonary dysplasia, congenital mal-formation causing narrowing of the intrathoracic airways, foreign body aspiration, primary ciliary dyskinesia syndrome, immune deﬁciency, and congenital heart disease. In adult patients, pulmonary disorders, other than those illustrated in Plate 4-20, include cystic ﬁbrosis, pneumoconiosis, and systemic vasculitis involving the lungs.
Physiologic Abnormalities in Asthma
Spirometry and Ventilatory Function in Asthma
In asthma, the prime physiologic disturbance is obstruction to airﬂow, which is more marked in expiration. This obstruction is variable in severity and in its site of involvement and is, by deﬁnition, reversible to some degree. Various combinations of smooth muscle constriction, inﬂammation, edema, and mucus hypersecretion produce this airﬂow impediment. In addition, low lung volumes with terminal airspace collapse may compound the airway obstruction. In the larger airways, the rigid cartilaginous rings help maintain patency. In the peripheral airways, however, there is little opposition to the smooth muscle action because of the paucity of cartilage. Instead, the patency of these airways is inﬂuenced by lung volume because they are imbedded in and partially supported by the lung parenchyma.
At the onset of an asthmatic attack, or in mild cases, obstruction is not extensive. As asthma progresses, airways resistance signiﬁcantly increases. Although inspiratory resistance also increases, the abnormality is more pronounced during expiration because of narrowing or closure of the airways as the lung empties. At this point, further expiratory effort does not produce any increase in expiratory ﬂow rate and may even intensify airway collapse.
Because of these mechanical resistances, the respiratory muscles must produce a greater degree of chest expansion. More important, the elastic recoil of the lungs is insufﬁcient for “passive” expiration. The respiratory muscles, therefore, must now play an active role in expiration. If obstruction is severe, air trapping will occur, with an increase in residual volume (RV) and functional residual capacity (FRC).
Airway obstruction is uneven and results in unequal distribution of gases to alveoli. This and other stimuli result in tachypnea and a consequently shortened respiratory cycle even though the bronchial obstruction requires a lengthened respiratory time for adequate ventilation. These conﬂicting demands cannot be reconciled while the asthmatic attack continues.
The severity of the obstruction is reﬂected in the spirometric measurements of expiratory volume and airﬂow. The FEV1, FVC, and inspiratory capacity (IC) are all reduced during an acute attack.
The peripheral airways have a proportionately large total cross-sectional area. For this reason, the resistance of the peripheral airways normally accounts for only 20% of the total airway resistance. Thus, extensive obstruction in these smaller airways may go undetected if the physician relies only on clinical ﬁndings. The reduction in FVC and FEV1 shows a good correlation with the decrease in PaO2, although carbon dioxide retention does not occur until the FEV1 is about 1 L or 25% of the level predicted.
With progressive obstruction, expiration becomes increasingly prolonged. Increases in RV and FRC occur (see Plate 4-39). These volume changes may represent an inherent physiologic response by the patient because breathing at higher lung volumes prevents the closure of terminal airways. The overall effect of these events is alveolar hyperinﬂation, which tends to further increase the diameter of the airways by exerting a greater lateral force on their walls. This hyperinﬂation may partially preserve gas exchange. It is disadvantageous because much more work is required, resulting in an increase in O2 consumption. Moreover, such a state compromises IC and vital capacity (VC). The symptoms of dyspnea and fatigue may also arise in part from this process. Finally, the effectiveness of cough is impaired because the velocity of respiratory airﬂow is seriously reduced.
As a result of the nonhomogeneous airway obstruction in asthma, the distribution of inspired air to the terminal respiratory units is not uniform throughout the lungs. Alveoli that are hypoventilated because they are supplied by obstructed airways are interspersed with normal or hyperventilated alveoli; hence, the severity of asthma is directly related to the ratio of poorly ventilated to well-ventilated alveolar groups. Arterial hypoxemia, which is the primary defect in gas exchange in asthma, is caused by this V· A Q· C nonhomogeneity (Plate 4-21). As the population of alveolar units with a low V· A Q· C ratio increases (because of advancing obstruction), the degree of arterial hypoxemia also intensiﬁes. The V· A Q· C disturbance is compounded if some airways are completely obstructed. The right-to-left intrapulmonary shunt effect results in arterial hypoxemia.
Carbon dioxide elimination is not impaired when the number of alveolar-capillary units with normal V· A Q· C ratios remains large relative to the number of those with low V· A Q· C ratios. As airway obstruction progresses, there are more and more hypoventilated alveoli. Simultaneously, appropriate increases in respiratory work, rate, and depth occur. Such a response initially minimizes the increase in physiologic dead space but eventually becomes limited, and alveolar ventilation ﬁnally fails to support the metabolic needs of the body. Carbon dioxide retention now occurs together with increasing hypoxemia. This is a state of ventilatory failure, and it monly arises when the FEV1 is less than 25% predicted.
PATHOGENESIS OF ASTHMA
Genetic and environmental factors interact in a complex manner to produce both asthma susceptibility and asthma expression. Several genes on chromosome 5q31-33 may be important in the development or progression of the inﬂammation associated with asthma and atopy, including the cytokines interleukin-3 (IL-3), IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, a number of other genes may play a role in the development of asthma or its pathogenesis, including the corticosteroid receptor and the β2-adrenergic receptor. Chromosome 5q32 contains the gene for the β2-adrenoceptor, which is highly polymorphic, and a number of variants of this gene have been discovered that alter receptor functioning and response to β-agonists.
Other chromosome regions linked to the development of allergy or asthma include chromosome 11q, which contains the gene for the β chain of the highafﬁnity IgE receptor (FcεRIβ). Chromosome 12 also contains several candidate genes, including interferon-γ (INF-γ), stem cell factor (SCF), IGF-1, and the constitutive form of nitric oxide synthase (cNOS). The ADAM 33 gene (a disintegrin and metalloproteinase 33) on chromosome 20p13 has been signiﬁcantly associated with asthma. ADAM proteins are membrane- anchored proteolytic enzymes. The restricted expression of ADAM 33 to mesenchymal cells and its close association with airways hyperresponsiveness (AHR) suggests it may be operating in airway smooth muscle or in events linked to airway remodeling.
Persistent airway inﬂammation is considered the characteristic feature of severe, mild, and even asymptomatic asthma. The characteristic features include inﬁltration of the airways by inﬂammatory cells, hypertrophy of the airway smooth muscle, and thickening of the lamina reticularis just below the basement membrane (see Plate 4-22).
An important feature of the airway inﬂammatory inﬁltrate in asthma is its multicellular nature, which is mainly composed of eosinophils but also includes neutrophils, lymphocytes, and other cells in varying degrees. Whereas neutrophils, eosinophils, and T lymphocytes are recruited from the circulation, mast cells are resident cells of the airways. Histologic evidence of mast cell degranulation and eosinophil vacuolation reveals that the inﬂammatory cells are activated. The mucosal mast cells are not increased but show signs of granule secretion in asthmatic patients. Postmortem studies have shown an apparent reduction in the number of mast cells in the asthmatic bronchi as well as in the lung parenchyma, which reﬂects mast cell degranulation rather than a true reduction in their numbers.
Eosinophils are considered to be the predominant and most characteristic cells in asthma, as observed from both bronchoalveolar lavage (BAL) and bronchial biopsy studies. The bronchial epithelium is inﬁltrated by eosinophils, which is evident in both large and small airways, with a greater intensity in the proximal airways in acute severe asthma. However, some studies report the virtual absence of eosinophils in severe or fatal asthma, suggesting some heterogeneity in this process. Alveolar macrophages are the most prevalent cells in the human lungs, both in normal subjects and in asthmatic patients and, when activated, secrete a wide array of mediators. Lymphocytes are critical for the development of asthma and are found in the airways of asthmatic subjects in relationship to disease severity. The function and contribution of lymphocytes in asthma are multifactorial and center on their ability to secrete cytokines. Activated T cells are a source of Th2 cytokines (e.g., IL-4, IL-13), which may induce the activated B cell to produce IgE and enhance expression of cellular adhesion molecules, in particular vascular cell adhesion molecule-1 (VCAM-1) and IL-5, which is essential for eosinophil development and survival in tissues.
Allergic asthma and other allergic diseases, such as allergic rhinitis and anaphylaxis, develop as a result of sensitization to environmental allergens and subsequent immunologically mediated responses when the allergens are encountered. These allergic reactions take place in speciﬁc target organs, such as the lungs, gastrointestinal tract, or skin. These immune processes leading to allergic reactions represent the disease state referred to clinically as “atopy.” The immune sequence consists of the sensitization phase followed by a challenge reaction, which produces the clinical syndrome concerned (see Plate 4-23).
Sensitization to an allergen occurs when the other- wise innocuous allergen is encountered for the ﬁrst time. Professional antigen-presenting cells (APCs) such as monocytes, macrophages, and immature dendritic cells capture the antigen and degrade it into short immunogenic peptides. Cleaved antigenic fragments are presented to naïve CD4+ T-helper (Th) cells on MHC class II molecules. Depending on a multitude of factors, particularly the cytokine microenvironment, these naïve T-helper cells are subsequently polarized into Th1 or Th2 lymphocytes. Th1 lymphocytes pre- dominantly secrete IL-2, INF-γ, and tumor necrosis factor (TNF)-β to induce a cellular immune response. In contrast, Th2 lymphocytes secrete IL-4, IL-5, IL-9, and IL-13 cytokines to induce a humoral immune response, particularly the B-cell class switch to allergen-speciﬁc immunoglobulin E (IgE) production. In allergic asthma, an imbalance exists between Th1 and Th2 lymphocytes, with a shift in immunity from a Th1 pattern toward a Th2 proﬁle. Accordingly, allergic asthma is often referred to a Th2-mediated disorder, with a persistent Th2-skewed immune response to inhaled allergens (Plate 4-23).
IgE is a γ-l-glycoprotein and is the least abundant antibody in serum, with a concentration of 150 ng/mL compared with 10 mg/mL for IgG in normal individuals. However, IgE concentrations in the circulation may reach more than 10 times the normal level in “atopic” individuals. IgE levels are also increased in patients with parasitic infestations and hyper-IgE-syndrome. Increased serum concentration is not necessarily a speciﬁc indicator of the extent or severity of allergy in the individual concerned. The IgE molecules attach to the surfaces of the mast cells or other cells such as basophils. The mast cells containing IgE are distributed in the mucosa of the upper and lower respiratory tract and perivascular connective tissues of the lung.
After sensitization to an allergen has occurred, reexposure of the patient to the allergen may result in an acute allergic reaction, also known as an immediate hypersensitivity reaction (Plate 4-23). IgE-sensitized mast cells in contact with the speciﬁc antigen secrete preformed and newly synthesized mediators, including histamine, cysteinyl leukotrienes, kinins, prostaglandins and thromboxane, and platelet activating factor. Also, mast cells are sources of proinﬂammatory cytokines. Each antigen molecule has to bridge at least two of the IgE molecules bound to the surface of the cell. The subsequent airway smooth muscle contraction, vasoconstriction, and hypersecretion of mucus, together with an inﬂammatory response of increased capillary permeability and cellular inﬁltration with eosinophils and neutrophils follows, producing asthma symptoms.
PATHOLOGIC CHANGES IN ASTHMA
The initial knowledge of the pathology of asthma came from postmortem studies of fatal asthma or airways of patients with asthma who have died of other causes or who had undergone lung resections. All showed similar, although variably severe, pathologic changes and provided key directives as to the causes and consequences of the inﬂammatory reactions in the airway (see Plate 4-24).
The characteristic mucus plugs in asthmatic airways can cause airway obstruction, leading to ventilation-perfusion mismatch and contributing to hypoxemia. Mucus plugs are composed of mucus, serum proteins, inﬂammatory cells, and cellular debris, which include desquamated epithelial cells and macrophages often arranged in a spiral pattern (Curschmann spirals). The excessive mucus production in fatal asthma is attributed to hypertrophy and hyperplasia of the submucosal glands. The mucus also contains increased quantities of nucleic acids, glycoproteins, and albumin, making it more viscous. This altered mucous rheology, coupled with the loss of ciliated epithelium, impairs mucociliary clearance.
The airway wall thickness is increased in asthma and is related to disease severity. Compared with non-asthmatic subjects, the airway wall thickness is increased from 50% to 300% in patients with fatal asthma and from 10% to 100% in nonfatal asthma. The greater thickness results from an increase in most tissue compartments, including smooth muscle, epithelium, submucosa, adventitia, and mucosal glands. The inﬂammatory edema involves the whole airway, particularly the submucosal layer, with marked hypertrophy and hyperplasia of the submucosal glands and goblet cell hyperplasia. Goblet cell hyperplasia and hypertrophy accompany the loss of epithelial cells. There is hyperplasia of the muscularis layer and microvascular vasodilation in the adventitial layers of the airways. Also, morphometric studies have shown that the bronchial lamina propria of asthmatic subjects had a larger number of vessels occupying a larger percentage area than in nonasthmatic subjects and in some circumstances correlated with the severity of disease.
LONG-TERM MANAGEMENT OF ASTHMA
Asthma treatment guidelines have been remarkably consistent in identifying the goals and objectives of asthma treatment. These are to (1) minimize or eliminate asthma symptoms, (2) achieve the best possible lung function, (3) prevent asthma exacerbations, (4) do the above with the fewest possible medications, (5) minimize short- and long-term adverse effects, and (6) educate the patient about the disease and the goals of management. One other important objective should be the prevention of the decline in lung function and the development of ﬁxed airﬂow obstruction, which occur in some asthmatic patients. In addition to these goals and objectives, each of these documents has described what is meant by the term asthma control. This includes the above objectives but also includes minimizing the need for rescue medications, such as inhaled β2- agonists, to less than daily use; minimizing the variability of ﬂow rates that is characteristic of asthma; and having normal activities of daily living. Achieving this level of asthma control should be an objective from the very ﬁrst visit of the patient to the treating physician.
The pharmacologic treatment of patients with asthma must only be considered in the context of asthma education and avoidance of inducers of the disease (see Plate 4-25).
Mild Persistent Asthma
Low doses of inhaled corticosteroids (ICS) can often provide ideal asthma control and reduce the risks of severe asthma exacerbations in both children and adults with mild persistent asthma, and they should be the treatment of choice. ICS are the most effective anti-inﬂammatory medications for asthma treatment. The mechanisms of action of asthma medications are depicted in Plate 4-26. There is no convincing evidence that regular use of combination therapy with ICS and inhaled long-acting β2-agonists (LABA) provides any additional beneﬁt. Leukotriene receptor antagonists (LTRAs) are another treatment option in this population, but they are also less effective than low-dose ICS. There are considerable inter- and intraindividual differences in responses to any therapy. This is also true for response to treatment with ICS and LTRAs in both adults and in children. Although on average, ICS improve almost all asthma outcomes more than LTRAs some patients may show a greater response to LTRAs. Currently, it is not possible to accurately identify these responders based on their clinical, physiologic, or pharmacogenomic characteristics.
The other issue that needs to be considered when making a decision to start ICS treatment in patients with mild asthma is the potential for side effects. ICS are not metabolized in the lungs, and every molecule of ICS that is administered into the lungs is absorbed into the systemic circulation. All of the studies in patients with mild persistent asthma have used low doses of ICS (maximal doses, 400 µg/d). A wealth of data are available demonstrating the safety of these low doses, even used long term, in adults. However, a signiﬁcant reduction in growth velocity has been demonstrated with low doses of ICS in children. This is unlikely to have any effect on the ﬁnal height of these children because the one study that has followed children treated with ICS to ﬁnal height did not show any detrimental effect even with a moderate daily ICS doses.
Moderate Persistent Asthma
These patients have asthma that is not well controlled on low doses of ICS. Asthma treatment guidelines recommend that combination therapy with ICS and a LABA is the preferred treatment option in these patients. This is because the use of combination treatment of ICS and LABA for moderate persistent asthma has also been demonstrated to improve all indicators of asthma control compared with ICS alone. It is important to note that the evidence of the enhanced beneﬁt of combination therapy with ICS and LABA in moderate persistent asthma exists mainly in adults with asthma. Another recently described treatment approach for the management of patients with moderate asthma is the use of an inhaler containing the combination of the ICS budesonide and the LABA formoterol, both as maintenance and as relief therapy, which has been shown to reduce the risk of severe asthma exacerbations compared with the other approaches studied with an associated reduction in oral corticosteroid use.
Several studies have compared the clinical beneﬁt when LTRAs are added to ICS in patients with moderate persistent asthma in both adults and children. The addition of LTRAs to ICS may modestly improve asthma control compared with ICS alone, but this strategy cannot be recommended as a substitute for increasing the dose of ICS. In addition, LTRAs have been shown to be less effective than LABAs when combined with ICS. Low-dose theophylline has also been evaluated as an add-on therapy to ICS. The magnitude of beneﬁt achieved is less than for LABAs. Another potential treatment option for patients with moderate asthma is omalizumab, which is a recombinant humanized monoclonal antibody against IgE. This anti-IgE antibody forms complexes with free IgE, thus blocking the interaction between IgE and effector cells and reducing serum concentrations of free IgE. Compared with placebo in patients on moderate to high doses of ICS, omalizumab reduces asthma exacerbations and enables a small but statistically signifycant reduction in the dose of ICS. However, this treatment has not been compared with proven additive therapies such as LABAs that are less expensive. Therefore, this therapy is currently recommended in international guidelines for patients with moderate to severe asthma.
Severe Persistent Asthma
Patients with severe asthma are those who do not respond adequately to even high doses of ICS and LABAs. This population disproportionately consumes health care resources related to asthma. Physiologically, these patients often have air trapping, airway collapsibility, and a high degree of AHR. Patients with severe difficult-to-treat asthma are most often adult patients with signifi cant comorbidities, including severe rhinosinusitis, gastroesophageal reflux, obesity, and anxiety disorders. Often this population requires oral corticosteroids in addition to ICS in an effort to achieve asthma control.
TREATMENT OF SEVERE ASTHMA
Episodes of acute severe asthma (asthma exacerbations) are episodes of progressive increase in shortness of breath, cough, wheezing, chest tightness, or some combination and are characterized by airflow obstruction that can be quantified by measurement of PEF or FEV1. These measurements are more reliable indicators of the severity of airflow limitation than is the degree of symptoms. Severe exacerbations are potentially life threatening, and their treatment requires close supervision. Patients with severe exacerbations should be encouraged to see their physicians promptly or to proceed to the nearest hospital that provides emergency access for patients with acute asthma. Close objective monitoring of the response to therapy is essential.
The primary therapies for severe asthma exacerbations include repetitive administration of rapid-acting inhaled β2-agonists, 2 to 4 puffs every 20 minutes for the first hour (see Plate 4-27). After the first hour, the dose of β2-agonists required depends on the severity of the exacerbation and the response of the previously administered inhaled β2-agonists. A combination of inhaled β2-agonist with an anticholinergic (ipratropium bromide) may produce better bronchodilation than either drug alone. Oxygen should be administered by nasal cannula or by mask and should be titrated against pulse oximetry to maintain a satisfactory oxygen saturation of 90% or above (≥95% in children).
Systemic glucocorticosteroids speed resolution of exacerbations and should be used in all but the mildest exacerbations, especially if the initial rapid-acting inhaled β2-agonist therapy fails to achieve lasting improvement. Oral glucocorticosteroids are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive. The aims of treatment are to relieve airflow obstruction and hypoxemia as quickly as possible and to plan the prevention of future relapses. Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs.
Patients at high risk of asthma-related death should be encouraged to seek urgent care early in the course of their exacerbations. These patients include those with a previous history of near-fatal asthma requiring intubation and mechanical ventilation, who have had a hospitalization or emergency care visit for asthma in the past year, who are currently using or have recently stopped using oral glucocorticosteroids, who are overdependent on rapid-acting inhaled β2-agonists, who have a history of psychiatric disease or psychosocial problems, and who have a history of noncompliance with an asthma medication plan.
The response to treatment may take time, and patients should be closely monitored using clinical as well as objective measurements. The increased treatment should continue until measurements of lung function return to their previous best level or there is a plateau in the response to the inhaled β2-agonists, at which time a decision to admit or discharge the patient can be made based on these values. Patients who can be safely discharged will have responded within the first 2 hours, at which time decisions regarding patient disposition can be made. Patients with a pretreatment FEV1 or peak expiratory flow (PEF) below 25% percent predicted or those with a posttreatment FEV1 or PEF below 40% percent predicted usually require hospitalization. Patients with posttreatment lung function of 40% to 60% predicted can often be discharged from the emergency setting provided that adequate follow-up is available in the community and their compliance with treatment is assured.
For patients discharged from the emergency department, a minimum of a 7-day course of oral glucocorticosteroids for adults and a shorter course (3-5 days) for children should be prescribed along with continuation of bronchodilator therapy. The bronchodilator can be used on an as-needed basis, based on both symptomatic and objective improvement. Patients should initiate or continue inhaled glucocorticosteroids. The patient’s inhaler technique and use of peak ﬂow meter to monitor therapy at home should be reviewed. The factors that precipitated the exacerbation should be identiﬁed and strategies for their future avoidance implemented. The patient’s response to the exacerbation should be evaluated, and an asthma action plan should be reviewed and written guidance provided.