Asthma is defined as a chronic inflammatory disease of airways that is characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli. It is manifested physiologically by a widespread narrowing of the air passages, which may be relieved spontaneously or as a result of therapy, and clinically by paroxysms of dyspnea, cough, and wheezing. Asthma is an episodic disease, with acute exacerbations interspersed with symptom-free periods. Typically, most attacks are short-lived, lasting minutes to hours, and clinically the patient seems to recover completely after an attack. However, there can be a phase in which the patient experiences some degree of airway obstruction daily. This phase can be mild, with or without superimposed severe episodes, or much more serious, with severe obstruction persisting for days or weeks; the latter condition is known as status asthmaticus. In unusual circumstances, acute episodes can cause death.
Prevalence and Etiology
Asthma is very common; it is estimated that 4 to 5% of the population of the United States is affected. Similar figures have been reported from other countries. Bronchial asthma occurs at all ages but predominantly in early life. About one-half of cases develop before age 10, and another third occur before age 40. In childhood, there is a 2:1 male/female preponderance, but the sex ratio equalizes by age 30.
From an etiologic standpoint, asthma is a heterogeneous disease. It is useful for epidemiologic and clinical purposes to classify asthma by the principal stimuli that incite or are associated with acute episodes. However, it is important to emphasize that this distinction may often be artificial, and the response of a given subclassification usually can be initiated by more than one type of stimulus. Furthermore, the application of molecular and cell biologic techniques to asthma pathogenesis is also beginning to blur this type of classification. With these reservations in mind, one can describe two broad types of asthma: allergic and idiosyncratic.
Atopy is the single largest risk factor for the development of asthma. Allergic asthma is often associated with a personal and/or family history of allergic diseases such as rhinitis, urticaria, and eczema, with positive wheal-and-flare skin reactions to intradermal injection of extracts of airborne antigens, with increased levels of IgE in the serum, and/or with a positive response to provocation tests involving the inhalation of specific antigen.
A significant fraction of patients with asthma present with no personal or family history of allergy, with negative skin tests, and with normal serum levels of IgE, and therefore have disease that cannot be classified on the basis of defined immunologic mechanisms. These patients are said to have idiosyncratic asthma. Many develop a typical symptom complex on contracting an upper respiratory illness. The initial insult may be little more than a common cold, but after several days the patient begins to develop paroxysms of wheezing and dyspnea that can last for days to months. These individuals should not be confused with persons in whom the symptoms of bronchospasm are superimposed on chronic bronchitis or bronchiectasis (Chaps. 256 and 258).
Many patients have disease that does not fit clearly into either of the preceding categories but instead falls into a mixed group with features of each. In general, asthma that has its onset in early life tends to have a strong allergic component, whereas asthma that develops late tends to be nonallergic or to have a mixed etiology.
Pathogenesis of Asthma
The common denominator underlying the asthmatic diathesis is a nonspecific hyperirritability of the tracheobronchial tree. When airway reactivity is high, symptoms are more severe and persistent, and the amount of therapy required to control the patient's complaints is greater. In addition, the magnitude of diurnal fluctuations in lung function is greater, and the patient tends to awaken at night or in the early morning with breathlessness.
In both normal and asthmatic individuals, airway reactivity rises after viral infections of the respiratory tract and exposure to oxidant air pollutants such as ozone and nitrogen dioxide (but not sulfur dioxide). Viral infections have more profound consequences, and airway responsiveness may remain elevated for many weeks after a seemingly trivial upper respiratory tract infection. In contrast, airway reactivity remains high for only a few days after exposure to ozone. Allergens can cause airway responsiveness to rise within minutes and to remain elevated for weeks. If the dose of antigen is high enough, acute episodes of obstruction may occur daily for a prolonged period after a single exposure.
The most popular hypothesis at present for the pathogenesis of asthma is that it derives from a state of persistent subacute inflammation of the airways. An active inflammatory process is frequently observed in endobronchial biopsy specimens even from asymptomatic patients. The airways can be edematous and infiltrated with eosinophils, neutrophils, and lymphocytes, with or without an increase in the collagen content of the epithelial basement membrane. There may also be glandular hypertrophy. The most ubiquitous finding is a generalized increase in cellularity associated with an elevated capillary density. Occasionally, denudation of the epithelium may also be observed.
Although the translation of these histologic observations into a disease process is still incomplete, it is widely believed that the physiologic and clinical features of asthma derive from an interaction among the resident and infiltrating inflammatory cells in the airway surface epithelium, inflammatory mediators, and cytokines. The cells thought to play important parts in the inflammatory response are mast cells, eosinophils, lymphocytes, and epithelial cells. The roles of neutrophils and macrophages are less well defined. Each of these cell types can contribute mediators and cytokines to initiate and amplify both acute inflammation and the long-term pathologic changes described above. The mediators released-histamine; bradykinin; the leukotrienes C, D, and E; platelet-activating factor; and prostaglandins (PGs) E2, F2, and D2-produce an intense, immediate inflammatory reaction involving bronchoconstriction, vascular congestion, and edema formation. In addition to their ability to evoke prolonged contraction of airway smooth muscle and mucosal edema, the leukotrienes may also account for some of the other pathophysiologic features of asthma, such as increased mucus production and impaired mucociliary transport. This intense local event can then be followed by a more chronic one. The chemotactic factors elaborated (eosinophil and neutrophil chemotactic factors of anaphylaxis and leukotriene B4) bring eosinophils, platelets, and polymorphonuclear leukocytes to the site of the reaction. These infiltrating cells as well as resident macrophages and the airway epithelium itself potentially are an additional source of mediators to enhance both the immediate and the cellular phase. The airway epithelium is both the target of, and a contributor to, the inflammatory cascade. These cells amplify bronchoconstriction by elaborating endothelin-1 and promoting vasodilatation through the release of nitric oxide, PGE2 and the 15-hydroxyeicosatetraenoic acid (15-HETE) products of arachidonic acid metabolism. They also generate cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)8, Rantes, and eotaxin.
Like the mast cell in the early reaction, the eosinophil appears to play an important part in the infiltrative component. The granular proteins in this cell (major basic protein and eosinophilic cationic protein) and oxygen-derived free radical are capable of destroying the airway epithelium, which then is sloughed into the bronchial lumen in the form of Creola bodies. Besides resulting in a loss of barrier and secretory function, such damage elicits the production of chemotactic cytokines, leading to further inflammation. In theory, it also can expose sensory nerve endings, thus initiating neurogenic inflammatory pathways. That, in turn, could convert a primary local event into a generalized reaction via a reflex mechanism.
T lymphocytes also appear to be important in the inflammatory response. These cells are present in increased numbers in asthmatic airways and produce cytokines that activate cell-mediated immunity, as well as humoral (IgE) immune responses. Activated T cells recovered from the lungs of persons with asthma express messenger RNA for the cytokines known to play a part in the recruitment and activation of mast cells and eosinophils. Furthermore, the TH1 and TH2 lymphocyte subtypes have functions that may influence the asthmatic response. The TH1 cytokines IL-2 and interferon (IFN) can promote the growth and differentiation of B cells and the activation of macrophages, respectively. The TH2 cytokines IL-4 and IL-5 stimulate B-cell growth and immunoglobulin secretion, and IL-5 promotes eosinophil proliferation, differentiation, and activation. It can also facilitate granule release from basophils.
Cytokine production is another central component of the inflammation of asthma. Cytokines are synthesized and released from many of the inflammatory cells mentioned above, as well as from epithelial cells, fibroblasts, endothelial cells, and airway smooth muscle. Cytokines activate specific cell-surface receptors that are coupled to signal transduction pathways, which often result in alterations of gene regulation and enzyme production. The cytokines that are particularly relevant to asthma are secreted by T lymphocytes and include IL-3 enhanced (mast cell survival), IL-4 and IL-13 (switching of B lymphocytes to IgE production and expression of adhesion molecules), and IL-5 (differentiation and enhanced survival of eosinophils). Other cytokines, such as IL-1B, IL-6, IL-11, tumor necrosis factor (TNF-) and GM-CSF, are proinflammatory and may amplify the inflammatory response.
The relative roles of each of the above elements in the production of heightened airway reactivity and clinical asthma have yet to be determined. Although inflammation is clearly important, recent evidence indicates that the intensity of the cellular infiltrate in the airways is not related either to the severity of the disease state or to the level of airway reactivity. Furthermore, it is unlikely that any one cell type or mediator accounts for every feature. For example, mast cell-derived mediators cannot explain the whole picture, for they have been found in the blood of individuals with mast cell-related diseases such as cold-induced and cholinergic-induced urticaria and in the airways of atopic individuals without asthma. Since these individuals had no lower respiratory illness or complaints, these alleged mediators of asthma would appear to need a unique background from which to exhibit their effects. Similarly, the inflammatory cells believed to be relevant to asthma are also found in the airways of atopic individuals without asthma, raising the possibility that they are merely nonspecific markers of atopy rather than specific indexes of asthma. Finally, the therapeutic administration of IL-2 and GM-CSF to patients with cancer results in eosinophilia with cell activation but not in asthma
Although there is little doubt that asthma has a strong familial component, the identification of the genetic mechanisms underlying the illness has proven difficult for multiple reasons, including such fundamental issues as a lack of uniform agreement on the definition of the disease, the inability to define a single phenotype, non-Mendelian modes of inheritance, and an incomplete understanding of how environmental factors modify genetic expression. Screening families for candidate genes has identified multiple chromosomal regions that relate to atopy, elevated IgE levels, and airway hyperresponsiveness. Evidence for genetic linkage of high total serum IgE levels and atopy has been observed on chromosomes 5q, 11q, and 12q in a number of populations scattered throughout the world. Regions of the genome demonstrating evidence for linkage to bronchial hyperreactivity also typically show evidence for linkage to elevated total serum IgE levels. Excellent candidate genes exist for specific abnormalities in asthma within the regions that were identified in the linkage studies. For example, chromosome 5q contains cytokine clusters including IL-4, IL-5, IL-9, and IL-13. Other regions on chromosome 5q also contain the beta-adrenergic receptors and the glucocorticoid receptors. Chromosome 6p contains regions that are important in antigen presentation and mediation of the inflammatory response. Chromosome 12q contains two genes that could influence atopy and airway hyperresponsiveness, including nitric oxide synthase.
The stimuli that interact with airway responsiveness and incite acute episodes of asthma can be grouped into seven major categories: allergenic, pharmacologic, environmental, occupational, infectious, exercise-related, and emotional.
Allergic asthma is dependent on an IgE response controlled by T and B lymphocytes and activated by the interaction of antigen with mast cell-bound IgE molecules. The airway epithelium and submucosa contain dendritic cells that capture and process antigen. After taking up an immunogen, these cells migrate to the local lymph nodes where they present the material to T cell receptors. In the appropriate genetic setting, the interaction of antigen with a naïve T cell TH0 in the presence of IL-4 leads to the differentiation of the cell to a TH2 subset. This process not only helps facilitate the inflammation of asthma but also causes B lymphocytes to switch their antibody production from IgG and IgM to IgE. Most of the allergens that provoke asthma are airborne, and to induce a state of sensitivity they must be reasonably abundant for considerable periods of time. Once sensitization has occurred, however, the patient can exhibit exquisite responsivity, so that minute amounts of the offending agent can produce significant exacerbations of the disease. Immune mechanisms appear to be causally related to the development of asthma in 25 to 35% of all cases and to be contributory in perhaps another third. Higher prevalences have been suggested, but it is difficult to know how to interpret the data because of confounding factors. Allergic asthma is frequently seasonal, and it is most often observed in children and young adults. A nonseasonal form may result from allergy to feathers, animal danders, dust mites, molds, and other antigens that are present continuously in the environment. Exposure to antigen typically produces an immediate response in which airway obstruction develops in minutes and then resolves. In 30 to 50% of patients, a second wave of bronchoconstriction, the so-called late reaction, develops 6 to 10 h later. In a minority, only a late reaction occurs. It was formerly thought that the late reaction was essential to the development of the increase in airway reactivity that follows antigen exposure. Recent data show that not to be the case.
The mechanism by which an inhaled allergen provokes an acute episode of asthma depends in part on antigen-antibody interactions on the surface of pulmonary mast cells, with the subsequent generation and release of the mediators of immediate hypersensitivity. Current hypotheses hold that very small antigenic particles penetrate the lung's defenses and come in contact with mast cells that interdigitate with the epithelium at the luminal surface of the central airways. The subsequent elaboration of mediators and cytokines then produces the sequence outlined above.
The drugs most commonly associated with the induction of acute episodes of asthma are aspirin, coloring agents such as tartrazine, -adrenergic antagonists, and sulfiting agents. It is important to recognize drug-induced bronchial narrowing because its presence is often associated with great morbidity. Furthermore, death sometimes has followed the ingestion of aspirin (or other nonsteroidal anti-inflammatory agents) or -adrenergic antagonists. The typical aspirin-sensitive respiratory syndrome primarily affects adults, although the condition may occur in childhood. This problem usually begins with perennial vasomotor rhinitis that is followed by a hyperplastic rhinosinusitis with nasal polyps. Progressive asthma then appears. On exposure to even very small quantities of aspirin, affected individuals typically develop ocular and nasal congestion and acute, often severe episodes of airways obstruction. The prevalence of aspirin sensitivity in patients with asthma varies from study to study, but many authorities feel that 10% is a reasonable figure. There is a great deal of cross reactivity between aspirin and other nonsteroidal anti-inflammatory compounds that inhibit prostaglandin G/H synthase 1 (cyclooxygenase type 1). Indomethacin, fenoprofen, naproxen, zomepirac sodium, ibuprofen, mefenamic acid, and phenylbutazone are particularly important in this regard. However, acetaminophen, sodium salicylate, choline salicylate, salicylamide, and propoxyphene are well tolerated. The exact frequency of cross reactivity to tartrazine and other dyes in aspirin-sensitive individuals with asthma is also controversial; again, 10% is the commonly accepted figure. This peculiar complication of aspirin-sensitive asthma is particularly insidious, however, in that tartrazine and other potentially troublesome dyes are widely present in the environment and may be unknowingly ingested by sensitive patients.
Patients with aspirin sensitivity can be desensitized by daily administration of the drug. After this form of therapy, cross tolerance also develops to other nonsteroidal anti-inflammatory agents. The mechanism by which aspirin and other such drugs produce bronchospasm appears to be a chronic overexcretion of cysteinyl leukotrienes, which activate mast cells. The adverse reaction to aspirin can be inhibited with the use of leukotriene synthesis blockers or receptor antagonists.
Beta-adrenergic antagonists regularly obstruct the airways in individuals with asthma as well as in others with heightened airway reactivity and should be avoided by such individuals. Even the selective beta1 agents have this propensity, particularly at higher doses. In fact, the local use of beta1 blockers in the eye for the treatment of glaucoma has been associated with worsening asthma.
Sulfiting agents, such as potassium metabisulfite, potassium and sodium bisulfite, sodium sulfite, and sulfur dioxide, which are widely used in the food and pharmaceutical industries as sanitizing and preserving agents, also can produce acute airway obstruction in sensitive individuals. Exposure usually follows ingestion of food or beverages containing these compounds, e.g., salads, fresh fruit, potatoes, shellfish, and wine. Exacerbation of asthma has been reported after the use of sulfite-containing topical ophthalmic solutions, intravenous glucocorticoids, and some inhalational bronchodilator solutions. The incidence and mechanism of action of this phenomenon are unknown. When suspected, the diagnosis can be confirmed by either oral or inhalational provocations.
Environment and Air Pollution
Environmental causes of asthma are usually related to climatic conditions that promote the concentration of atmospheric pollutants and antigens. These conditions tend to develop in heavily industrial or densely populated urban areas and are frequently associated with thermal inversions or other situations creating stagnant air masses. In these circumstances, although the general population can develop respiratory symptoms, patients with asthma and other respiratory diseases tend to be more severely affected. The air pollutants known to have this effect are ozone, nitrogen dioxide, and sulfur dioxide. Sulfur dioxide needs to be present in high concentrations and produces its greatest effects during periods of high ventilation. In some regions of North America, seasonal concentrations of airborne antigens such as pollen can rise high enough to result in epidemics of asthma admissions to hospitals and an increase in the death rate. These events may be ameliorated by treating patients prophylactically with anti-inflammatory drugs before the allergy season begins.
Occupation-related asthma is a significant health problem, and acute and chronic airway obstruction has been reported to follow exposure to a large number of compounds used in many types of industrial processes. Bronchoconstriction can result from working with or being exposed to metal salts (e.g., platinum, chrome, and nickel), wood and vegetable dusts (e.g., those of oak, western red cedar, grain, flour, castor bean, green coffee bean, mako, gum acacia, karay gum, and tragacanth), pharmaceutical agents (e.g., antibiotics, piperazine, and cimetidine), industrial chemicals and plastics (e.g., toluene diisocyanate, phthalic acid anhydride, trimellitic anhydride, persulfates, ethylenediamine, p-phenylenediamine, and various dyes), biologic enzymes (e.g., laundry detergents and pancreatic enzymes), and animal and insect dusts, serums, and secretions. It is important to recognize that exposure to sensitizing chemicals, particularly those used in paints, solvents, and plastics, also can occur during leisure or non-work-related activities.
There seem to be three underlying mechanisms for this airway obstruction: (1) In some cases, the offending agent results in the formation of a specific IgE, and the cause seems immunologic (the immunologic reaction can be immediate, late, or dual); (2) in other cases, the substance causes a direct liberation of bronchoconstrictor substances; and (3) in other instances, the substance causes direct or reflex stimulation of the airways of individuals with either latent or frank asthma. If the occupational agent causes an immediate or dual immunologic reaction, the history is similar to that which occurs with exposure to other antigens. Often, however, patients will give a characteristic cyclic history. They are well when they arrive at work, and symptoms develop toward the end of the shift, progress after the work site is left, and then regress. Absence from work during weekends or vacations brings about remission. Frequently, there are similar symptoms in fellow employees.
Respiratory infections are the most common of the stimuli that evoke acute exacerbations of asthma. Well-controlled investigations have demonstrated that respiratory viruses and not bacteria or allergy to microorganisms are the major etiologic factors. In young children, the most important infectious agents are respiratory syncytial virus and parainfluenza virus. In older children and adults, rhinovirus and influenza virus predominate as pathogens. Simple colonization of the tracheobronchial tree is insufficient to evoke acute episodes of bronchospasm, and attacks of asthma occur only when symptoms of an ongoing respiratory tract infection are, or have been, present. Viral infections can actively and chronically destabilize asthma, and they are perhaps the only stimuli that can produce constant symptoms for weeks. The mechanism by which viruses induce exacerbations of asthma may be related to the production of T cell-derived cytokines that potentiate the infiltration of inflammatory cells into already susceptible airways.
Exercise is a very common precipitant of acute episodes of asthma. This stimulus differs from other naturally occurring provocations, such as antigens, viral infections, and air pollutants, in that it does not evoke any long-term sequelae, nor does it increase airway reactivity. Exercise can be made to provoke bronchospasm in every patient with asthma, and in some it is the only trigger that produces symptoms. When such patients are followed for sufficient periods, however, they often develop recurring episodes of airway obstruction independent of exercise; thus, the onset of this problem frequently is the first manifestation of the full-blown asthmatic syndrome. The critical variables that determine the severity of the postexertional airway obstruction are the levels of ventilation achieved and the temperature and humidity of the inspired air. The higher the ventilation and the lower the heat content of the air, the greater the response. For the same inspired air conditions, running produces a more severe attack of asthma than walking. Conversely, for a given task, the inhalation of cold air markedly enhances the response, while warm, humid air blunts or abolishes it. Consequently, activities such as ice hockey, cross-country skiing, and ice skating are more provocative than is swimming in an indoor, heated pool. The mechanism by which exercise produces obstruction may be related to a thermally produced hyperemia and engorgement of the microvasculature of the bronchial wall and does not appear to involve smooth-muscle contraction.
Abundant objective data demonstrate that psychological factors can interact with the asthmatic diathesis to worsen or ameliorate the disease process. The pathways and nature of the interactions are complex but are operational to some extent in almost half the patients studied. Changes in airway caliber seem to be mediated through modification of vagal efferent activity, but endorphins also may play a role. The most frequently studied variable has been that of suggestion, and the weight of current evidence indicates that it can be quite important in selected individuals with asthma. When psychically responsive individuals are given the appropriate suggestion, they can actually decrease or increase the pharmacologic effects of adrenergic and cholinergic stimuli on their airways. The extent to which psychological factors participate in the induction and/or continuation of any given acute exacerbation is not established but probably varies from patient to patient and in the same patient from episode to episode.
In a patient who has died of acute asthma, the most striking feature of the lungs at necropsy is their gross overdistention and failure to collapse when the pleural cavities are opened. When the lungs are cut, numerous gelatinous plugs of exudate are found in most of the bronchial branches down to the terminal bronchioles. Histologic examination shows hypertrophy of the bronchial smooth muscle, hyperplasia of mucosal and submucosal vessels, mucosal edema, denudation of the surface epithelium, pronounced thickening of the basement membrane, and eosinophilic infiltrates in the bronchial wall. There is an absence of any of the well-recognized forms of destructive emphysema.
The pathophysiologic hallmark of asthma is a reduction in airway diameter brought about by contraction of smooth muscle, vascular congestion, edema of the bronchial wall, and thick, tenacious secretions. The net result is an increase in airway resistance, a decrease in forced expiratory volumes and flow rates, hyperinflation of the lungs and thorax, increased work of breathing, alterations in respiratory muscle function, changes in elastic recoil, abnormal distribution of both ventilation and pulmonary blood flow with mismatched ratios, and altered arterial blood gas concentrations. Thus, although asthma is considered to be primarily a disease of airways, virtually all aspects of pulmonary function are compromised during an acute attack. In addition, in very symptomatic patients there frequently is electrocardiographic evidence of right ventricular hypertrophy and pulmonary hypertension. When a patient presents for therapy, his or her forced vital capacity tends to be 50% of normal. The 1-s forced expiratory volume (FEV1) averages 30% or less of predicted, while the maximum and minimum midexpiratory flow rates are reduced to 20% or less of expected. In keeping with the alterations in mechanics, the associated air trapping is substantial. In acutely ill patients, residual volume (RV) frequently approaches 400% of normal, while functional residual capacity doubles. The patient tends to report that the attack has ended clinically when the RV has fallen to 200% of its predicted value and the FEV1 reaches 50% of the predicted level.
Hypoxia is a universal finding during acute exacerbations, but frank ventilatory failure is relatively uncommon, being observed in 10 to 15% of patients presenting for therapy. Most individuals with asthma have hypocapnia and a respiratory alkalosis. In acutely ill patients, the finding of a normal arterial carbon dioxide tension tends to be associated with quite severe levels of obstruction. Consequently, when found in a symptomatic individual, it should be viewed as representing impending respiratory failure, and the patient should be treated accordingly. Equally, the presence of metabolic acidosis in the setting of acute asthma signifies severe obstruction. Usually, there are no clinical counterparts to the derangements in blood gases. Cyanosis is a very late sign. Hence, a dangerous level of hypoxia can go undetected. Likewise, signs attributable to carbon dioxide retention, such as sweating, tachycardia, and wide pulse pressure, or to acidosis, such as tachypnea, tend not to be of great value in predicting the presence of hypercapnia or hydrogen ion excess in individual patients, because they are too frequently seen in anxious patients with more moderate disease. Trying to judge the state of an acutely ill patient's ventilatory status on clinical grounds alone can be extremely hazardous, and clinical indicators should not be relied on with any confidence. Therefore, in patients with suspected alveolar hypoventilation, arterial blood gas tensions must be measured.
The symptoms of asthma consist of a triad of dyspnea, cough, and wheezing, the last often being regarded as the sine qua non. In its most typical form, asthma is an episodic disease, and all three symptoms coexist. At the onset of an attack, patients experience a sense of constriction in the chest, often with a nonproductive cough. Respiration becomes audibly harsh, wheezing in both phases of respiration becomes prominent, expiration becomes prolonged, and patients frequently have tachypnea, tachycardia, and mild systolic hypertension. The lungs rapidly become overinflated, and the anteroposterior diameter of the thorax increases. If the attack is severe or prolonged, there may be a loss of adventitial breath sounds, and wheezing becomes very high pitched. Furthermore, the accessory muscles become visibly active, and a paradoxical pulse often develops. These two signs are extremely valuable in indicating the severity of the obstruction. In the presence of either, pulmonary function tends to be significantly more impaired than in their absence. It is important to note that the development of a paradoxical pulse depends on the generation of large negative intrathoracic pressures. Thus, if the patient's breathing is shallow, this sign and/or the use of accessory muscles could be absent even though obstruction is quite severe. The other signs and symptoms of asthma only imperfectly reflect the physiologic alterations that are present. Indeed, if the disappearance of subjective complaints or even of wheezing is used as the end point at which therapy for an acute attack is terminated, an enormous reservoir of residual disease will be missed.
The end of an episode is frequently marked by a cough that produces thick, stringy mucus, which often takes the form of casts of the distal airways (Curschmann's spirals) and, when examined microscopically, often shows eosinophils and Charcot-Leyden crystals. In extreme situations, wheezing may lessen markedly or even disappear, cough may become extremely ineffective, and the patient may begin a gasping type of respiratory pattern. These findings imply extensive mucus plugging and impending suffocation. Ventilatory assistance by mechanical means may be required. Atelectasis due to inspissated secretions occasionally occurs with asthmatic attacks. Spontaneous pneumothorax and/or pneumomediastinum occur but are rare.
Less typically, a patient with asthma may complain of intermittent episodes of nonproductive cough or exertional dyspnea. Unlike other individuals with asthma, when these patients are examined during symptomatic periods, they tend to have normal breath sounds but may wheeze after repeated forced exhalations and/or may show ventilatory impairments when tested in the laboratory. In the absence of both these signs, a bronchoprovocation test may be required to make the diagnosis.
The differentiation of asthma from other diseases associated with dyspnea and wheezing is usually not difficult, particularly if the patient is seen during an acute episode. The physical findings and symptoms listed above and the history of periodic attacks are quite characteristic. A personal or family history of allergic diseases such as eczema, rhinitis, or urticaria is valuable contributory evidence. An extremely common feature of asthma is nocturnal awakening with dyspnea and/or wheezing. In fact, this phenomenon is so prevalent that its absence raises doubt about the diagnosis. Upper airway obstruction by tumor or laryngeal edema can occasionally be confused with asthma. Typically, a patient with such a condition will present with stridor, and the harsh respiratory sounds can be localized to the area of the trachea. Diffuse wheezing throughout both lung fields is usually absent. However, differentiation can sometimes be difficult, and indirect laryngoscopy or bronchoscopy may be required. Asthma-like symptoms have been described in patients with glottic dysfunction. These individuals narrow their glottis during inspiration and expiration, producing episodic attacks of severe airway obstruction. Occasionally, carbon dioxide retention develops. However, unlike asthma, the arterial oxygen tension is well preserved, and the alveolar-arterial gradient for oxygen narrows during the episode, instead of widening as with lower airway obstruction. To establish the diagnosis of glottic dysfunction, the glottis should be examined when the patient is symptomatic. Normal findings at such a time exclude the diagnosis; normal findings during asymptomatic periods do not.
Persistent wheezing localized to one area of the chest in association with paroxysms of coughing indicates endobronchial disease such as foreign-body aspiration, a neoplasm, or bronchial stenosis.
The signs and symptoms of acute left ventricular failure occasionally mimic asthma, but the findings of moist basilar rales, gallop rhythms, blood-tinged sputum, and other signs of heart failure (Chap. 232) allow the appropriate diagnosis to be reached.
Recurrent episodes of bronchospasm can occur with carcinoid tumors (Chap. 93), recurrent pulmonary emboli (Chap. 261), and chronic bronchitis (Chap. 258). In chronic bronchitis there are no true symptom-free periods, and one can usually obtain a history of chronic cough and sputum production as a background on which acute attacks of wheezing are superimposed. Recurrent emboli can be very difficult to separate from asthma. Frequently, patients with this condition present with episodes of breathlessness, particularly on exertion, and they sometimes wheeze. Pulmonary function studies may show evidence of peripheral airway obstruction (Chap. 250); when these changes are present, lung scans also may be abnormal. The therapeutic response to bronchodilators and to the institution of anticoagulant therapy may be helpful, but pulmonary angiography may be necessary to establish the correct diagnosis.
Eosinophilic pneumonias (Chap. 253) are often associated with asthmatic symptoms, as are various chemical pneumonias and exposures to insecticides and cholinergic drugs. Bronchospasm occasionally is a manifestation of systemic vasculitis with pulmonary involvement.
The diagnosis of asthma is established by demonstrating reversible airway obstruction. Reversibility is traditionally defined as a 15% or greater increase in FEV1 after two puffs of a -adrenergic agonist. When the spirometry results are normal at presentation, the diagnosis can be made by showing heightened airway responsiveness to challenges with histamine, methacholine, or isocapnic hyperventilation of cold air. Once the diagnosis is confirmed, the course of the illness and the effectiveness of therapy can be followed by measuring peak expiratory flow rates (PEFRs) at home and/or the FEV1 in the laboratory. Positive wheal-and-flare reactions to skin tests can be demonstrated to various allergens, but such findings do not necessarily correlate with the intrapulmonary events. Sputum and blood eosinophilia and measurement of serum IgE levels are also helpful but are not specific for asthma. Chest roentgenograms showing hyperinflation are also nondiagnostic.
Elimination of the causative agent(s) from the environment of an allergic individual with asthma is the most successful means available for treating this condition (for details on avoidance, see Chap. 310). Desensitization or immunotherapy with extracts of the suspected allergens has enjoyed widespread favor, but controlled studies are limited and have not proved it to be highly effective.
The available agents for treating asthma can be divided into two general categories: drugs that inhibit smooth muscle contraction, i.e., the so-called "quick relief medications" (beta-adrenergic agonists, methylxanthines, and anticholinergics) and agents that prevent and/or reverse inflammation, i.e., the "long-term control medications" (glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cell-stabilizing agents).
The drugs in this category consist of the catecholamines, resorcinols, and saligenins. These agents are analogues and produce airway dilation through stimulation of beta-adrenergic receptors and activation of G proteins with the resultant formation of cyclic adenosine monophosphate (AMP). They also decrease release of mediators and improve mucociliary transport. The catecholamines available for clinical use are epinephrine, isoproterenol, and isoetharine. As a group, these compounds are short-acting (30 to 90 min) and are effective only when administered by inhalational or parenteral routes. Epinephrine and isoproterenol are not 2-selective and have considerable chronotropic and inotropic cardiac effects. Epinephrine also has substantial alpha-stimulating effects. The usual dose is 0.3 to 0.5 mL of a 1:1000 solution administered subcutaneously. Isoproterenol is devoid of alpha activity and is the most potent agent of this group. It is usually administered in a 1:200 solution by inhalation. Isoetharine is the most 2-selective compound of this class, but it is a relatively weak bronchodilator. It is employed as an aerosol and supplied as a 1% solution. The use of these agents in treating asthma has been superceded by longer acting selective 2 agonists.
The commonly used resorcinols are metaproterenol, terbutaline, and fenoterol, and the most widely known saligenin is albuterol (salbutamol). With the exception of metaproterenol, these drugs are highly selective for the respiratory tract and virtually devoid of significant cardiac effects except at high doses. Their major side effect is tremor. They are active by all routes of administration, and because their chemical structures allow them to bypass the metabolic processes used to degrade the catecholamines, their effects are relatively long-lasting (4 to 6 h). Differences in potency and duration among agents can be eliminated by adjusting doses and/or administration schedules.
Inhalation is the preferred route of administration because it allows maximal bronchodilation with fewer side effects. In the past it was fashionable to treat episodes of severe asthma with intravenous sympathomimetics such as isoproterenol. This approach no longer appears justifiable. Isoproterenol infusions clearly can induce myocardial damage, and even for the 2-selective agents such as terbutaline and albuterol, intravenous administration offers no advantages over the inhaled route.
Salmeterol is a very long-lasting (9 to 12 h) congener of albuterol. When given every 12 h, it is effective in providing sustained symptomatic relief. It is particularly helpful for conditions such as nocturnal and exercise-induced asthma. It is not recommended for the treatment of acute episodes because of its relatively slow onset of action (approximately 30 min), nor is it intended as a rescue drug for breakthrough symptoms. In addition, its long half-life means that administration of extra doses can cause cumulative side effects.
Theophylline and its various salts are medium-potency bronchodilators that work by increasing cyclic AMP by the inhibition of phosphodiesterase. The therapeutic plasma concentrations of theophylline traditionally have been thought to lie between 10 and 20 g/mL. Some sources, however, recommend a lower target range between 5 and 15 g/mL to avoid toxicity. The dose required to achieve the desired level varies widely from patient to patient owing to differences in the metabolism of the drug. Theophylline clearance, and thus the dosage requirement, is decreased substantially in neonates and the elderly and those with acute and chronic hepatic dysfunction, cardiac decompensation, and cor pulmonale. Clearance is also decreased during febrile illnesses. Clearance is increased in children. In addition, a number of important drug interactions can alter theophylline metabolism. Clearance falls with the concurrent use of erythromycin and other macrolide antibiotics, the quinolone antibiotics, and troleandomycin, allopurinol, cimetidine, and propranolol. It rises with use of cigarettes, marijuana, phenobarbital, phenytoin, or any other drug that is capable of inducing hepatic microsomal enzymes.
For maintenance therapy, long-acting theophylline compounds are available and are usually given once or twice daily. The dose is adjusted on the basis of the clinical response with the aid of serum theophylline measurements. Single-dose administration in the evening reduces nocturnal symptoms and helps keep the patient complaint-free during the day. Aminophylline and theophylline are available for intravenous use. The recommendations for intravenous therapy in children aged 9 to 16 and in young adult smokers not currently receiving theophylline products are a loading dose of 6 mg/kg followed by an infusion of 1 mg/kg per hour for the next 12 h and then 0.8 mg/kg per hour thereafter. In nonsmoking adults, older patients, and those with cor pulmonale, congestive heart failure, and liver disease, the loading dose remains the same, but the maintenance dose is reduced to between 0.1 and 0.5 mg/kg per hour. In patients already receiving theophylline, the loading dose is frequently withheld or, in extreme situations, reduced to 0.5 mg/kg.
The most common side effects of theophylline are nervousness, nausea, vomiting, anorexia, and headache. At plasma levels greater than 30 g/mL there is a risk of seizures and cardiac arrhythmias.
Anticholinergic drugs such as atropine sulfate produce bronchodilation in patients with asthma, but their use is limited by systemic side effects. Nonabsorbable quaternary ammonium congeners (atropine methylnitrate and ipratropium bromide) have been found to be both effective and free of untoward effects. They may be of particular benefit for patients with coexistent heart disease, in whom the use of methylxanthines and -adrenergic stimulants may be dangerous. The major disadvantages of the anticholinergics are that they are slow to act (60 to 90 min may be required before peak bronchodilation is achieved) and they are only of modest potency.
Glucocorticoids are the most potent and most effective anti-inflammatory medications available. Systemic or oral steroids are most beneficial in acute illness when severe airway obstruction is not resolving or is worsening despite intense optimal bronchodilator therapy, and in chronic disease when there has been failure of a previously optimal regimen with frequent recurrences of symptoms of increasing severity. Inhaled glucocorticoids are used in the long-term control of asthma.
Glucocorticoids are not bronchodilators and the correct dose to use in acute situations is a matter of debate. The available data indicate that very high doses do not offer any advantage over more conventional amounts. In the United States, a usual starting dose is 40 to 60 mg of methylprednisolone intravenously every 6 h. Since intravenous and oral administration produce the same effects, prednisone, 60 mg every 6 h, can be substituted. Clinical impressions suggest that smaller quantities may work as effectively, but there are no confirmatory data. In the United Kingdom and elsewhere, acute asthma both in and out of hospital is frequently treated with doses of prednisolone ranging from 30 to 40 mg given once daily. It should be emphasized that the effects of steroids in acute asthma are not immediate and may not be seen for 6 h or more after the initial administration. Consequently, it is mandatory to continue vigorous bronchodilator therapy during this interval. Irrespective of the regimen chosen, it is important to appreciate that rapid tapering of glucocorticoids frequently results in recurrent obstruction. Most authorities recommend reducing the dose by one-half every third to fifth day after an acute episode. In situations in which it appears that continued steroid therapy will be needed, an alternate-day schedule should be instituted to minimize side effects. This is particularly important in children, since continuous glucocorticoid administration interrupts growth. Long-acting preparations such as dexamethasone should not be used in this approach, for they defeat the purpose of alternate-day schedules by causing prolonged suppression of the pituitary-adrenal axis. The availability of inhaled agents has all but eliminated the need for this form of therapy.
These drugs are indicated in patients with persistent symptoms. The agents currently available in the United States are beclomethasone, budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide. Each has relative advantages and disadvantages, and they are not absolutely interchangeable on either a microgram or a per puff basis. However, all of these drugs share the ability to control inflammation, facilitate the long-term prevention of symptoms, and reduce the need for oral glucocorticoids.
There is no fixed dose of inhaled steroid that works for all patients. Requirements are dictated by the response of the individual and wax and wane in concert with progression of the disease. Generally, the worse the patient's condition, the more inhaled steroid is needed to gain control. Once achieved, however, remission can often be maintained with quantities as low as one or two puffs/day. Inhaled steroids can take up to a week or more to produce improvements; consequently, in rapidly deteriorating situations, it is best to prescribe oral preparations and initiate inhaled drugs as the dose of the former is reduced. In less emergent circumstances, the quantity of inhaled drug can be increased up to 2 to 2.5 times the recommended starting doses. It is critical to remember that the side effects increase in proportion to the dose-time product. In addition to thrush and dysphonia, the increased systemic absorption that accompanies larger doses of inhaled steroids has been reported to produce adrenal suppression, cataract formation, decreased growth in children, interference with bone metabolism, and purpura. As is the case with oral agents, suppression of inflammation, per se, cannot be relied upon to provide optimal results. It is essential to continue adrenergic or methylxanthine bronchodilators if the patient's disease is unstable.
Mast Cell-Stabilizing Agents
Cromolyn sodium and nedocromil sodium do not influence airway tone. Their major therapeutic effect is to inhibit the degranulation of mast cells, thereby preventing the release of the chemical mediators of anaphylaxis.
Cromolyn sodium and nedocromil, like the inhaled steroids, improve lung function, reduce symptoms, and lower airway reactivity in persons with asthma. They are most effective in atopic patients who have either seasonal disease or perennial airway stimulation. A therapeutic trial of two puffs four times daily for 4 to 6 weeks frequently is necessary before the beneficial effects of the drug appear. Unlike steroids, nedocromil and cromolyn sodium, when given prophylactically, block the acute obstructive effects of exposure to antigen, industrial chemicals, exercise, or cold air. With antigen, the late response is also abolished. Therefore, a patient who has intermittent exposure to either antigenic or nonantigenic stimuli that provoke acute episodes of asthma need not use these drugs continuously but instead can obtain protection by taking the drug only 15 to 20 min before contact with the precipitant.
As mentioned earlier, the cysteinyl leukotrienes (LTC4, LTD4, and LTE4) produce many of the critical elements of asthma, and drugs have been developed to either reduce the synthesis of all of the leukotrienes by inhibiting 5-lipoxygenase (5-LO), the enzyme involved in their production, or competitively antagonizing the principal moiety (LTD4). Zileuton is the only 5-lipoxygenase synthesis inhibitor that is available in the United States. It is a modest bronchodilator that reduces asthma morbidity, provides protection against exercise-induced asthma, and diminishes nocturnal symptoms, but it has limited effectiveness against allergens. Hepatic enzyme levels can be elevated after its use, and there are significant interactions with other drugs metabolized in the liver. The LTD4 receptor antagonists (zafirlukast and montelukast) have therapeutic and toxicologic profiles similar to that of zileuton but are long acting and permit twice to single daily dose schedules.
This class of drugs does not appear to be uniformly effective in all patients with asthma. Although precise figures are lacking, most authorities put the number of positive responders at less than 50%. As yet, there is no way of determining prospectively who will benefit, so clinical trials are required. Typically, if there is no improvement after one month, treatment can be discontinued.
It has been suggested that steroid-dependent patients might benefit from the use of immunosuppressant agents such as methotrexate or gold salts. The effects of these agents on steroid dosage and disease activity are minor, and side effects can be considerable. Consequently, this form of treatment can be viewed only as experimental. Opiates, sedatives, and tranquilizers should be absolutely avoided in the acutely ill patient with asthma because the risk of depressing alveolar ventilation is great, and respiratory arrest has been reported to occur shortly after their use. Admittedly, most individuals are anxious and frightened, but experience has shown that they can be calmed equally well by the physician's presence and reassurances. -Adrenergic blockers and parasympathetic agonists are contraindicated because they can cause marked deterioration in lung function.
Expectorants and mucolytic agents have enjoyed great vogue in the past, but they do not add significantly to the treatment of the acute or chronic phases of this disease. Mucolytic agents such as acetylcysteine may actually produce bronchospasm when administered to susceptible patients with asthma. This effect can be overcome by aerosolizing them in solution with a -adrenergic agent. The use of intravenous fluids in the treatment of acute asthma also has been advocated. There is little evidence that this adjunct hastens recovery. Nonstandard bronchodilators, such as intravenous magnesium sulfate, for the treatment of acute asthma attacks are not yet warranted in clinical practice because of the controversy surrounding their efficacy.
The treatment of patients with asthma who have coexisting conditions such as heart disease or pregnancy does not differ materially from that outlined above. Therapy with inhaled 2-selective and anti-inflammatory agents is the mainstay. The lowest doses of adrenergics that produce the desired effects should be used.
Framework for Management
The most effective treatment for acute episodes of asthma requires a systematic approach based on the aggressive use of sympathomimetic agents and serial monitoring of key indices of improvement. Reliance on empirism and subjective assessment is no longer acceptable. Multiple inhalations of a short-acting sympathomimetic, such as albuterol, are the cornerstone of most regimens. These drugs provide three to four times more relief than does intravenous aminophylline. Anticholinergic drugs are not first-line therapy because of their long lag time to onset (~ 30 to 40 min) and their relatively modest bronchodilator properties. In emergency situations, 2 agonists can be given every 20 min by handheld nebulizer for 2 to 3 doses. The optimum cumulative dose of albuterol appears to lie between 5 and 10 mg. It does not matter how the adrenergic agonists are inhaled. Treatment with albuterol administered by jet nebulizer, metered dose inhaler, or dry powder inhaler all provide equal resolution in acute situations. Aminophylline or ipratropium can be added to the regimen after the first hour in an attempt to speed resolution. Recent studies in a large series of patients demonstrate that 2 agonists alone terminate attacks in approximately two-thirds of patients, and that another 5 to 10% benefit from a methylxanthine or ipratropium in combination with a sympathomimetic. The remainder have a poor acute response to all forms of therapy.
Acute episodes of bronchial asthma are one of the most common respiratory emergencies seen in the practice of medicine, and it is essential that the physician recognize which episodes of airway obstruction are life-threatening and which patients demand what level of care. These distinctions can be made readily by assessing selected clinical parameters in combination with measures of expiratory flow and gas exchange. The presence of a paradoxical pulse, use of accessory muscles, and marked hyperinflation of the thorax signify severe airways obstruction, and failure of these signs to remit promptly after aggressive therapy mandates objective monitoring of the patient with measurements of arterial blood gases and the peak expiratory flow rate (PEFR) or FEV1.
In general, there is a correlation between the severity of the obstruction with which the patient presents and the time it takes to resolve it. Those individuals with the most impairment typically require the most extensive therapy for resolution. If the PEFR or FEV1 is equal to or less than 20% of predicted on presentation and does not double within an hour of receiving the preceding therapy, the patient is likely to require extensive treatment including glucocorticoids before the obstruction dissipates. This group represents approximately 20% of all the patients who present for acute care. They generally require 3 to 4 days of inpatient treatment before becoming asymptomatic. In such individuals, if the clinical signs of a paradoxical pulse and accessory muscle use are diminishing, and/or if PEFR is increasing, there is no need to change medications or doses; the patient need only be followed. However, if the PEFR falls by more than 20% of its previous value or if the magnitude of the pulsus paradoxicus is increasing, serial measures of arterial blood gases are required, as well as a reconsideration of the therapeutic modalities being employed. If the patient has hypocarbia, one can afford to continue the current approaches a while longer. On the other hand, if the PaCO2 is within the normal range or is elevated, the patient should be monitored in an intensive care setting, and therapy should be intensified to reverse or arrest the patient's respiratory failure.
The goal of chronic therapy is to achieve a stable, asymptomatic state with the best pulmonary function possible using the least amount of medication. The first step is to educate patients to function as partners in their management. The severity of the illness needs to be assessed and monitored with objective measures of lung function. Asthma triggers should be avoided or controlled, and plans should be made for both chronic management and treatment of exacerbations. Regular follow-up care is mandatory. With respect to pharmacologic interventions, in general, the simplest approach works best. Infrequent symptoms require only the use of an inhaled sympathomimetic on an "as needed" basis. When the disease worsens, as manifested by nocturnal awakenings and daytime symptoms, inhaled steroids and/or mast cell-stabilizing agents should be added. If symptoms do not abate, the dose of inhaled steroids can be increased. An upper limit has not yet been established, but side effects of glucocorticoid excess begin to appear more frequently when the dose exceeds 2.0 mg/d. Persistent asthma complaints can be treated with long-acting inhaled 2 agonists, sustained-release theophylline, and/or parasympatholytics. In patients with recurrent or perennial symptoms and unstable lung function, oral steroids in a single daily dose are added to the regimen. Once control is reached and sustained for several weeks, a step-down reduction in therapy should be undertaken, beginning with the most toxic drug, to find the minimum amount of medication required to keep the patient well. During this process, the PEFR should be monitored and medication adjustments should be based on objective changes in lung function as well as on the patient's symptoms.
Prognosis and Clinical Course
The mortality rate from asthma is small. The most recent figures indicate fewer than 5000 deaths per year out of a population of approximately 10 million patients at risk. Death rates, however, appear to be rising in inner-city areas where there is limited availability of health care.
Information on the clinical course of asthma suggests a good prognosis particularly for those whose disease is mild and develops in childhood. The number of children who still have asthma 7 to 10 years after the initial diagnosis varies from 26 to 78%, averaging 46%; however, the percentage who continue to have severe disease is relatively low (6 to 19%).
Although there are reports of patients with asthma developing irreversible changes in lung function, these individuals frequently have comorbid stimuli such as cigarette smoking that could account for these findings. Even when untreated, individuals with asthma do not continuously move from mild to severe disease with time. Rather, their clinical course is characterized by exacerbations and remissions. Some studies suggest that spontaneous remissions occur in approximately 20% of those who develop the disease as adults and that 40% or so can be expected to experience improvement, with less frequent and severe attacks, as they grow older.