ASTHMA
Asthma is a chronic inflammatory disease of airways that affects an estimated 5% to 7% of the population, with prevalence and mortality greatest among inner city residents and increasing. A heightened appreciation for the underlying inflammatory pathophysiology of asthma has markedly altered the approach to therapy in the past decade. Antiinflammatory agents have superseded bronchodilators as the mainstay of treatment.
Although there are no cures for asthma, effective outpatient management is available. Many exacerbations leading to emergency room visits are preventable, so much so that the frequency of emergency room visits for asthma has become a common outcome measure and proxy for quality of primary care. The primary care physician needs to be skilled in asthma management and able to design a practical, cost-effective program that minimizes side effects, maximizes functional status, and reduces the frequency and severity of flares. Because patient involvement in asthma care is essential to a good outcome, the development of a strong patient–doctor relationship and the provision of detailed patient education are extremely important.
Airway inflammation underlies the pathology and pathophysiology of asthma; characteristic features are mast cell degranulation, eosinophilic infiltration, endothelial activation, and recruitment and proliferation of T cells. The normal respiratory epithelium is denuded and replaced by proliferating goblet cells. The resulting edema, inflammatory exudate, and such bronchial hyperresponsiveness lead to airway obstruction. Bronchial hyperresponsiveness is exacerbated by loss of the normal epithelial barrier and can be triggered by exposure to allergens, exercise, cold, and pharmacologic agents. Epidemiologically important allergens leading to sensitization include dust mite and cockroach antigens, which helps to explain the high prevalence of asthma among inner city residents. Air pollutants and occupational exposures sensitize others.
Many precipitants and mediators of the bronchoconstriction, edema, and mucous production that characterize asthma have been identified; however, their precise roles and interrelationships remain to be elucidated. The list of mediators includes prostaglandin D2, leukotrienes (slow-reacting substance of anaphylaxis), eosinophilic chemotactic factor, and histamine. Leukotrienes are emerging as particularly important mediators of inflammation. They increase the migration of eosinophils, production of mucus, airway wall edema, and bronchial hyperresponsiveness. They appear to be important triggers of bronchoconstriction on airway exposure to cold dry air, as in exercise- and cold-induced asthma.
Asthmatic reactions have early and late phases. The acute bronchoconstrictive phase involves the rapid development of reversible airway obstruction in response to stimuli that fail to affect normal persons. Stimuli include allergens (e.g., molds, sulfites, animal dander, pollens), aspirin, exercise, emotional stress, viral respiratory infections, and respiratory irritants, such as perfumes and dusts.
In addition to the initial mediator-induced bronchospasm, asthmatic patients experience a second or late-phase reaction 6 to 12 hours later. This late-phase reaction is believed to be a manifestation of the inflammatory response that is more refractory to bronchodilator treatment than the initial one. Neutrophil chemotactic factor is believed to play a role. Even some patients with exercise-induced asthma experience a late reaction.
Elements of a neurogenic pathway have also been elucidated. Bronchial smooth muscle is responsive to autonomic influences; it has not been determined whether the effect is direct or by way of biochemical mediators. Vagal stimulation and cholinergic drugs cause bronchial constriction; b-adrenergic stimulation appears capable of countering the cholinergic influences. Bronchial irritants and emotional stress are thought to precipitate bronchospasm, in part, by way of triggering vagal reflexes. The nerve endings of asthmatic patients have been found to be devoid of the bronchodilator neuropeptide vasoactive intestinal polypeptide.
Traditionally, asthma has been divided clinically into “extrinsic” and “intrinsic” categories, with extrinsic disease believed to be a manifestation of immunologic reactivity to environmental antigens, and intrinsic disease thought to be unrelated to allergen exposure. However, patients in both groups have demonstrated reactivity related to immunoglobulin E (IgE), which challenges the notion of separate allergen-related and non–allergen-related categories of asthma. Nonetheless, the categories are still used clinically (see following discussion).
It used to be thought that asthma was not associated with any permanent sequelae, but airway remodeling has been detected pathologically. The full physiologic significance of this remodeling remains to be determined, but declines in pulmonary function over time have been identified in long-term epidemiologic studies.
Regardless of precipitant, the pathophysiologic final common pathway is airway inflammation, with bronchial edema, smooth-muscle contraction, and excessive mucus production. Clinical manifestations include wheezing, dyspnea, cough, and sputum. Presentations range from pure bronchospasm, with little cough and sputum production, to a predominance of bronchorrhea and coughing that mimics bronchitis or an upper respiratory tract infection. In fact, cough and sputum production may be the initial symptoms of an asthmatic attack. Nocturnal exacerbation of symptoms is common, linked to the diurnal variation in blood levels of catecholamines and vagal tone.
Extrinsic Asthma. Although classifying asthma according to allergen responsiveness may be an oversimplification, the extrinsic and intrinsic categories do describe two relatively distinct clinical presentations. Patients with extrinsic asthma typically give a history of atopy, onset of symptoms during childhood or adolescence, predictable seasonal occurrence, and response to environmental stimuli. However, the condition can occur at any age, and attacks may take place seasonally or year-round, precipitated by such common household allergens as dust mites, animal dander, and fungal spores. Anxiety, inhalation of airway irritants, and exposure to perfumes and strong household odors can also precipitate asthmatic episodes in these patients. The course of attacks is usually self-limited, although some patients have severe bouts requiring hospitalization. Prognosis is relatively good, with 70% found to be symptom-free 20 years after onset.
Intrinsic Asthma. Patients with intrinsic asthma usually begin having symptoms in the third or fourth decade. Although no identifiable extrinsic allergen is associated with attacks in these patients, they do demonstrate elevations in serum IgE, similar to those of patients with intrinsic disease. Sputum production can be considerable, so that differentiation from chronic bronchitis is sometimes difficult. Minor upper respiratory tract infections often precipitate attacks. Some patients present with exertional dyspnea or cough and no demonstrable wheezing, although expiratory flow rates are clearly reduced. Intrinsic asthma is sometimes more refractory to treatment than is extrinsic disease.
Postexertional Asthma is a form of airway hyperreactivity most common in children and adolescents. The stimulus is believed to be a reduction in the temperature of inhaled air, which leads to mediator release (especially leukotrienes) in susceptible patients. Both initial and late-phase reactions have been identified. Vigorous exercise on a cold, dry day is particularly apt to trigger an attack; airway temperature can become quite low in such circumstances. Although bronchospasm does not occur during exercise, it becomes marked shortly after exercise ends and can last for up to an hour.
Occupational Asthma has gained increasing recognition as an important cause of work-related disability. True occupational asthma involves the development of sensitization through inhalation exposure to an occupationally related allergen. Exposure to irritant or toxic pollutants in the workplace can also trigger bronchospasm, especially in a person with preexisting airway hyperresponsiveness. Cold air, sulfur dioxide in low concentrations, fluorocarbons, and inert dusts are common irritants that stimulate reflex bronchospasm. Toxic gases such as sulfur dioxide in high concentrations, halogens, ammonia, acid fumes, and solvent vapors cause inflammatory bronchoconstriction. Important allergens include animal proteins, enzymes, grain and cereal dusts, seeds, vegetable gums, and legumes. Other substances have pharmacologic activity; histamine-releasing compounds are present in cotton dust, organic acids are found in wood dust, and numerous chemicals have anticholinesterase activity. Some agents provoke asthma through multiple mechanisms; toluene diisocyanate (TDI) has reflex, pharmacologic, b-blocking, and IgE effects.
Patients with occupational asthma caused by toxic or irritant substances characteristically report a direct relation between exposure and onset of symptoms. Those with allergen-induced disease note no symptoms at the time of the first exposure but marked wheezing after even minor repeated contact with the allergen (anamnestic response). Typically, patients with occupational asthma are symptom-free during days off from work, only to have a flare-up on returning.
Nasal Polyps and Aspirin Sensitivity comprise a curious but important familial asthma syndrome. The bronchospasm associated with aspirin intake may be marked. The finding of nasal polyps in a person with a history of asthma should lead to consideration of aspirin sensitivity.
Categories of Asthma. For management purposes (see below), four categories of asthma have been defined:
Regardless of the type of asthma, subclinical but significant bronchospasm remains for days to weeks after the wheezing of an acute attack subsides. The continuing bronchial hyperresponsiveness is believed to be related to ongoing inflammation. Often, small airways may remain constricted even after large airways have relaxed. The clinical recurrences that commonly develop shortly after the apparent resolution of an acute attack are most often not new episodes but relapses.
The natural history of asthma and the consequences of airway remodeling that result from chronic airway inflammation remain to be fully established, but in population studies with long-term follow-up, asthmatic patients demonstrate a significant and steady decline in FEV1 in comparison with those without asthma. This decline is exacerbated by smoking. Overall mortality for all forms of asthma is 0.1% annually; the rate increases markedly to 3.3% for patients with episodes of status asthmaticus. A disturbing increase in asthma mortality has occurred in the past two decades despite the availability of increasingly effective therapy. The cause for this increase is unclear, but much of it is localized to inner city populations in New York and Chicago, which suggests that increased exposure to potent allergens and air pollution may be contributing, in addition to inadequate access to proper health care.