Diagnosis and Management of Exercise-Induced Asthma
Ned T. Rupp, MEd, MDTHE PHYSICIAN AND SPORTSMEDICINE - VOL 24 - NO. 1 - JANUARY 96
In Brief: Exercise-induced asthma (EIA) affects 12% to 15% of the general population. Its symptoms include chest tightness, shortness of breath, coughing, wheezing, fatigue, and prolonged recovery times after exercise. Diagnosis depends on accurate history, physical examination, and lung function testing. Nonpharmacologic management includes modification of both activity and ambient conditions, along with rigorous patient education. Short-acting inhaled beta2 agonists are the pharmacologic treatment of choice for isolated and breakthrough EIA. Anti-inflammatory medications such as inhaled cromolyn sodium, nedocromil sodium, and corticosteroids are used to control underlying asthma as well as EIA. Other agents such as oral theophylline or long-acting beta agonists may be important but their roles aren't clearly defined.
When undiagnosed, exercise-induced asthma (EIA), a common clinical syndrome characterized by a transient increase in airway resistance following several minutes of exercise (1,2), can be an obstacle to an active lifestyle. But when the disease is identified and well managed, the results can be remarkable for patients of all activity levels. Of the 597 members of the 120214 United States Olympic Team, 67 (11.2%) experienced EIA (3). The athletes who had EIA won 41 medals during the games. Their superb achievements indicate the high level of performance that people who have EIA can reach with appropriate therapy.
How Common is EIA?
EIA affects a broad segment of the population. Up to 90% of people who have asthma experience EIA during the course of their disease, and most consider exercise to be a major precipitant of their asthma (4-6). In addition, 35% to 40% of patients who have allergic rhinitis experience EIA precipitated by allergens, viruses, cold air, air pollutants, or a combination of these factors (2,4-7). The general population who are not diagnosed as asthmatic and do not have noted respiratory allergies have a much lower EIA incidence of 3% to 10%. Combining these groups gives an overall EIA incidence of 12% to 15% (8). The incidence is somewhat higher in children than in adults (8).
Among active people, the incidence of EIA ranges from 3% to more than 12% (3,6,9-11). The presence of EIA in active people, however, may be underreported, as many athletes may not be aware they have the condition. The symptoms of EIA can often be perceived as part of the experience of normal vigorous exercise (11). In addition, denial of illness is common among young athletes.
When Exercise Obstructs
Asthma is an obstructive disease of the airways characterized by airway inflammation and hyperreactivity. Airflow obstruction is influenced by bronchial wall edema, mucus production, airway smooth muscle contraction, and hypertrophy. The obstruction may be initiated by inflammatory events in the airways, particularly the release of inflammatory mediators from mast cells, macrophages, and epithelial cells. Airway hyperreactivity is an exaggerated bronchoconstriction response to various stimuli including allergens, environmental irritants, viral respiratory infections, cold air, and exercise. Airway obstruction brought on by exercise is termed EIA.
The etiology of EIA is probably multifactorial. Though much has been discovered about EIA, complete understanding of the pathophysiology of the disease has not yet been obtained. For example, the concept of airway inflammation contributing to asthma is relatively new, and its impact on management of the disease is still being determined.
There is a general consensus that the airway obstruction that develops in EIA is related to thermodynamic events within the airway during hyperpnea. As a result of hyperventilation during and after exercise, the upper airway is unable to bring inspired air to body temperature and 100% humidity. Heat and water are drawn from the respiratory tissue in order to warm and humidify the inspired air, resulting in respiratory tissue water loss and airway cooling (12-14).
Typically, EIA begins with bronchodilation either during or immediately following exercise. All people experience bronchodilation in response to exercise. Normally, widening of the glottis and bronchodilation meet the increased oxygen requirements during exercise. In EIA, however, the glottis widens but the lower airways constrict. Respiratory demand increases, and forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR) decrease significantly. Maximal bronchoconstriction generally occurs 3 to 15 minutes after exercise ceases (15). Factors that can vary the usual bronchoconstriction timing include environmental conditions such as temperature, humidity, air quality, or pollens; the type, duration, or intensity of the exercise; the time from a previous exercise session; and the degree of bronchial hyperreactivity.
With a second exercise challenge, less than half of the original degree of obstruction will occur—this is defined as the refractory period. Approximately half of patients are refractory within 1 hour, but nearly everyone loses the effect after 2 to 3 hours. It is impossible to predict whether a person will be refractory to EIA, and occurrence of a refractory period may be intermittent in any patient. Original bronchospasm severity plays no role in a patient's refractory status, though certain factors encourage the refractory period: a warm-up session before exercise; breathing or exercising in warm, humid air; and prolonged submaximal exercise.
Though most patients recover from EIA within 1 hour (2), late asthmatic responses that occur 3 to 9 hours after exercise have been reported (16,17). Patients at higher risk for late responses appear to be children and those with severe early responses (2). Some investigators have doubted the existence of this late response or its clinical relevance (19) because bronchoconstriction during the late response is usually much less severe.
In other words, repeated exercise challenge during the refractory period may still reduce FEV1 and PEFR, but less than half as much as with the initial postchallenge reduction (18).
The factors that influence the severity of EIA (table 1) are similar to those that affect the refractory period and include the degree of underlying bronchial hyperreactivity; duration, type and intensity of exercise; environmental conditions; exposure to allergens; respiratory infections; interval since the last episode of EIA (refractory period) (16); and low fitness level. Environmental factors such as cold, dry air, airborne allergens such as pollens or house dust mites, and air pollutants can exacerbate EIA. In patients with EIA who are susceptible to allergens, antigen challenge during exercise has been found to double the intensity of EIA (20). Therefore, designing an individual treatment regimen requires consideration of seasonal and geographic factors. Activities such as running and cycling that require high levels of activity at or near maximal levels of aerobic capacity are most likely to cause EIA. Generally, the more vigorous the exercise, the more rapid and severe the bronchospasm (21). The relationship of duration of exercise to intensity of EIA is more complex. With a short period of activity, the severity of bronchospasm is related to exercise length; however, some patients find that if they continue to exercise after symptoms develop, they may be able to "run through" their bronchospasm (2,8). This effect may be related to the refractory period.
EIA Workup Strategies
In the workup of a patient who has suspected EIA, a thorough history is vital (table 2). The signs and symptoms of EIA are typically those of classic airway obstruction: dyspnea, cough, and chest tightness with or without wheezing, though some patients may also complain of gastrointestinal discomfort. EIA may also present as chest pain in children and adolescents (22). Without a careful history, possibly augmented by teammates, coaches, family, or friends, these signs and symptoms may be easily misinterpreted as postexercise fatigue. Also, denial of symptoms is common, especially among student-athletes because of peer pressure, embarrassment, and fear of losing their place on the team (11).
A careful physical examination of the upper and lower respiratory tracts is important. However, because of the episodic nature of EIA, the physical exam is often normal despite the presence of significant disease. The pharynx should be examined for mucus indicating postnasal drainage. Examination of the nose may reveal erythema, congestion, and enlarged turbinates. Sinuses should be percussed to assess for tenderness. Examination of the lower respiratory tract should include auscultation of the lungs to determine the presence of a prolonged expiratory phase, wheezing, or coughing with inspiration.
Pulmonary function testing is an integral part of EIA diagnosis. Initial FEV1, forced vital capacity (FVC), FEV1/FVC ratio, and PEFR values should be determined. FEV1 and FEV1/FVC values below 80% of predicted value indicate obstructive airway disease. Caution should accompany a diagnosis based on PEFR measurements: Peak flow is highly effort dependent, and a low PEFR may indicate either obstructive or restrictive respiratory disease. Once the EIA diagnosis has been made, PEFR measurements may be useful in following the course of the disease and response to treatment.
However, many patients have symptoms of EIA but a normal resting pulmonary function test. These patients may require inhalation challenge, exercise challenge, or a therapeutic trial to establish the diagnosis. (See "Exercise Challenge for Exercise-Induced Bronchospasm: Confirming Presence, Evaluating Control," August 1995, page 47.) Furthermore, active patients often have lung function well above normal predicted values; for example, a 30% drop in a patient with 150% of normal function may appear satisfactory, but could represent a bronchospastic problem for that individual.
Bronchoprovocation testing is sensitive for diagnosing hyperreactive airways (6). Patients inhale gradually increasing concentrations of a bronchoconstrictor, usually methacholine (though histamine may also be used), while spirometric changes in airflow are recorded. The degree of airway hyperreactivity is related to the amount of bronchoconstrictor required to cause bronchospasm. Another laboratory test that has gained popularity is bronchoprovocation with cold air.
Exercise challenge testing involves determining baseline lung function before exercise and measuring forced expiration at 5- to 10-minute intervals following exercise for 15 to 30 minutes. Exercise challenge should consist of 6 to 10 minutes of strenuous exercise at 85% to 90% of the predicted maximal heart rate. Postexercise decreases of 10% to 20% in FEV1 indicate mild EIA, 20% to 40% moderate, and more than 40% severe (23). When the patient's history is compatible with EIA yet spirometry at 15 minutes is nondiagnostic, a prolonged postexercise evaluation is necessary (15).
Exercise challenge is less sensitive than methacholine challenge, so negative results do not exclude the diagnosis of EIA; however, exercise testing is highly specific for EIA, and positive results provide good assurance of the presence of the disease. Results of provocation testing may vary due to the influences of allergens, air pollution, temperature, or upper respiratory infections. These same factors can account for the seasonal occurrence of EIA in many people.
Because a patient who has EIA may have normal "at rest" pulmonary function, a history consistent with EIA should prompt patient education about the condition and its treatment. A trial of a short-acting beta2 agonist prior to exercise, with symptom monitoring by the patient, is often the next appropriate step. Follow-up exercise challenge is often unnecessary in cases of clear benefit, so this strategy can be a very cost-effective management approach.
Challenge testing is warranted when the patient history is unclear or when the patient's coach or parents have brought the symptoms to the physician's attention. Testing can help avoid overuse or unnecessary use of medication when the patient's breathing problems are caused by anxiety, hyperventilation syndrome, poor conditioning, upper airway obstruction, or seasonal EIA. Finally, an exercise challenge can not only reproduce the symptoms for the patient, but also encourage compliance by demonstrating the effectiveness of therapy.
The goal of EIA management is to allow patients to participate fully in athletic activities without difficulty. The ultimate success of pharmacologic therapy will depend on the following nonpharmacologic strategies: activity modification, improvement in ambient air conditions, and patient education.
Management should begin with efforts to increase physical conditioning, which can reduce the requirements for pharmacotherapy and decrease the incidence of asthma attacks (7,24). Also, short bursts of activity have been shown to decrease EIA (25). By incorporating warm-up activities into their exercise program, patients may be able to take advantage of the refractory period and decrease the frequency and severity of bronchospastic episodes.
Warm, humid environments or breathing in warm, humid air will ameliorate EIA and will improve the patient's chances of being refractory to repeated exercise challenge over the next 1 to 3 hours. Wearing a face mask during activity warms and humidifies inspired air when outdoor conditions are cold and dry. Breathing through the nose rather than the mouth will filter, warm, and humidify inspired air.
Education can boost the effectiveness of other therapeutic interventions. Patients must be aware of the conditions that exacerbate their disease and how to avoid them, early signs of an impending asthma attack, and appropriate use of medications for prevention and flares.
The pharmacologic goals of treating EIA are preventing the onset of asthma episodes and treating breakthrough episodes that may occur following exercise. Several classes of drugs with bronchodilating and anti-inflammatory effects are used to treat EIA, including beta agonists, cromolyn sodium, nedocromil sodium, and corticosteroids—all most frequently given by inhalation—and oral theophylline.
Beta agonists are the drugs of choice for preventing isolated EIA and for on-demand treatment of exercise-induced acute asthma exacerbations (2,6,7,15,24,26). This group includes the established short-acting agents albuterol, bitolterol mesylate, metaproterenol sulfate, pirbuterol acetate, terbutaline sulfate, and the newer, longer-acting salmeterol. Both short and long-acting beta agonists are effective in nearly all patients who have asthma—those with chronic obstruction and those who have only exercise-related obstruction. However, short-acting beta agonists are the most effective agents for preventing EIA, and are effective in 80% to 95% of patients (27). They reverse contraction of bronchial smooth muscle and are very effective bronchodilators (28). In the laboratory, beta agonists have exhibited some anti-inflammatory activity through stabilization of mast cells and prevention of release of histamine and other inflammatory mediators; however, the clinical relevance of these effects is not yet known (29). Short-acting inhaled beta agonists have a rapid onset of action, usually within 5 minutes, and maximal bronchodilation usually occurs within 15 minutes (30). Therefore, to achieve maximal effect during intense exercise, short-acting beta agonists should be administered 15 minutes before exercise. Duration of action varies, but effectiveness against EIA generally lasts 3 to 6 hours.
Salmeterol, the long-acting beta agonist approved for use in patients age 12 or older in the United States, has been shown to protect against EIA for up to 12 hours in 55% of patients who have EIA and take no chronic asthma medications (31). Because its onset of action is slower than that of the short-acting beta agonists, salmeterol is never to be used as a rescue medication, and dosing is limited to 2 puffs every 12 hours (32). Patients who take salmeterol, therefore, must have a short-acting beta agonist available to relieve sudden onset of bronchospasm (33). The effectiveness of short-acting beta agonists for rescue purposes may be blunted if salmeterol is being used (34).
In addition, tolerance to the effects of beta agonists is an area of active research. In general, tachyphylaxis appears to occur with regular use of beta agonists (33,35,36). With regard to EIA, a recent study (37) reported that after 4 weeks of regular salmeterol administration, tachyphylaxis developed to the point that there was no significant difference in effectiveness between the drug and placebo. The controversy surrounding the regular use of beta agonists has led to the current consensus recommendation of on-demand use (24,26,38,39).
Current guidelines for the management of EIA begin with administration of a short-acting inhaled beta agonist 15 minutes before exercise. Patients should then undertake a 15-minute warm-up period of stretching and low-level exercise, followed by a 15-minute rest period before intense exercise if possible. If asthma symptoms develop during exercise, on-demand therapy with two puffs of short-acting beta agonist should be repeated (6).
Patients must be carefully educated about the proper use and roles of short- and long-acting beta agonists. If a patient's use of a short-acting beta agonist increases, he or she should immediately contact the physician: Increased use may be a sign of worsening disease, and the patient may need further evaluation and anti-inflammatory therapy. Patients should also clearly understand that a long-acting beta agonist is not intended as rescue medication nor as a replacement for inhaled anti-inflammatory therapy. Recent reports of deaths attributable to respiratory arrest in patients using salmeterol (40,41) emphasize the importance of patient education and proper use of asthma medication.
Cromolyn sodium is another frequently used medication for the treatment of EIA; its anti-inflammatory effects prevent EIA in 70% to 85% of patients, with a very low incidence of side effects (28). Administered before exercise, it is most effective in patients who have normal pulmonary function tests. Cromolyn combined with a beta agonist is highly effective in patients who don't respond to single-medication therapy. Early- and late-phase asthmatic responses are inhibited by cromolyn sodium, though its exact mechanism of action in EIA is unknown. Theories include inhibition of mast cell mediator release and alteration of calcium influx. Because the duration of action and efficacy of cromolyn sodium are less than those of the beta agonists, it is generally used as a second-line agent (7). The greatest inhibitory effect of cromolyn sodium on EIA may occur at much higher doses than provided by two puffs of the metered dose inhaler (42).
Cromolyn is most effective for EIA when given by inhaler 10 to 45 minutes prior to exercise (43). Cromolyn does not have any bronchodilating action, and if it fails to prevent bronchoconstriction, a beta agonist inhaler should be used for immediate relief.
Nedocromil sodium, an inhaled anti-inflammatory agent, has also been found to inhibit exercise-induced asthma (44,45), showing effectiveness equal to that of cromolyn sodium (46). Like cromolyn, nedocromil is administered before exercise and is most effective in patients who have normal pulmonary function tests. Nedocromil combined with a beta agonist is highly effective in patients who don't respond to single-medication therapy.
Corticosteroids administered through an inhaler improve asthma symptoms by reducing airway inflammation and bronchial hyperreactivity. They do not have any immediate bronchodilator effect and are not effective if used alone just prior to exercise. Corticosteroids should instead be used as maintenance therapy to control asthma. Such use can improve the effectiveness of pre-exercise beta agonists in preventing or decreasing the severity of EIA (6,47). Inhaled dosages of less than 400 g daily have a low incidence of side effects. When side effects occur, the most common are oropharyngeal candidiasis and dysphonia; both can be avoided by using a spacer (28).
Oral theophylline has been widely used in the treatment of asthma for decades. Its bronchodilating effects are directly related to plasma concentration, and theophylline may also have some anti-inflammatory effects (29). Theophylline is not a first-line agent in the prevention and treatment of EIA—it is generally used for patients who do not respond well to inhaled beta agonists. Theophylline would be a third choice behind beta agonists and cromolyn for patients under age 12, and would rank behind beta agonists, cromolyn or nedocromil, and perhaps ipratropium bromide in those over age 12. Theophylline may be given either in rapid-release form 1 to 2 hours before exercise or regularly in the sustained-release form for prophylaxis. Even in rapid-release form, theophylline's long onset of action (approximately 90 minutes) limits its use in an athletic setting (29). Factors influencing serum concentration and the possible effect on classroom concentration in children make theophylline less desirable than other options in most patients. As with cromolyn sodium, the combination of theophylline and a beta agonist may be additive in the prevention of EIA (29), though concerns have been raised regarding increased incidence of side effects when these two agents are used together (7).
Ipratropium bromide is a derivative of atropine and has bronchodilating effects. The inhaled drug is used in some patients with EIA who are unable to tolerate or who do not respond well to beta agonists. It may also be used in combination with beta agonists or cromolyn sodium. If cromolyn or nedocromil combined with a beta agonist do not adequately control bronchospasm, a trial of ipratropium bromide would be recommended. The drug has a slower onset of action than beta agonists, and its use in EIA is limited: When used alone, the drug is effective in only 30% to 40% of patients and requires nearly normal baseline pulmonary function to be effective (7). When combined with a beta agonist, ipratropium bromide may be a helpful adjunct in adults who have moderate-to-severe asthma. Though some studies have reported effective prophylaxis of EIA with ipratropium bromide, others have not found it to be effective (48).
Other agents that have been used in the treatment of EIA include antihistamines and calcium channel blockers. Antihistamines decrease bronchospasm in some individuals but will not prevent EIA. However, they can improve nasal function, allowing the patient to breathe better through his or her nose. The calcium channel blockers nifedipine and verapamil hydrochloride have been shown to inhibit mast cell mediator release and prevent symptoms of EIA in a select group of patients (49); however, data are insufficient to recommend them for EIA control.
Recent studies (50,51) report that leukotriene inhibitors and heparin relieve EIA. The clinical effectiveness and use of these medicines will become more apparent after further trials.
Removing Breathing Barriers
From allergies to air temperature, many factors can affect the bronchospastic response of EIA, and the physician must be aware of the nuances of each patient's response. Fortunately, there are many nonpharmacologic and pharmacologic options that can be combined to control nearly any degree of EIA.
The efforts put into the diagnostic workup, follow-up, and patient education are rewarding because they enable patients to perform at or near maximal activity levels.
Dr Rupp is assistant professor of pediatrics and medicine at the Medical College of Georgia in Augusta, Georgia. He is a fellow of the American College of Allergy, Asthma, and Immunology and the American Academy of Allergy, Asthma, and Immunology; he is a member of the sports medicine subcommittee for both organizations. Address correspondence to Ned T. Rupp, MEd, MD, Medical College of Georgia, Section of Allergy and Immunology, Dept of Pediatrics and Medicine, BG-247, Augusta, GA 30912; e-mail to [email protected]