Vincent J. Lacroix, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 27 - NO. 12 - NOVEMBER 1999
In Brief: Exercise-induced asthma (EIA) is a common condition that can impede physical activity, particularly for children, adolescents, and young adults. A detailed patient history can help the physician identify subtle EIA clues such as fatigue or poorer performance than training would predict. A careful physical exam can help rule out conditions that mimic EIA such as respiratory infections or cardiac conditions. Pulmonary function testing is often useful for assessing severity and establishing a baseline for assessing treatment efficacy. Treatment options include nonpharmacologic measures that address the exercise environment and warm-up routines. Several medication options and combinations can help patients avoid symptoms and participate fully in fitness and sports activities.
Exercise-induced asthma is one of the most common conditions among active children, adolescents, and young adults (1). It occurs in almost 90% of people who have chronic asthma and in 40% of individuals who have allergic rhinitis or atopic dermatitis (2).
In random testing of asymptomatic children, the prevalence of EIA was 7% (3). It is important to remember that some children with EIA tend to avoid play; their parents and teachers never realize that they have EIA. Avoidance of physical activity can lead to low fitness levels and lack of motor skills, and the impact of these handicaps on the epidemic of childhood obesity is receiving increasing attention. Children with undiagnosed EIA may also have psychological problems from a poor self-image and poor peer-group acceptance because they do not participate in regular childhood or adolescent activities.
Although the exact prevalence of EIA in athletes is unknown, prevalence varies by sport, from 12% of basketball players (4) to 55% of cross-country skiers (5). Depending on the sport and diagnostic criteria used, it appears that the prevalence of EIA in elite athletes is much higher than originally recognized and may vary between 10% and 50% (6).
Chronic Asthma at a Glance
Chronic asthma is characterized by increased responsiveness of the tracheobronchial tree to a wide variety of stimuli (pollens, cigarette smoke, air pollutants, cold air, viral infections, physical exertion) (7,8). When these are present, smooth-muscle contraction, mucous membrane swelling, bronchial wall edema, and excess mucus production lead to airway narrowing (9). Clinical manifestations include paroxysmal or persistent coughing, wheezing, dyspnea, and/or chest tightness (10). Symptoms reverse with treatment.
Unlike other chronic airway diseases, asthma is not progressive, even without treatment (11). Airway inflammation or its consequences are believed to be important in the pathogenesis and persistence of asthma; therefore, management focuses on reducing inflammation with environmental control and disease-modifying agents, rather than symptomatic therapy alone (10). The possibility has been raised that undertreated asthma could lead to pulmonary fibrosis from chronic inflammation of the bronchial tissues.
Because people who have asthma differ with respect to provocation factors, clinical manifestations, disease progression, and treatment responsiveness, asthma is often viewed as a syndrome, rather than a unique disease entity (11).
EIA develops when vigorous physical activity triggers airway narrowing in people who have heightened bronchial reactivity (12). In short, EIA is a reversible airway obstruction that occurs during or after exertion; its symptoms include cough, wheezing, dyspnea, and/or chest tightness.
EIA can occur in otherwise healthy people who do not have chronic asthma. Exercise is the only stimulus for their asthma symptoms, which most likely reflect a different pathophysiologic event than chronic asthma does. However, EIA can also occur in people who have chronic asthma and may not be aware that their symptoms during exercise are a manifestation of asthma. Because the treatments for EIA and chronic asthma are different, it is imperative that every new patient with asthma symptoms be assessed with either peak expiratory flow rates or baseline pulmonary function tests to determine whether the asthma is chronic or exercise induced (6).
What Causes EIA?
The pathophysiology of EIA is still unknown. There are two main theories.
Water loss theory. Normally, when dry air at 32°F (0°C) is inspired through the nose, the nose, pharynx, and first seven generations of bronchi "condition" the air, warming it to 98.6°F (37°C) and saturating it with water vapor before the air reaches delicate alveolar membranes.
With exercise, the ventilation rate increases markedly and can exceed 200 L per minute. Most breathing then occurs through the mouth, bypassing upper-airway conditioning. For the air reaching the small airways to be warmed and saturated with water, the upper airways of the lungs must contribute water vapor from the surface liquid on the respiratory epithelium. This loss of water from the epithelium of the bronchial mucosa dries the airway, changing the osmolarity, pH, and temperature of the periciliary fluid. Hyperosmolarity of the airways is believed to cause mediator release and bronchoconstriction. Bronchoactive mediators may include histamine, leukotrienes, and prostaglandins released from mast cells and/or epithelial cells (6).
Heat-exchange theory. The second theory, which may account for why EIA can occur after exercise is terminated, is that increased ventilation during vigorous exercise cools the airways. Once exercise ceases, the bronchial vasculature dilates and engorges to rewarm the epithelium. Rebound hyperemia of the bronchial vascular bed impinges and narrows the airway. Engorged vessels can also leak, leading to mediator release and bronchospasm (6).
Tracking the EIA Response
Normally, airways dilate during exercise, allowing airflow to meet increased muscular oxygen demands. Bronchodilation is thought to result from decreased cholinergic activity in the airways as exercise begins. Increasing concentrations of the catecholamines epinephrine and norepinephrine may play a role (13).
Immediate response. In patients who have EIA, initial bronchodilation is diminished, and bronchoconstriction develops after 6 to 8 minutes of vigorous exercise. (Though 6 to 8 minutes of exercise is traditionally used for clinical exercise testing, most athletes exercise longer, and their symptoms may begin after 8 minutes) (6). The maximal decrease in pulmonary function (nadir) occurs about 15 minutes after exercise begins. Pulmonary function returns to its original level 30 to 60 minutes after exercise has ended (12,14,15).
For this immediate response to occur, a critical level of exercise intensity is required, usually greater than 80% of the maximum predicted heart rate. The mode of exercise (eg, running vs cycling) may be relatively unimportant, as long as the minute-ventilation values are comparable (14). The asthmogenicity of any given sport is likely determined by the intensity of exertion and the ambient conditions. In general, interrupted, mild exercise is less likely to cause EIA than continuous, high-intensity exercise (table 1) (6).
Late response. Late response, a second drop in lung function 6 to 8 hours after the onset of exercise, occurs in about 30% of patients with EIA, particularly children. The term is normally used to describe an asthmatic response to allergen exposure; it is thought that mast-cell activation and mediator release attract inflammatory cells to the airways.
If exercise induces a delayed release of mediators from the mast cells and if these mediators trigger an inflammatory response, the late response may indeed be exercise induced (14). But many investigators believe the late response is caused by diurnal variations in pulmonary function rather than an exercise stimulus (15).
Refractory period. In 50% of athletes with EIA, vigorous exercise within 2 hours after an initial exercise-induced episode provokes a weaker (less than half as intense) bronchoconstriction response (14). This interval is defined as the refractory period. The mechanism that induces the refractory period is unclear. Mast cell degranulation or the release of a bronchodilating prostaglandin has been suggested. The refractory period can be used to benefit athletes who have asthma, as described below (15).
History. When a patient presents with symptoms that suggest EIA, one must take a good history to rule out other airway diseases that are associated with increased airway responsiveness during or after exercise, such as cystic fibrosis, chronic bronchitis, and pneumonia (table 2). It is important to differentiate between chronic and acute asthma because treatments differ (tables 3 and 4 [table 4 not shown]).
The classic presentation of EIA is coughing, excessive sputum production, wheezing, dyspnea, and/or chest tightness immediately following 6 to 8 minutes of strenuous exercise. However, many individuals will present with more subtle findings of chest discomfort, stomachache, fatigue, feeling out of shape, inability to keep up with peers, or poorer performance than training would predict. These symptoms may occur during or after exercise. Syncope is not a symptom of EIA, and its occurrence during exercise signals the need for a cardiac evaluation.
Environmental factors are also important EIA triggers. As described above, cold, dry air is especially asthmogenic. Air pollutants such as tobacco smoke, sulfur dioxide, and nitrogen oxide (smog), as well as airborne allergens such as molds and pollens can aggravate EIA. While competitive athletes may adjust their training schedules to avoid exposure to pollutants and allergens, for competition they must deal with the triggers present in the environment (6).
Physical examination. Physical examination includes inspection of the facies for allergic "shiners" and the nasal cavity to detect nasal polyps or other inflammatory changes. Examination of the skin may reveal eczematous plaques on the extensor surface of the extremities, and inspection of the hands may reveal digital clubbing. A complete cardiovascular exam should be done, especially to detect murmurs or arrhythmias. Finally, the lungs should be thoroughly auscultated to detect wheezing, rales, or rhonchi. If wheezing is heard at rest, the patient most likely has chronic asthma. However, the lungs of most patients with EIA are clear at rest, and the physician must use other means to objectively diagnose EIA.
Empiric testing. While not as scientific as the methods described below, a therapeutic trial is a practical way to confirm EIA. Patients take beta-2 agonists and/or mast-cell stabilizers before exercise; the EIA diagnosis is confirmed if the medications prevent or diminish symptoms (12). This method is commonly used in busy clinical practices. The problem is that it does not allow the physician to determine if the patient has chronic asthma with an exercise exacerbation or has solitary EIA. Because treatment is different for these two conditions, it is important to determine the patient's baseline pulmonary function by formal testing or at least by review of medical symptoms and past diagnoses and treatments (6).
Pulmonary function testing. Baseline pulmonary function can be measured using spirometry in the physician's office or clinic or in a laboratory. The disadvantage of spirometry is that it requires cumbersome equipment that cannot easily be transported to the field of play. Certain authors and researchers prefer the portable, inexpensive peak flow meters that can be used by athletes and coaches in the field. The peak expiratory flow rate (PEFR) more accurately reflects real-life exercise conditions, including intensity, outdoor air temperature and pollutants, mode (eg, mountain biking), and warm-up (15).
The most precise testing method, however, is exercise challenge in a laboratory. A variety of pulmonary function variables can be measured: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), PEFR, and forced expiratory flow between 25% and 75% of forced vital capacity (FEF 25%-75%). The index most often used is FEV1. In an athlete with solitary EIA, the preexercise baseline FEV1 will be within 80% to 100% of predicted normal values, depending on current status and the effectiveness of and compliance with treatment. In an athlete with chronic asthma, the baseline FEV1 will be less than 80% of the predicted normal value.
For the exercise challenge, laboratories commonly use treadmill running, but one can also use ergometric equipment to simulate the athlete's sport, such as cycling or rowing. The protocol consists of 5 to 8 minutes of steady-state exercise at high intensity (75% to 80% of maximum predicted heart rate). The exercise should be as aerobically intense as possible without reaching the anaerobic threshold. If the anaerobic threshold is crossed, the athlete may be unable to complete the test, and catecholamines may be released, causing bronchodilation. No warm-up is allowed, as it may blunt bronchospasm (1).
After the test, spirometry measurements are taken at, for example, every 3 minutes (2, 5, 8, 11, 14, 17, 20) after exercise. More frequent measurements could enhance the test's sensitivity, but in practice they may increase the chance of false-positive results from inadvertent poor efforts or from bronchospasm due to the maneuvers themselves. A 15% fall in FEV1 or PEFR is often chosen as the arbitrary threshold for a positive test (6). A 15% to 20% drop in FEV1 suggests mild EIA, a 20% to 30% drop suggests moderate EIA, and a more than 30% drop suggests severe EIA (9). Spirometric data should be correlated with the patient's history, risk factors, and physical examination before, during, and after the procedure (1).
Spirometry, peak flow meter, and exercise challenge data can all be used to evaluate how well an athlete's current medical regimen controls symptoms during exercise. Serial testing can help develop an effective long-term treatment program that involves the fewest medications, doses, and side effects (1).
If the exercise tests are negative but EIA is still suspected, a methacholine challenge can be performed. This test is more sensitive than an exercise challenge, but it is less specific. It can be useful when an indoor exercise challenge fails to duplicate cold, dry, or polluted environmental conditions that usually provoke a patient's symptoms. Methacholine challenge involves administering increasing concentrations of nebulized methacholine until the patient reaches a predetermined fall in FEV1 (usually 20% from baseline). The concentration of methacholine required to produce a 20% drop in a predetermined marker of pulmonary function is termed the provocative dose (15). Persons without EIA may require a methacholine concentration as high as 16.0 mg/mL to undergo a minimal drop in FEV1 (about 10%). In patients who have asthma, a low concentration of methacholine (eg, 4.0 mg/mL) will provoke a greater-than-20% drop in FEV1.
Exercise conditioning is an important part of asthma management. A well-conditioned athlete can exercise at a lower ventilation rate for a given workload and is less likely to suffer an asthma attack (16). Some researchers (17) also believe that adherence to regular aerobic exercise decreases airway responsiveness.
Avoiding exercise in cold, dry air is an important part of prevention. In winter, patients should be advised to exercise indoors or should cover their mouth and nose with a scarf or breathing mask to warm and humidify the air they breathe.
Appropriate warm-up before vigorous exercise is recommended because it may induce a refractory period. Researchers agree that the warm-up should last 15 minutes, but they disagree on the type of warm-up exercise. Some support repeated short bursts of high-intensity exercise (sprints) so that a higher ventilatory rate can be reached in the shortest time, while others advocate more continuous, moderate activity (18). Refractoriness is partial for most athletes, and they still need to take their premedication.
Cooling down, instead of stopping exercise abruptly, can also make EIA less severe because it slows airway rewarming and mitigates the resultant vascular dilation and edema (19,20).
Exercise should be done on days when chronic asthma symptoms are well controlled. Concurrent problems (rhinitis, allergies, sinusitis) should also be well controlled.
Finally, aerobic activities such as running and cross-country skiing that may, in a given patient, always provoke symptoms despite appropriate pharmacologic control, could be replaced with activities that demand short bursts of exercise, such as volleyball, tennis, or downhill skiing.
Some patients who have EIA do well with a single drug to prevent symptoms, but many patients need two or more drugs to control their symptoms.
Preexercise medications. Inhaled beta-2 agonists are the drugs of choice for the prevention of EIA (table 5). They have a rapid onset of action (within 5 minutes), produce a prolonged effect (up to 6 hours), and are convenient to use, and side effects are generally managable. When given about 30 minutes before exercise (figure 1: not shown), they prevent asthma symptoms in 90% of patients (figure 1: not shown).
For maximum deposition of the inhaled drug into the lungs, patients should be instructed to inhale properly from the metered dose inhaler. Patients should be advised to shake the canister before use, place the mouthpiece about 4 cm (about 1 1/2 in.) in front of the mouth, exhale comfortably, and discharge the inhaler while taking a slow, deliberate breath to total lung capacity (15). Holding the breath for 10 seconds and exhaling through pursed lips will further enhance drug deposition. Patients should pause 30 seconds between inhalations (21). For those who have trouble mastering the inhalation technique, a spacer device can diminish drug waste and improve drug delivery (15).
As beta-adrenergic drugs, inhaled beta-2 agonists act through adenyl cyclase to increase intracellular concentrations of cyclic adenosine monophosphate (AMP), which modulates contraction and relaxation of bronchial and vascular smooth muscle. Increased concentrations of cyclic AMP also inhibit the release of mediators from mast cells. However, despite their beta-2 selectivity, drugs such as albuterol and terbutaline sulfate interact with alpha and beta-1 adrenergic receptors, causing side effects such as tachycardia, palpitations, increased wakefulness, and mild tremors. These extrapulmonary effects can affect athletic performance (15).
Longer-acting beta-2 agonists such as salmeterol have a slower onset of action, act for up to 12 hours, and for maximal effect should be taken at least 4 hours before exercise (19). They are useful for athletes competing in endurance sports such as marathons and triathlons. All-day protection also has a particular appeal for children, who are often involved in periods of unplanned physical activity. However, it is important to note that when taken twice daily and continuously, salmeterol loses some effectiveness after 9 hours (22). This loss of response can be reduced if an inhaled corticosteroid, or possibly a mast-cell stabilizer, is also being used.
All athletes who have EIA should carry a quick-acting beta-2 agonist inhaler with them during exercise to relieve symptoms that develop despite preexercise prophylaxis (6).
Mast-cell stabilizers such as cromolyn sodium are the next most commonly used prophylactic medications for EIA. They have no bronchodilatory effect and should not be used to treat acute symptoms. When given about 20 minutes before exercise, they prevent asthma symptoms in 70% to 85% of patients with EIA (21).
Cromolyn sodium is believed to decrease calcium entry into cells, inhibiting mast-cell degranulation and subsequent bronchoconstriction (21). Cromolyn sodium is slightly less effective than beta-2 agonists in preventing early EIA symptoms. However, like nedocromil sodium, cromolyn sodium has anti-inflammatory properties and seems to prevent late-phase EIA response.
Inhaled mast-cell stabilizers are attractive for athletes who exercise repeatedly in a single day. Unlike the beta-2 agonists, they cause no side effects and can be taken many times during the day. Recent evidence (21) suggests that the routinely prescribed combination therapy of cromolyn and beta-2 agonist may be no better than beta-2 agonists alone. Therefore, mast-cell stabilizers should be used in patients who do not tolerate the side effects of inhaled beta-2 agonists, those who have late-phase responses, and those whose EIA symptoms are not completely prevented by beta-2 agonists (9).
Long-term drugs. Inhaled corticosteroids are the mainstay of treatment for patients who have chronic asthma. These medications decrease airway responsiveness to various stimuli, including exercise, allowing a higher level of exertion before a response is triggered (21).
For patients who have solitary EIA, inhaled corticosteroids offer no benefit when used only before exercise; they are not effective on an as-needed basis (6,21). They may be useful on a long-term basis, however. In some athletes, at least 4 weeks of inhaled corticosteroid use may be effective when combined with inhaled beta-2 agonists. Therefore, a trial of inhaled corticosteroids is appropriate for patients whose EIA symptoms are refractory to bronchodilators and/or mast- cell stabilizers (15).
Side effects of inhaled corticosteroids include local irritation, dysphonia, and candidiasis. The use of a spacer, proper inhalation technique, and mouth rinsing after doses decrease the risk of side effects (21).
Leukotriene modifiers include the leukotriene-receptor antagonists montelukast and zafirlukast and the 5-lipoxygenase inhibitor zileuton (19). These drugs are currently recommended for long-term asthma therapy. They appear to protect against EIA in many, but not all, patients with chronic asthma. The leukotriene modifiers offer certain advantages over other EIA medications: they come in oral form, have few side effects, and offer 24-hour protection (8).
Leukotrienes are inflammatory mediator products of phospholipid metabolism. Formerly known as slow-reacting substances of anaphylaxis, leukotrienes are thought to induce a bronchoconstriction response 1,000 times greater than that triggered by histamines. Therefore, their role in asthma is under close scrutiny (21). Particularly interesting are the cysteinyl leukotrienes (leukotrienes C4, D4 and E4), products of arachidonic acid metabolism that cause bronchoconstriction by increasing eosinophil migration, mucus production, and airway-wall edema (23).
Experimental agents. Because so many mechanisms may contribute to the development of EIA, the list of possible medications to counteract its symptoms is ever growing (21). Inhaled heparin has been used to evaluate the pathophysiology of EIA and has been shown to significantly block symptoms of EIA through its effect on mast cells. It does not appear to have a direct effect on smooth muscle. At this time, the use of inhaled heparin is experimental (6,21).
Diuretics have traditionally been used to treat bronchopulmonary dysplasia. Inhaled furosemide has been shown to attenuate the symptoms of EIA. Though evidence is inconclusive, it appears to exert a local effect at the lung epithelium. The use of inhaled furosemide remains experimental (6,21).
Inhaled indomethacin has also been shown to benefit patients who have EIA. Indomethacin is a cyclo-oxygenase inhibitor and can block the production of prostaglandins, some of which are bronchoconstrictors. However, other prostaglandins, such as prostaglandin E2, are bronchodilators, and blocking these products may be problematic for some patients (21).
Vitamin C has also been studied in the context of EIA (24). Despite using very large doses, studies showed variable protection; a minority of patients were partially protected. The use of vitamin C in EIA deserves further evaluation (21).
Be Vigilant About Banned Substances
Athletic organizations around the world are concerned about the potential of EIA medications to improve ventilatory capacity and provide stimulant and anabolic effects. Though bronchodilators usually return constricted airways to baseline in patients with asthma, they have not been shown to improve normal tone, ventilatory capacity, or athletic performance beyond baseline in patients without EIA (21,25). Most bronchodilators are restricted or banned because they can be considered stimulants.
The Canadian Center for Ethics in Sports has banned all beta-2 agonists except albuterol, terbutaline, and salmeterol, and these are permitted by inhalation only. Athletes must provide a written declaration from a physician before a doping control test. Failure to do so may result in a doping infraction. The same policy applies to inhaled corticosteroids used as anti-inflammatory treatments for asthma and rhinitis. Systemic corticosteroids (eg, prednisone, cortisone, dexamethasone) are prohibited.
The International Olympic Committee has prohibited the use of beta-2 agonists except for albuterol, salmeterol, terbutaline, and albuterol/ipratropium; these agents may be used only in the aerosol or inhalant form and only with written notification from the athlete's physician. Up-to-date information can be found at the Web site of the United States Olympic Committee at https://www.usoc.org/inside/in_1_3_7_1.html. The National Collegiate Athletic Association allows beta-2 agonists by inhalation only. The NCAA's banned drug list is available on-line at https://www.ncaa.org/sports_sciences/drugtesting/banned_list.html. Mast-cell stabilizers and leukotriene antagonists are currently permitted by sports organizations.
Physicians must remember that a substance banned by a national or international sports organization remains banned even when prescribed by a doctor for a justifiable medical purpose (15). Because sports organizations have varying policies, team physicians and athletes must consult the current list of banned substances and make sure a banned drug is not prescribed. This should be done well before competition so alternative therapeutic strategies may be chosen well before the event (15,26).
No Limits to Exercise Performance
It is difficult to determine what deleterious effects EIA has on competitive athletes. Though several studies have shown a higher incidence of EIA in those who perform longer-duration exercise, EIA does not clearly affect the performance of most athletes (27). On the other hand, athletes with asthma exercise with a higher ventilatory equivalent and work harder at breathing, which results in a lower maximum oxygen consumption. This suggests that, even though they may not have overt airway obstruction during exercise, EIA may result in a subtle yet important impairment of performance (27).
If asthma symptoms are well controlled through nonpharmacologic measures and appropriate prophylactic medications, EIA does not limit exercise performance. This is exemplified by the many elite athletes who have EIA yet have participated in the Olympics and won medals. For the everyday athlete, the measure of treatment success is full participation in sports and physical activities.
Practical Guide for the Diagnosis and Management of Asthma. Bethesda, MD, National Institutes of Health, National Heart, Lung, and Blood Institute, 1997. NIH publication 97-4053 (https://www.nhlbi.nih.gov/health/prof/lung/asthma/practgde.htm)
Dr Lacroix is director of the Primary Care Sports Medicine Fellowship Program, assistant professor in the Department of Family Medicine, and team physician in the Department of Athletics at McGill University in Montreal. Address correspondence to Vincent J. Lacroix, MD, McGill University Sport Medicine Clinic, 475 Pine Ave W, Montreal, QB, Canada H2W 1S4; address e-mail to [email protected].