Butcher, Janus D. MD
Exercise-induced asthma (EIA), also referred to as exercise--induced bronchospasm (EIB), describes a transient and reversible airway narrowing precipi-tated by vigorous exercise. It is a common condition affecting athletes of all ages, pursuits, and levels of participation. Exercise has long been recognized as a common precipitant of asthma symptoms and indeed is described in medical texts since the 18th century . It entered into the modern clinical awareness as a distinct entity in the last quarter of the 20th century. These early studies described asthma in collegiate and summer Olympic athletes and suggested an incidence ranging from 2.8% to 11.2%, with the highest frequency found in track and field [2,3].
EIA affects a much greater proportion of cold weather athletes. In studies in winter Olympic athletes, the overall incidence is consistently above 35% with the highest rates found in cross-country skiers [4–6]. Two studies completed recently have reinforced this high incidence. Pohjantahti et al.  reported that 42% of elite cross-country skiers tested positive for previously undiagnosed EIA. Durand et al.  found that nearly 50% of competitive ski mountaineers tested positive for EIA and 73% of those found to be positive had not been previously diagnosed with this condition.
EIA has been reported with increasing frequency in recent years. This is probably due to an increased awareness of the condition among medical providers and athletes alike. The increasing number of athletes being treated for EIA combined with the ergogenic potential of many of the medications used has resulted in stringent doping control measures.
Exercise is a common precipitator of bronchial spasm in individuals with classic asthma and can affect up to 80% of these individuals. The incidence of asthma in the general population is approximately 10%, whereas the incidence of EIA can be significantly higher in certain athletic populations. The majority of athletes affected by EIA do not have a prior history of asthma. These facts suggest that the mechanism for EIA is distinct from that of classic asthma.
Although the precise mechanism of EIA is not fully established, our understanding continues to evolve. The commonly recognized etiologic factor is the low humidity of inspired air at low temperature. These two physical stresses have previously been identified in collateral principles; the heat loss theory and the water loss theory. The importance of airway cooling as an independent variable has steadily lost favor. This was highlighted in the 2005 work of Evans et al. [9•], which demonstrated no increase in forced expiratory volume in 1 second (FEV1) decrement with exercise in dry conditions when the inspired air was cooled when compared with warmer dry air.
Current theory suggests that a high ventilation rate in low relative humidity results in water loss in the airway. Airway drying then leads to substantial osmotic changes in the epithelium with subsequent release of bronchial constricting chemical mediators via the inflammatory cascade. Several substances have been shown to play a role in this including histamine , cystenyl-leukotrienes (cysLT) , and bronchial constricting prostenoids . Csoma et al.  recently demonstrated that this process may be modulated by adenosine release.
The notion of EIA/EIB as a diagnosis that is distinct from classic asthma has been debated within the medical community for decades. It is widely accepted as a separate entity in the sports medicine literature but less so within the broader medical community, in which EIA is often treated strictly as a subset of classic asthma. Although the importance of identifying and effectively managing asthma to avoid death cannot be understated, there is a large group of people who have asthmatic symptoms that are only precipitated by extreme exercise in severe environments. In this regard, EIA may be more like a respiratory injury rather than a chronic disease process, and as such, it may be that nearly every athlete is susceptible to EIA given an adequate severe exposure. This could explain the incidence of 50% in otherwise healthy populations of elite athletes [7,8].
There are other sports without the typical low temperature and humidity factors that report an incidence similar to winter sports. Examples include swimming and indoor skating sports (figure skating and ice hockey). Although the symptoms seen in these represents a form of exercise-associated asthma, the pathoetiology more closely resembles that of an occupational asthma. Commonly cited causative agents include chlorine and carbon monoxide gas, respectively.
Recognition and Diagnosis
Establishing a diagnosis of EIA can present several challenges. Although an athlete with classic asthma has a relatively predictable response to exercise, it is common for athletes with EIA to exhibit symptoms only intermittently. These athletes will develop symptoms only in extreme environmental circumstances with exercise involving a high respiratory minute volume, and may experience no symptoms with lower intensity exercise or when exercising in mild or humid conditions.
Although quite variable, the more common symptoms include postexercise dyspnea, cough, burning chest pain, and, rarely, wheezing. Some athletes may complain of symptoms while exercising; however, the symptoms more commonly arise 3 to 5 minutes after cessation of exercise and peak at 10 to 20 minutes after exercise. A late inflammatory phase, characterized by a hacking cough will often arise 2 to 12 hours after cessation of exercise. These late-phase symptoms are common following maximal exertion in extreme environmental conditions such as a mid season ski race at altitude. These symptoms commonly persist for 1 or 2 days and are often mistaken for an upper respiratory illness.
Unless the symptoms develop while the physician is on the sidelines, the athlete will typically present for evaluation when asymptomatic. As a result, the majority of cases will be diagnosed exclusively based on the patient history with a completely normal physical examination result. Although studies have questioned the efficacy of self--reported EIA symptoms , evaluation by an experienced clinician remains the most reliable and indeed most commonly utilized diagnostic means. Empiric therapy has long been a standard treatment approach and thus has been the diagnostic modality of choice. This approach has become problematic in Olympic, collegiate, and other world-class athletes due to the stringent doping control measures that surround the use of b-agonists. Many sports governing bodies require these athletes show objective evidence of exercise-induced reduction in respiratory function to use these asthma medications in training and competition.
Many different testing protocols have been used to assess respiratory function in EIA. Testing is useful in patients who have an unusual clinical presentation, who fail to respond to medical therapy, or who require objective documentation to use a restricted medication. Several of these studies require laboratory settings and specialized equipment while others can be done on the athletic field. Many different protocols may be allowed at any one time by the sports governing body. Which test is chosen is determined by the available resources and expertise.
Passive chemical challenge using methacholine, hista-mine, or mannitol powder remains a mainstay in the assessment of classic asthma. However, these tests are not particularly useful in exercise induced asthma due to their low negative predictive value and sensitivity in this condition . Additionally these tests require a controlled laboratory setting and are fairly expensive.
The exercise challenge test has gained widespread acceptance as a viable testing modality for EIA. Numerous laboratory-based and free exercise challenge protocols have been described. The majority of these protocols use running as the exercise; however, one study describes a cross-country skiing–specific protocol similar to the free running test . These tests typically compare pre- and postexercise pulmonary functions with a positive test result defined as a postexercise reduction in FEV1 of 10% to 15% [16,17]. Although most of these protocols have been validated the functional results appear somewhat variable. Several factors influence the validity of this testing, including ambient temperature, exercise intensity, humidity, and pre-exercise warm up [6,18,19]. This form of testing is both activity and environmentally specific, and additionally tends to be relatively inexpensive compared with laboratory testing, and facilitates screening of larger groups. The results can be variable if the environmental conditions and exercise intensity are not the same as the usual precipitating conditions. This is particularly true of Nordic ski racers who may only experience symptoms in very cold conditions at higher altitudes.
A recent innovation in testing is the Eucapnic Voluntary Hyperventilation Challenge (EVHC). Because of its simplicity and ease of reproducibility EVHC is becoming the standard testing protocol for EIA/EIB. This test measures FEV1 decrement in response to hyper-ventilation of a fixed mixture of dry gas consisting of 5% CO2, 21% O2, and the balance in nitrogen. The subject hyperventilates at a predetermined rate, typically 85% of their maximal voluntary hyperventilation rate for 6 minutes . Spirometry measurements are made before and serially after the exercise. An FEV1 decrement of 10% is considered a positive result. In a recent study, Dickinson et al. [21••] undertook a comparison of laboratory and free exercise testing versus EVHC in predicting EIA in athletes. In their work, they found EVHC to be much more sensitive than either type of exercise testing in establishing the diagnosis of EIA.
In general, EIA is easily managed with medical therapy. If the athlete has intermittent or persistent classic asthma, the mainstay of therapy is inhaled corticosteroids as a controller medication with inhaled bronchodilator used for breakthrough symptom management as a rescue medication. Leukotriene inhibitors and long-acting bronchodilators may also be required to manage this condition appropriately.
With EIA, the main goal is prevention of airway irritability and subsequent bronchospasm through pre-exercise administration of preventative medications. Preventive medications include short-acting b-agonists (albuterol, pirbuterol) or less commonly, long-acting b-agonists (salmeterol). These medications function through relaxation of bronchial smooth muscle. The short-acting γ-agonists are usually effective and have the advantage of low cost, ease of use, and high rate of patient compliance. For mild symptoms, the short-acting medications are administered as two puffs spaced 5 to 10 minutes apart, 20 to 40 minutes prior to exercise. Aerosolized preparations should be used with a chamber or spacer to maximize the delivered dosage. The longer-acting bronchodilators, salmeterol or formoterol, have a limited role in pure EIA but serve an adjunctive role in classic asthma when combined with inhaled corticosteroids. This is administered twice daily for persistent asthma and 30 to 60 minutes before exercise when used exclusively for EIA.
Although not approved for use in EIA, the leuko-triene inhibitor montelukast sodium (Singulair; Merck, Whitehouse Station, NJ) has been shown to be effective in preventing EIA symptoms [22,23]. It functions by binding selectively to the CysLT1 receptor. The typical dose of montelukast sodium is 10 mg given once daily. Recently, Rundell et al. [24•] confirmed the protective effects of this medication in athletes with known EIA during a EVCH challenge. Because of cost and US Food and Drug Administration approval issues, leukotriene inhibitors should usually be reserved as a second-line medication. In general, they should always be prescribed with a γ-agonist to use as a rescue medication for symptoms that may develop after exercise.
Chromolyn sodium (Intal; King Pharmaceuticals, Bristol, TN) is also approved for use in mild EIA. This medication, however, is rarely effective when used alone and may require up to 30 inhalations prior to exercise for effective use and tends to be quite expensive in the required dosages.
The addition of inhaled corticosteroids (budesonide, fluticasone) should be considered in treated athletes who have persistent symptoms after exercise or who experience frequent late phase symptoms of EIA. Several preparations are available, including long-acting b-agonist/corticosteroid combinations. In recent work, Weiler et al.  found the combination of fluticasone/salmeterol (Advair Discus; Glaxo-Wellcome, Research Triangle Park, NC) to be highly effective in preventing exercise-induced symptoms in athletes with persistent asthma. In addition to their preventive effects, inhaled corticosteroids are effective in alleviating the postexercise cough brought on by late phase inflammatory effects of EIA.
A new class of anti-inflammatory medications, the selective phosphodiesterase 4 inhibitors, has shown promise in the treatment of inflammatory airway diseases. Roflumilast, a member of this class of drugs, has been shown to reduce exercise induced symptoms when used as a single 500-mg dose daily . Further study is required to determine if there is an advantage to this new class of medication over the established treatment options.
An area of interest in recent years has been dietary manipulation and the use of supplements to avoid EIA symptoms. The potential effects of a high-sodium diet in accentuating EIA has been previously suggested and was recently further substantiated by Mickleborough et al. . In another study, Baumann et al.  looked at the effects of glutathione supplementation on EIA. They found a significant therapeutic effect of this supplement presumably due to the antioxidant effects on the inflammatory cascade. Further study is needed to determine the role of dietary manipulation in the management of EIA.
Over the past 30 years the sports community has taken an increasingly aggressive approach to ending the use of artificial performance enhancing drugs. The World Anti-Doping Agency (WADA) oversees these efforts and serves to educate athletes and coaches, implement doping control policies, and monitor drug testing. In addition, WADA coordinates the various national and sport governing body doping programs throughout the world.
Asthma medications have come under significant scrutiny because of their ergogenic potential and their widespread use. The medications of greatest concern are the inhaled γ-agonists and the corticosteroid preparations (inhaled and oral). The main concern with γ-agonists involves their stimulant and anabolic effects. The published data on the ergogenic effects of these drugs are quite variable with the effects seen almost exclusively from oral preparations [29,30]. As a result, all oral b-agonists are banned from use. The inhaled γ-agonists that are on the restricted use list and only allowed for use in EIA or asthma by WADA with appropriate documentation of disease and include formoterol, salbutamol (albuterol), salmeterol, and terbutaline. All others are banned, including the commonly used pirbuterol acetate (Maxair-3M, St. Paul, MN).
Care must be taken to ensure compliance with doping control measures in elite-level athletes. Although most asthma medications are either banned or restricted, some are allowed without documentation at all. An example of this is montelukast sodium. It is the responsibility of the treating physician to ensure that the medication they prescribe is allowed and appropriately reported to the sports governing body. The required procedures for documenting and thus allowing the use of these medications do continue to evolve and the banned/restricted use list is updated annually. These requirements need to be followed closely by those health care providers involved in the care of elite and Olympic athletes.
The most accurate source of information regarding these medications and documentation requirements is found at the websites for the doping agencies. The WADA website (http://www.wada-ama.org) provides information on the substances that are controlled and provides many resources for the athletes. The United States Anti Doping Agency (USADA) is also a comprehensive resource (http://www.usantidoping.org). USADA has a telephone hotline for any questions regarding the use of these medications (1-800-223-0393). Other resources include the individual sport governing bodies.
Our understanding of the pathoetiology of exercise-induced asthma continues to evolve. A great deal of active research continues to better define the precise mechanisms and inflammatory cascade pathways involved in the symptom development. These studies will lead to additional treatment options as well as preventative measures that will allow these athletes to minimize the impact of EIA on their performance. Continued work on diagnostic testing will streamline the process to allow these athletes to compete on their medications and allow clinicians to more readily and accurately identify athletes who require treatment for EIA. This continued study will also lead to a more realistic and fair system to prevent the use of these medications as ergogenic aids while allowing the athlete with EIA to use them for their intended therapeutic purposes.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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This study compared subjects with EIA using dry bottled air at room temperature and at cold temperature. They showed no change in FEV1 decrement between the challenges.
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This group studied 14 winter sport athletes using three methods: sport-specific exercise challenge, laboratory exercise challenge, and EVHC. This well-designed comparison clearly demonstrated EVHC to be the most sensitive test for EIA in athletes.
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This study utilized a single dose of montelukast, 10 mg, in a randomized double crossover design. They found protection against EIA as measured by multiple testing protocols.
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