Asthma, Bronchial Hyperresponsiveness and Sports
Updated: September 2016
Originally Posted: July 2009
Kai-Håkon Carlsen, MD, PhD
Professor emeritus of Paediatric Respiratory Medicine and Allergology
Medical Faculty, University of Oslo
Professor emeritus of Sports Medicine, Norwegian School of Sport Sciences, Oslo
Voksentoppen, Dept. of Paediatrics, Rikshospitalet University Hospital
Oslo, Norway
Luis Delgado, MD, PhD
Professor of Internal Medicine and Allergology
Serviço e Laboratório de Imunologia, Faculdade de Medicina da Universidade do Porto,
Hospital de S. João
Porto, Portugal
Introduction
Exercise-induced asthma (EIA) is a concern for children and adolescents with asthma during growth and development. According to most International and National guidelines on treating asthma, one of the main objectives in children is to master EIA. Among elite athletes EIA and bronchial hyperresponsiveness (BHR) have become major problems, interfering with the performance of sports and representing a health risk. Athletes have, in the same manner as ordinary patients, the need for optimal diagnosis and treatment of their asthma. This was fully shown by Becker et al who reported deaths linked to athletic performance over a seven-year period in the USA. Out of 263 deaths, 61 were related to asthma. Only one of the 61 athletes who died had used inhaled steroids1. This underlines the need for optimal asthma treatment and follow-up among competitive athletes.
Due to reports of frequent use of inhaled β2-agonists, the Medical Commission of the International Olympic Committee (IOC-MC) in 1993 introduced restrictions in their use in relationship to sport. These rules have been altered several times and from 2002 with the introduction of applications to obtain approval for the use of the drugs when competing as an international athlete presenting measurements of lung function and bronchial responsiveness. A joint Task Force established by the European Respiratory Society and the European Academy of Allergy and Clinical Immunology reviewed the problems of asthma in athletes and published an overview as well as guidelines for diagnosing and treating asthma in athletes in three publications2-4. The present article focuses on the problems raised by this report in respect to diagnosis, treatment as well as novel research results outlining a hypothesis of why athletes do develop asthma due to their sports activity5.
Also, other allergic diseases represent a problem in elite sports. Especially exercise -induced anaphylaxis, which is a major problem for those affected. In addition, allergic rhinoconjunctivitis and urticaria both physical and allergic types, represent major problems for those affected.
Asthma and sports, the history
In 1986, in a screening reported by the US Olympic Committee, 67 out of 597 American Olympic Athletes for the Los Angeles 1984 summer Olympic Games suffered from EIA or asthma. These 67 asthmatic athletes won 41 medals during the Olympic Games6. The prevalence of EIA of 11% among the American Olympic athletes from 19847, increased to >20% among the American participants in the 1996 summer Olympic Games in Atlanta8. The asthma prevalence was 45% in cyclist and mountain bikers compared to none in divers and weight-lifters8. Larsson et al reported in 1993 that 23 of 42 elite cross country skiers had a combination of BHR and asthma symptoms compared to only one of 23 referents9. In a questionnaire-based report, Heir and Oseid showed a prevalence of doctor-diagnosed asthma of 14 % in 155 actively competing skiers compared to 5 % in twice matched controls. Moreover, the prevalence of asthma diagnosis increased with increasing age in the actively competing skiers10. This was followed by reports of high prevalence in Norwegian and Swedish skiers11, in competitive figure skaters12,13, in elite cold-weather athletes14 and among participants in the 1998 American Olympic National team for winter sports including gold medalists15. Langdeau and his coworkers reported that 49 out of 100 competitive athletes (in various sports) suffered from BHR to metacholine (49%) compared to 28% of sedentary subjects (28%)16.
Feinstein et al found EIB in nine of 48 male football players17 whereas a positive bronchodilator test (increase in FEV1 ≧ 12%) to inhaled salbutamol was found in 56% of Canadian professional football players18. Helenius and Haahtela reported on several studies of Finnish elite track and field athletes, showing physician-diagnosed asthma in 17% of long-distance runners, 8 % of speed and power athletes and 3 % of controls19. In another study total asthma (current asthma, physician diagnosed asthma or BHR) was found in 23% of the athletes compared to 4% of the controls; current asthma in 14% compared to 2% among controls and positive skin prick test (SPT) in 48% of the athletes compared to 36% among controls20. High prevalence of BHR (48%) to histamine was also found among swimmers21. Maiolo et al reported an asthma prevalence of 15% and atopy in 18% of 1060 Italian competing summer athletes22. Higher prevalence of asthma among endurance athletes as compared to speed and power athletes was reported in a Norwegian study23. Employing the objective criteria for diagnosing asthma and/or bronchial hyperresponsiveness as were given by the IOC Medical Commission, Dickinson reported prevalence among the British participants in the Olympic Games in 2000 and 2004 to be 21.2% and 20.7%, respectively, with a positive bronchial challenge or bronchodilator test24.
How do athletes contract EIA and BHR?
1. Exercise-induced asthma, why?
Two hypotheses attempt to explain the relationship between physical activity and EIA. One relates to cooling of the airways due to the increased ventilation during exercise while the other hypothesis relates to increased water loss from the respiratory tract also caused by increased ventilation during exercise. The airway cooling due to respiratory heat loss from the increased ventilation during exercise is thought to cause smooth muscle contraction due to anticholinergic stimulation through a vagal reflex and vasoconstriction in bronchial vessels followed by a secondary reactive hyperaemia with resulting oedema and airways narrowing25. On the other hand, symptoms may be due to water loss caused by the high ventilation rates of top athletes (up to >280 L/minute) during exercise, with saturation of the inhaled air with water. The resulting increase in osmolarity of the extracellular fluid of the respiratory mucosa is thought to cause extravasation of water from the intracellular to the extracellular space initiating cells to release mediator resulting in increased airways inflammation and bronchial constriction26. The use of inhaled mannitol as a tool to diagnose bronchial hyperresponsiveness further confirms this hypothesis27.
2. Why do competitive athletes develop EIA and BHR?
That high intensive exercise may cause an increase in BHR was first demonstrated in Norwegian competitive swimmers after swimming exercises of 3000 meters28 and then in young ski athletes during the competitive season10. Heavy endurance training, especially when performed in an unfavorable environment, presents stress to the mucosal membrane of the airways. This was elegantly shown by Sue Chu and coworkers in bronchial biopsies from heavily training young skiers without asthma, but with increased airways responsiveness to cold air29,30, describing increased airways inflammation with lymphoid aggregates and increased tenascin expression (the thickness of the tenascin-specific immunoreactivity band in the basement membrane) in the skiers. These findings were recently reproduced by Bougault et al in elite competitive swimmers31. Signs of epithelial damage was also found in Alaskan dogs after a winter race of several days32 and experimentally in exercising mice as compared to sedentary mice33. Also in runners, respiratory epithelial damage with apoptosis of epithelial cells were found after repeated half-marathon races34. Inflammatory changes were found in induced sputum of competitive swimmers21. Thus, respiratory epithelial damage, as a result of repeated heavy physical endurance training over prolonged periods of time, may initiate and contribute to airways inflammation and the development of athlete’s asthma.
3. The environment
An unfavorable environment in which repeated competitions and training sessions take place is thought to be an important contribution to the development of asthma and BHR among top athletes, as in cross country skiers exposed to cold air9,35,36, competitive swimmers exposed to organic chlorine products from the water in indoor pools21 and figure skaters and ice hockey players in ice rinks with increased levels of ultrafine particles originating from the ice polishing machines13,37,38. Larsson showed that cold air inhalation increased the number of inflammatory cells in broncho-alveolar lavage35. In children, Bernard and co-workers reported that time spent in swimming pools during early childhood are related to the development of asthma and signs of lung involvement by increased serum levels of surfactant proteins39 and reduced levels of Clara cell protein40. It has also been shown that respiratory tract infections increase bronchial responsiveness in actively training athletes41. Thus, the combination of heavy repeated exercise with an unfavorable environmental milieu is probably important for the development of asthma among top athletes. On top of this comes the effect of respiratory infections.
4. Parasympathetic (cholinergic) stimulation
The increased ventilation during exercise causes a cooling of the airways as the inspired air is warmed to 37℃42. The cooling of the airways causes parasympathetic stimulation that contributes to bronchoconstriction and increased cholinergic inflammation.43 Endurance training has been shown to cause increased parasympathetic tonus and parasympathetic modulation, as measured by heart rate variation related to physical fitness.44
It is thought that the combination of repeated respiratory epithelial damage during endurance training and competitions, increasing airways inflammation together with exposure to possible environmental pollution and respiratory infections during sports performance are all factors leading to increased bronchial hyperresponsiveness and respiratory symptoms in the endurance athlete. As also endurance training has been shown to increase parasympathetic tonus45, this may contribute to bronchoconstriction and increased bronchial hyperresponsiveness. The combination of these multiple factors partly related to training effect and partly to environmental exposure during sports performance may explain the increased developing of asthma among endurance athletes.5
Diagnosis of exercise induced asthma and bronchial hyperresponsiveness in athletes
The diagnosis of asthma is clinical and should be based on the history of symptoms, physical examination for the presence of bronchial obstruction and variability in lung function spontaneously, or due to bronchodilators (Table 1)46. The main symptoms of asthma are recurring episodes of bronchial obstruction. The term 'current asthma' is used when at least one episode of asthma has occurred during the last year. The competing athlete frequently reports the presence of respiratory symptoms in relationship to exercise, but the diagnosis of asthma or exercise-induced asthma (EIA) may be difficult due to the variability and non-specificity of symptoms14,47. Recently two different phenotypes of asthma in athletes, diagnosed according to the criteria of the IOC, MC and WADA, were identified by latent class analysis in elite Portuguese and Norwegian athletes and classified as atopic asthma and sports asthma48. An exact clinical history, examination with lung function measurements before and after inhalation of a ß2-agonist or another bronchodilator (requiring an increase in FEV1 of 12%), before and after a standardized exercise test such as a treadmill run and/or a cold-air inhalation test and measurement of BHR by metacholine inhalation, are parts of the diagnostic process. One important part of the diagnostic process is the follow-up of patients to evaluate the treatment effect. The eucapnic voluntary hyperpnoea test is, by many, recommended as both sensitive and specific although it is debated if a cut off should be 10 or 15% 49,50.
Table 1. Diagnostic methods recommended by the Medical Commission (MC) of the International Olympic Committee (IOC) and by the World Anti-Doping Association (WADA) for diagnosing asthma in athletes participating in Olympic Games and international sports. A clinical history in combination with a positive bronchodilator response or a positive response to EIA test or another test of bronchial responsiveness is recommended.
| Diagnostic procedure | Results as recommended |
| Clinical history of respiratory symptoms and clinical examination | Positive clinical history |
| Lung function (Spirometry or maximum expiratory flow volume loops). Reversibility to inhaled bronchodilator |
Increase in FEV1 after inhaled bronchodilator |
| Exercise induced bronchoconstriction by standardised exercise test | FEV1 decrease of 10% from before to after standardized exercise challenge |
| Bronchial hyperresponsiveness to metacholine (histamine presently not allowed by IOC-MC)) | PD20 < 2 μmol, PC20 < 4 mg/ml. Other values when on inhaled steroids. |
| Eucapnic voluntary hyperpnoea test | Reduction in FEV1 of 10%, alternatively 15% or more. |
| Mannitol inhalation test (Airidol® test) |
Reduction in FEV1 of 15% or more. Determination of PD15 of mannitol |
| Exercise field test | Reduction in FEV1 of 10% or more |
EIA may be diagnosed in different ways; running provokes exercise-induced bronchoconstriction more easily than cycling and swimming51,52. A heavy exercise load is recommended. At the University of Oslo, a motor driven treadmill with an inclination of 5.5% is employed, rapidly increasing speed until a steady heart rate of approximately 90-95% of calculated maximum is reached and maintained for 4-6 minutes. The widespread use of inhaled steroids necessitates this level of exercise53. Maximum heart rate is calculated approximately by taking 220 minus the age of the patient, and can be measured electronically or by electrocardiogram. The running is performed at a room temperature of approximately 20℃ and a relative humidity of approximately 40 %. Lung function is measured by FEV1 before running, immediately after stopping, then 3, 6, 10, 15 and 20 minutes after running. A fall of 10 % in FEV1 is taken as a positive sign of EIA. When adding an extra stimulus to the exercise test, as by combining running on a treadmill with the inhalation of dry cold air of -20°C, the sensitivity of the test is markedly increased while simultaneously maintaining a high degree of specificity54. Other tests used for the diagnosis of exercise-induced bronchoconstriction and BHR are eucapnic voluntary hyperpnoea50 and mannitol bronchial provocation, determining the inhaled dose causing a 15% decrease in FEV1 27.
There are several differential diagnoses to EIA, including exercise-induced laryngeal obstruction (EILO)55 and hyperventilation during exercise. These conditions should be borne in mind, as many such patients have been given unnecessary drugs for treatment of asthma, including both inhaled steroids and β2-agonists, which will have no effect upon the exercise-induced laryngeal stridor. EILO is more common among top trained female athletes during adolescence. Marked inspiratory stridor during maximal exercise with a flattening of the maximal inspiratory flow volume curve56 is typical of EILO. In contrast with EIA, the dyspnea occurs after exercise and is expiratory due to the lower airways obstruction. EILO may be of glottic or supraglottic type. The diagnosis of this condition may be made by continuous laryngoscopic exercise test (CLE)57. Other differential diagnoses to EIB include exercise-induced arterial hypoxemia58 and swimming induced pulmonary edema59 (Table 2).
Table 2. Differential diagnoses to EIA in athletes.
| Diagnosis | Presentation |
| EIA | Symptoms occurring shortly after (sometimes during) physical exercise. If observed: Expiratory dyspnoea, expiratory rhonchi and other signs of bronchial obstruction. Gradual improvement either spontaneously or after inhaled bronchodilator |
| Exercise induced laryngeal obstruction (EILO) | Symptoms occurring during maximum exertion. Symptoms disappear after stopping exercise (unless hyperventilating) If observed: Inspiratory stridor, audible inspiratory sounds from laryngeal area. No signs of bronchial obstruction. No effect of pretreatment with inhaled bronchodilator. Glottic or supraglottic type |
| Poor physical fitness | Related to expectations High heart rate after low-grade exercise load |
| Other chronic lung diseases | Reduced baseline lung function may reduce physical performance due to limitations in airflow and lung volumes |
| Other general disease | Chronic heart diseases and others |
| Exercise induced arterial hypoxemia (EIAH) | Occurs in well-trained athletes with high max. VO2 Primarily due to diffusion limitations and ventilation-perfusion inequality. Incomplete diffusion in the healthy lung may be due to a rapid red blood cell transit time through the pulmonary capillary |
| Swimming induced pulmonary edema (SIPE) | Often hemoptysis after heavy swimming exercise, reduced diffusion capacity |
Asthma treatment and performance
Recommendations
Despite the epidemiological evidence about increased prevalence of EIA and BHR in top athletes, the frequent use of asthma drugs caused concern about possible improvement of performance by asthma drugs and especially so by inhaled 2-agonists. Thus, already by 1993, the Medical Commission of the International Olympic Committee (IOC-MC) had introduced restrictions to the use of asthma drugs in sports. Among the β2-agonists only salbutamol and terbutaline were allowed for use in sports, and only by the inhaled route. Only athletes with a confirmed diagnosis of asthma were allowed to use these drugs. Later regulations have been changed several times. Shortly before the Salt Lake City Winter Olympic Games in 2002, the IOC-MC introduced new rules for the use of inhaled β2-agonists and inhaled steroids during the games60. Applications had to be submitted beforehand, and results of laboratory tests such as exercise tests, bronchial provocation tests with metacholine, eucapnic hyperpnoea tests or documented reversibility to inhaled 2-agonists had to be submitted to obtain approval for the use of asthma drugs60. It was recommended that after appropriate objective diagnosis, the treatment of the athlete with asthma or other respiratory problems should follow the common guidelines, taking into consideration the rules set up by the doping authorities (WADA and for the Olympic Games; IOC-MC).
Asthma is the most common chronic disease reported among Olympic participants.61 For the Beijing Summer Olympic Games, 813 applications were made for the use of inhaled β2-agonists, and 781 of these were approved. Of the 781 athletes with approval for the use of inhaled β2-agonists, 711 also used inhaled steroids. Inhaled steroids alone were used by 121 additional athletes (From Report of the Independent observers, XXIX Beijing Olympic Games)
As the regulations for the use of asthma drugs among athletes have been repeatedly changed, the physician treating asthmatic athletes and children and adolescents with asthma should keep updated on the present regulations. This may be done by going to the website of the World Antidoping Association (WADA) https://www.wada-ama.org. On this website, a guide for team physicians on treating asthma in athletes may be found. The rules for asthma drugs were last changed from 2012. Presently, all inhaled corticosteroids are allowed for use in sports, also inhaled ipratropium bromide and montelukast. All β2 –agonists are prohibited except inhaled salbutamol, salmeterol, and formoterol. For salbutamol, a maximum dose of 1.6 mg inhaled over 24 hours is given, for formoterol a maximum dose of 64 μg over 24 hours are given, and for salmeterol, the dose should follow the manufacturer’s recommendation. The concentration of salbutamol and formoterol will be controlled in the urinary sample if the athlete is taken out for a doping test. If the physician finds a reason to prescribe salbutamol inhaled by nebulization, an application for Therapeutic Use Exemption (TUE) should be made.
Physicians caring for athletes should know the rules for doping given by WADA and check for the latest updates. New updates are given each year being effective usually from 1st of January. The athletes should also be made aware of that they should know the regulations themselves, as it is their own responsibility not to use prohibited drugs.
References
1. Becker JM, Rogers J, Rossini G, Mirchandani H, D'Alonzo GE, Jr. Asthma deaths during sports: report of a 7-year experience. J Allergy Clin Immunol 2004; 113(2): 264-7.
2. Carlsen KH, Anderson SD, Bjermer L, et al. Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy 2008; 63(4): 387-403.
3. Carlsen KH, Anderson SD, Bjermer L, et al. Treatment of exercise-induced asthma, respiratory and allergic disorders in sports and the relationship to doping: Part II of the report from the Joint Task Force of European Respiratory Society (ERS) and European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA(2)LEN. Allergy 2008; 63(5): 492-505.
4. Carlsen KH, Delgado L, Del Giacco S. Diagnosis, Prevention and treatment of Exercise-Related Asthma, Respiratory and Allergic Disorders in Sports. 10 ed: European Respiratory Monograph; 2005.
5. Carlsen KH, Lodrup Carlsen KC. Asthma and the Olympics. J Allergy Clin Immunol 2016; 138(2): 409-10.
6. Voy RO. The U.S. Olympic Committee experience with exercise-induced bronchospasm, 1984. MedSciSports Exerc 1986; 18(3): 328-30.
7. Weiler JM, Metzger J, Donnelly AL, Crowley ET, Sharath MD. Prevalence of bronchial responsiveness in highly trained athletes. Chest 1986; 90: 23-8.
8. Weiler JM, Layton T, Hunt M. Asthma in United States Olympic athletes who participated in the 1996 Summer Games. J Allergy Clin Immunol 1998; 102(5): 722-6.
9. Larsson K, Ohlsen P, Larsson L, Malmberg P, Rydstrom PO, Ulriksen H. High prevalence of asthma in cross country skiers. BMJ 1993; 307(6915): 1326-9.
10. Heir T, Oseid S. Self-reported asthma and exercise-induced asthma symptoms in high-level competitive cross-country skiers. Scand J Med Sci Sports 1994; 4: 128-33.
11. Sue-Chu M, Larsson L, Bjermer L. Prevalence of asthma in young cross-country skiers in central Scandinavia: differences between Norway and Sweden. Respir Med 1996; 90(2): 99-105.
12. Provost Craig MA, Arbour KS, Sestili DC, Chabalko JJ, Ekinci E. The incidence of exercise-induced bronchospasm in competitive figure skaters. J Asthma 1996; 33(1): 67-71.
13. Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F. Exercise-induced asthma in figure skaters. Chest 1996; 109(2): 312-5.
14. Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR. Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc 2001; 33(2): 208-13.
15. Wilber RL, Rundell KW, Szmedra L, Jenkinson DM, Im J, Drake SD. Incidence of exercise-induced bronchospasm in Olympic winter sport athletes. Med Sci Sports Exerc 2000; 32(4): 732-7.
16. Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagne P, Boulet LP. Airway hyperresponsiveness in elite athletes. Am J Respir Crit Care Med 2000; 161(5): 1479-84.
17. Feinstein RA, LaRussa J, Wang Dohlman A, Bartolucci AA. Screening adolescent athletes for exercise-induced asthma. Clin J Sport Med 1996; 6(2): 119-23.
18. Ross RG. The prevalence of reversible airway obstruction in professional football players. Med Sci Sports Exerc 2000; 32(12): 1985-9.
19. Helenius IJ, Tikkanen HO, Haahtela T. Association between type of training and risk of asthma in elite athletes. Thorax 1997; 52: 157-60.
20. Helenius IJ, Tikkanen HO, Sarna S, Haahtela T. Asthma and increased bronchial responsiveness in elite athletes: atopy and sport event as risk factors. J Allergy Clin Immunol 1998; 101(5): 646-52.
21. Helenius IJ, Rytila P, Metso T, Haahtela T, Venge P, Tikkanen HO. Respiratory symptoms, bronchial responsiveness, and cellular characteristics of induced sputum in elite swimmers. Allergy 1998; 53(4): 346-52.
22. Maiolo C, Fuso L, Todaro A, et al. Prevalence of asthma and atopy in Italian Olympic athletes. Int J Sports Med 2004; 25(2): 139-44.
23. Nystad W, Harris J, Borgen JS. Asthma and wheezing among Norwegian elite athletes. Med Sci Sports Exerc 2000; 32(2): 266-70.
24. Dickinson JW, Whyte GP, McConnell AK, Harries MG. Impact of changes in the IOC-MC asthma criteria: a British perspective. Thorax 2005; 60(8): 629-32.
25. Gilbert IA, McFadden ER, Jr. Airway cooling and rewarming. The second reaction sequence in exercise-induced asthma. Journal of Clinical Investigation 1992; 90: 699-704.
26. Anderson SD, Daviskas E. The airway microvasculature and exercise induced asthma. Thorax 1992; 47: 748-52.
27. Brannan JD, Koskela H, Anderson SD, Chew N. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma. AmJRespirCritCare Med 1998; 158(4): 1120-6.
28. Carlsen KH, Oseid S, Odden H, Mellbye E. The response to heavy swimming exercise in children with and without bronchial asthma. In: Morehouse CA, ed. Children and Exercise XIII. Champaign, Illinois: Human Kinetics Publishers, Inc.; 1989: 351-60.
29. Sue-Chu M, Karjalainen EM, Altraja A, et al. Lymphoid aggregates in endobronchial biopsies from young elite cross-country skiers. AmJRespirCritCare Med 1998; 158(2): 597-601.
30. Karjalainen EM, Laitinen A, Sue-Chu M, Altraja A, Bjermer L, Laitinen LA. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. AmJRespirCrit Care Med 2000; 161(6): 2086-91.
31. Bougault V, Loubaki L, Joubert P, et al. Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools. J Allergy Clin Immunol 2012; 129(2): 351-8, 8 e1.
32. Davis MS, McKiernan B, McCullough S, et al. Racing Alaskan sled dogs as a model of "ski asthma". Am J Respir Crit Care Med 2002; 166(6): 878-82.
33. Chimenti L, Morici G, Paterno A, et al. Endurance training damages small airway epithelium in mice. AmJRespirCrit Care Med 2007; 175(5): 442-9.
34. Chimenti L, Morici G, Paterno A, et al. Bronchial epithelial damage after a half-marathon in nonasthmatic amateur runners. Am J Physiol Lung Cell Mol Physiol 2010; 298(6): L857-62.
35. Larsson K, Tornling G, Gavhed D, Muller-Suur C, Palmberg L. Inhalation of cold air increases the number of inflammatory cells in the lungs in healthy subjects. European Respiratory Journal 1998; 12(4): 825-30.
36. Heir T, Oseid S. Self-reported asthma and exercise-induced asthma symptoms in high-level competitive cross-country skiers. Scand J, Med Sci Sports 1994; 4: 128-33.
37. Rundell KW. Pulmonary function decay in women ice hockey players: is there a relationship to ice rink air quality? Inhal Toxicol 2004; 16(3): 117-23.
38. Lumme A, Haahtela T, Ounap J, et al. Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players. Eur Respir J 2003; 22(1): 113-7.
39. Bernard A, Carbonnelle S, Michel O, et al. Lung hyperpermeability and asthma prevalence in schoolchildren: unexpected associations with the attendance at indoor chlorinated swimming pools. Occupational & Environmental Medicine 2003; 60(6): 385-94.
40. Lagerkvist BJ, Bernard A, Blomberg A, et al. Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance. Environmental Health Perspectives 2004; 112(17): 1768-71.
41. Heir T, Larsen S. The influence of training intensity, airway infections and environmental conditions on seasonal variations in bronchial responsiveness in cross-country skiers. Scandinavian Journal of Medicine & Science in Sports 1995; 5: 152-9.
42. Deal EC, Jr., McFadden ER, Jr., Ingram RH, Jr., Strauss RH, Jaeger JJ. Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979; 46(3): 467-75.
43. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 2008; 154(8): 1558-71.
44. Goldsmith RL, Bigger JT, Jr., Bloomfield DM, Steinman RC. Physical fitness as a determinant of vagal modulation. Med Sci Sports Exerc 1997; 29(6): 812-7.
45. Filipe JA, Falcao-Reis F, Castro-Correia J, Barros H. Assessment of autonomic function in high level athletes by pupillometry. Auton Neurosci 2003; 104(1): 66-72.
46. Global Strategy for Asthma Mangement and Prevention. 2016.
47. Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: Challenges for diagnosis. JAllergy ClinImmunol 2002; 110(3): 374-80.
48. Couto M, Stang J, Horta L, et al. Two distinct phenotypes of asthma in elite athletes identified by latent class analysis. J Asthma 2015; 52(9): 897-904.
49. Dickinson JW, Whyte GP, McConnell AK, Harries MG. Screening elite winter athletes for exercise induced asthma: a comparison of three challenge methods. BrJSports Med 2006; 40(2): 179-82.
50. Price OJ, Ansley L, Levai IK, et al. Eucapnic Voluntary Hyperpnea Testing in Asymptomatic Athletes. Am J Respir Crit Care Med 2016; 193(10): 1178-80.
51. Fitch KD, Morton AR. Specificity of exercise in exercise-induced asthma. Br Med J 1971; 4(5787): 577-81.
52. Anderson SD, Silverman M, Tai E, Godfrey S. Specificity of exercise in exercise-induced asthma. Br Med J 1971; 4(5790): 814-5.
53. Carlsen KH, Engh G, Mork M. Exercise-induced bronchoconstriction depends on exercise load. Respir Med 2000; 94(8): 750-5.
54. Carlsen KH, Engh G, Mork M, Schroder E. Cold air inhalation and exercise-induced bronchoconstriction in relationship to metacholine bronchial responsiveness: different patterns in asthmatic children and children with other chronic lung diseases. Respir Med 1998; 92(2): 308-15.
55. McFadden ER, Jr., Zawadski DK. Vocal cord dsfunction masquerading as exercise-induced asthma. A physiologic cause for "choking" during athletic activities. AmJRespirCritCare Med 1996; 153(3): 942-7.
56. Refsum HE, Fõnstelien E, Oseid S, Edwards AM. Exercise-associated ventilatory insufficiency in adolescent athletes. The asthmatic child in play and sports. London: Pitmann Books Limited; 1983: 128-39.
57. Heimdal JH, Roksund OD, Halvorsen T, Skadberg BT, Olofsson J. Continuous laryngoscopy exercise test: a method for visualizing laryngeal dysfunction during exercise. Laryngoscope 2006; 116(1): 52-7.
58. Williams JH, Powers SK, Stuart MK. Hemoglobin desaturation in highly trained athletes during heavy exercise. MedSciSports Exerc 1986; 18(2): 168-73.
59. Adir Y, Shupak A, Gil A, et al. Swimming-induced pulmonary edema: clinical presentation and serial lung function. Chest 2004; 126(2): 394-9.
60. Anderson SD, Fitch K, Perry CP, et al. Responses to bronchial challenge submitted for approval to use inhaled beta2-agonists before an event at the 2002 Winter Olympics. JAllergy ClinImmunol 2003; 111(1): 45-50.
61. Fitch KD. An overview of asthma and airway hyper-responsiveness in Olympic athletes. Br J Sports Med 2012; 46(6): 413-6.
