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 of 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 (1). Out of 263 deaths, 61 were related to asthma. Only one of the 61 athletes who died had used inhaled steroids (1). This underlines the need for optimal asthma treatment and follow-up among competitive athletes. Due to the reports of the frequent use of inhaled 2-agonists and the reasons for athletes to use these drugs, 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 with the introduction of the requirement to make applications to obtain approval for the use of the drugs when competing as an international athlete. Pulmonologists and allergologists considered these rules to be very restrictive, and a joint Task Force was established by the European Respiratory Society and the European Academy of Allergy and Clinical Immunology. This task force recently gave its reports in three publications (2-4). The present article focuses on the problems raised by this report as well as outlining a Pan-European study initiated to focus on asthma and bronchial hyperrepsonsiveness in top athletes. Also other allergic diseases represent a problem in elite sports. Especially exercise induced anaphylaxis is a major problem for those affected, but also allergic rhinoconjunctivitis and uritcaria of 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 Games (5). The prevalence of EIA of 11% among the American Olympic athletes from 1984 (6), increased to >20% among the American participants in the 1996 summer Olympic Games in Atlanta (7). The asthma prevalence was 45% in cyclist and mountain bikers compared to none in divers and weight-lifters (7). 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 referents (8). 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 skiers (9). This was followed by reports of high prevalence in Norwegian and Swedish skiers (10), in competitive figure skaters (11;12), in elite cold-weather athletes (13) and among participants in the 1998 American Olympic National team for winter sports including gold medalists (14). 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%) (15).

Feinstein et al found EIB in nine of 48 male football players (16), whereas BHR to methacholine (PD20-methacholine < 16.3 mol) was found in 35.5% of the Norwegian national female soccer team (17). Of Canadian professional football players 56% had a positive bronchodilator test (increase in FEV1 >e; 12%) to inhaled salbutamol (18). 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 controls (19). 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 controls (20). High prevalence of BHR (48%) to histamine was also found among swimmers (21). Maiolo et al reported an asthma prevalence of 15% and atopy in 18% of 1060 Italian competing summer athletes (22). Higher prevalence of asthma among endurance athletes as compared to speed and power athletes was reported in a Norwegian study (23). Employing the objective criteriae for diagnosing asthma and/or bronchial hyperresponsiveness as given by the IOC Medical Comission, 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 bronchoprovocation or bronchodilator test (24).

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, 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 during the increased ventilation during exercise is thought to cause vasoconstriction in bronchial vessels followed by a secondary reactive hyperaemia with resulting oedema and airways narrowing (25). 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, caused by the saturation of the inhaled air with water. The resulting increase in osmolarity of the periciliary fluid lining the respiratory mucosal membranes is thought to cause mediator release, increased airways inflammation and bronchial constriction (26). The use of inhaled mannitol as a tool to diagnose bronchial hyperresponsiveness further confirms this hypothesis (27). 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 meters (28) and then in young ski athletes during the competitive season (9). Heavy endurance training, especially when performed in an unfavourable 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 air (29;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. Similar findings have been described in Alaskan dogs (31) and

experimentally in exercising as compared to sedentary mice (32). Inflammatory changes have been reported in induced sputum of competitive swimmers (21). Thus, heavy and repeated physical endurance training over prolonged periods of time in combination with non-optimal environmental conditions may contribute to the development of asthma and BHR among top athletes. 3. The environment An unfavourable environment in which repeated competitions and training sessions take place is thought to contribute to the development of asthma and BHR among top athletes, as in cross country skiers exposed to cold air (8;33), competitive swimmers exposed to organic chlorine products from the water in indoor pools (21) and figure skaters and ice hockey players in ice rinks with increased levels of ultrafine particles originating from the ice freeze machines (34-36). Larsson showed that cold air inhalation increased the number of inflammatory cells in bronchoalveolar lavage (37). In children Bernard and co-workers reported that time spent in swimming pools during early childhood are related to development of asthma and signs of lung involvement by increased serum levels of surfactant proteins (38) and reduced levels of Clara cell protein (39). It has also been shown that respiratory tract infections increase bronchial responsiveness in actively training athletes (40). Thus, the combination of heavy repeated exercise with an unfavourable environmental milieu is probably important for the development of asthma among top athletes.

Diagnosis of exercise induced asthma and bronchial hyperresponsiveness in athletes

The diagnosis of asthma is clinical and should be based upon history of symptoms, physical examination for the presence of bronchial obstruction and variability in lung function spontaneously, or due to bronchodilators (Table 1) (41). 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 symptoms (13;42). An exact clinical history, examination with lung function measurements before and after inhalation of a 2-agonist (requiring an increase in FEV1 of 12%), before and after a standardized exercise-test such as a tread-mill 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. Table 1. Diagnostic exercises required to obtain approval from the Medical Comission (MC) of the International Olympic Committee (IOC) for the use of inhaled 2-agonists during Olympic Games. Similar procedures are required by the World Anti Doping Association (WADA) for international sports. A clinical history in combination with a positive bronchodilator response or a positive response to EIA test or other test of bronchial responsiveness is required. Diagnostic procedure Results as required by IOC-MC

Clinical history of respiratory symptoms and clinical Positive clinical history examination Lung function (Spirometry or maximum expiratory Increase in FEV1 after inhaled flow volume loops). bronchodilator Reversibility to inhaled bronchodilator Exercise induced bronchoconstriction by standardised FEV1 decrease of 10% from before to after exercise test standardized exercise challenge Bronchial hyperresponsiveness to metacholine PD20 < 2 mol, PC20 < 4 mg/ml. (histamine presently not allowed by IOC-MC)) Other values when on inhaled steroids. Eucapnic hyper ventilation test or Mannitol inhalation test (Airidol test) Exercise field test Reduction in FEV1 of 15% or more. Reduction in FEV1 of 15% or more. Determination of PD15 of mannitol Reduction in FEV1 of 10% or more

EIA may be diagnosed in different ways; running provokes exercise-induced bronchoconstriction more easily than cycling. 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 95% of calculated maximum is reached and maintained for 46 minutes. The widespread use of inhaled steroids necessitates this level of exercise (43). Maximum heart rate is calculated approximately by taking 220 minus the age of the patient, and can be measured electronically. The running is performed at a room temperature of approximately 20 C 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 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 -20C, the sensitivity of the test is markedly increased while simultaneously maintaining a high degree of specificity (44). Other tests used for the diagnosis of exercise induced bronchoconstriction and BHR are eucapnic hyperventilation (45) and mannitol bronchial provocation, determining the inhaled dose causing a 15% decrease in FEV1 (46).

Differential diagnoses
There are several differential diagnoses to EIA, including exercise induced laryngeal inspiratory stridor (also called exercise induced vocal cord dysfunction) (47;48) 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 2-agonists, which will have no effect upon the exercise induced laryngeal stridor. Exercise induced laryngeal stridor 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 curve (49), is typical, in contrast to EIA, when the dyspnoea occurs after exercise, and is expiratory due to the lower airways obstruction. Other differential diagnoses to EIB include exercise induced arterial hypoxemia (50-52) and swimming induced pulmonary edema (53) (Table 2).

Table 2. Differential diagnoses to EIA in athletes. Diagnosis EIA Presentation 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 vocal Symptoms occurring during maximum exertion. Symptoms disappear cord dysfunction after stopping exercise (unless hyperventilating) (VCD) If observed: Inspiratory stridor, audible inspiratory sounds from laryngeal area. No signs of bronchial obstruction. No effect of pretreatment with inhaled bronchodilator Poor physical fitness Related to expectations High heart rate after low grade exercise load Other chronic lung Reduced baseline lung function may reduce physical performance due to diseases limitations in air flow and lung volumes Other general disease Chronic heart diseases and others Exercise induced Occurs in well trained athletes with high max. VO2 arterial hypoxemia Primarily due to diffusion limitations and ventilation-perfusion (EIAH) inequality. Incomplete diffusion in the healthy lung may be due to a rapid red blood cell transit time through the pulmonary capillary Swimming induced Often hemoptysis after heavy swimming exercise, reduced diffusion pulmonary edema capacity (SIPE)

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 lead to 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 2-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 2-agonists and inhaled steroids during the games (54). Applications had to be submitted beforehand, and results of laboratory tests such as exercise tests, bronchial provocation tests with metacholine, eucapnic hyper ventilation tests or documented reversibility to inhaled 2-agonists had to be submitted to obtain approval for the use of asthma drugs (55). Several allergologists and pulmonologists felt these rules too strict as they focused upon the specificity of asthma diagnosis and not upon sensitivity (56), and a joint Task Force was established by the European Respiratory Society (ERS) and European Academy of

Allergy and Clinical Immunology (EAACI). This task force published a European Respiratory Monograph (4) viewing the topic from different angles and published a report reviewing the problem of asthma and allergy among athletes, explaining pathogenetic mechanisms and giving recommendations with regard to the diagnosis of asthma and BHR among athletes, as well as to recommended treatment (2;3). After appropriate 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). 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 Web site of the World Antidoping Association (WADA) (http://www.wada-ama.org/en/t1.asp) for international sports, or to the Web site of the IOC for the Olympic Games: (http://www.olympic.org/uk/utilities/reports/level2_uk.asp?HEAD2=1&HEAD1=1). Applications for the use of asthma drugs for the Olympic Games may be submitted by filling in an electronic form on the IOC website; for other international sports by filling in the written forms for a Therapeutic Use Exemption (TUE) for submission to WADA and/or the relevant international sporting association. Beijing and further on Much concern was raised before the Summer Olympic Games in Beijing August 2008 with respect to possible harmful effects of the environmental air pollution in Beijing. The Norwegian Olympic Committee was much concerned about this problem and asked the author of the present article (Kai-Hkon Carlsen) to examine all Norwegian athletes qualifying for the Beijing Olympics for respiratory problems, to initiate treatment when needed following the regulations given by IOC-MC, and to follow the athletes up to and through the Beijing Olympics. This led to a study related to asthma and bronchial responsiveness among all athletes of different types of sports and then further to a pan-European study initiated through GA2LEN, the European Network of Centres of Excellence with participation of nine European countries. The main aim was to investigate the prevalence of asthma, bronchial responsiveness and allergy in the different types of summer sports. The results are not yet available, but it should be emphasized that during the Beijing Summer Olympic Games, 813 applications were made for the use of inhaled 2agonists, and 781 of these were approved. Of the 781 athletes with approval for the use of inhaled 2-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; http://www.wadaama.org/rtecontent/document/WADA_IO_Report_Beijing_2008_FINAL_FINAL.pdf

Reference List
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 Feb;113(2):264-7. 2. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, 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 Apr;63(4):387-403. 3. Carlsen KH, Anderson SD, Bjermer L, Bonini S, Brusasco V, Canonica W, 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 May;63(5):492-505. 4. Carlsen KH, Delgado L, Del Giacco S. Diagnosis, Prevention and treatment of ExerciseRelated Asthma, Respiratory and Allergic Disorders in Sports. 10[33]. 2005. 3. European Respiratory Monograph. Ref Type: Serial (Book,Monograph) 5. Voy RO. The U.S. Olympic Committee experience with exercise-induced bronchospasm, 1984. Med Sci Sports Exerc 1986 Jun;18(3):328-30. 6. Weiler JM, Metzger J, Donnelly AL, Crowley ET, Sharath MD. Prevalence of bronchial responsiveness in highly trained athletes. Chest 1986;90:23-8. 7. Weiler JM, Layton T, Hunt M. Asthma in United States Olympic athletes who participated in the 1996 Summer Games. J Allergy Clin Immunol 1998 Nov;102(5):7226. 8. 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. 9. Heir T, Oseid S. Self-reported asthma and exercise-induced asthma symptoms in highlevel competitive cross-country skiers. Scand J Med Sci Sports 1994;4:128-33. 10. 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 Feb;90(2):99-105. 11. 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):6771. 12. Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F. Exercise-induced asthma in figure skaters. Chest 1996;109(2):312-5. 13. 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 Feb;33(2):208-13. 14. 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 Apr;32(4):732-7.

15. Langdeau JB, Turcotte H, Bowie DM, Jobin J, Desgagne P, Boulet LP. Airway hyperresponsiveness in elite athletes. Am J Respir Crit Care Med 2000 May;161(5):147984. 16. 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. 17. Sdal A. Bronchial hyperreactivity, exercise induced asthma and allergy. A study of female national team athletes in soccer. Norwegian University of Sport and Physical Education; 1997. 18. Ross RG. The prevalence of reversible airway obstruction in professional football players. Med Sci Sports Exerc 2000 Dec;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 May;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 Apr;53(4):346-52. 22. Maiolo C, Fuso L, Todaro A, Anatra F, Boniello V, Basso S, et al. Prevalence of asthma and atopy in Italian Olympic athletes. Int J Sports Med 2004 Feb;25(2):139-44. 23. Nystad W, Harris J, Borgen JS. Asthma and wheezing among Norwegian elite athletes. Med Sci Sports Exerc 2000 Feb;32(2):266-70. 24. Dickinson JW, Whyte GP, McConnell AK, Harries MG. Impact of changes in the IOCMC asthma criteria: a British perspective. Thorax 2005 Aug;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. Am J Respir Crit Care Med 1998 Oct;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: Oseid S, Carlsen KH, editors. Children and Exercise XIII.Champaign, Illinois: Human Kinetics Publishers, Inc.; 1989. p. 351-60.

29. Sue-Chu M, Karjalainen EM, Altraja A, Laitinen A, Laitinen LA, Naess AB, et al. Lymphoid aggregates in endobronchial biopsies from young elite cross-country skiers. Am J Respir Crit Care 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. Am J Respir Crit Care Med 2000 Jun;161(6):208691. 31. Davis MS, McKiernan B, McCullough S, Nelson S Jr, Mandsager RE, Willard M, et al. Racing Alaskan sled dogs as a model of "ski asthma". Am J Respir Crit Care Med 2002 Sep 15;166(6):878-82. 32. Chimenti L, Morici G, Paterno A, Bonanno A, Siena L, Licciardi A, et al. Endurance training damages small airway epithelium in mice. Am J Respir Crit Care Med 2007 Mar 1;175(5):442-9. 33. Heir T, Oseid S. Self-reported asthma and exercise-induced asthma symptoms in highlevel competetive cross-country skiers. Scand J Med Sci Sports 1994;4:128-33. 34. Mannix ET, Farber MO, Palange P, Galassetti P, Manfredi F. Exercise-induced asthma in figure skaters. Chest 1996;109(2):312-5. 35. Lumme A, Haahtela T, Ounap J, Rytila P, Obase Y, Helenius M, et al. Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players. Eur Respir J 2003 Jul;22(1):113-7. 36. Thunqvist P, Lilja G, Wickman M, Pershagen G. Asthma in children exposed to nitrogen dioxide in ice arenas. Eur Respir J 2002 Sep;20(3):646-50. 37. 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. Eur Respir J 1998 Oct;12(4):825-30. 38. Bernard A, Carbonnelle S, Michel O, Higuet S, De Burbure C, Buchet JP, et al. Lung hyperpermeability and asthma prevalence in schoolchildren: unexpected associations with the attendance at indoor chlorinated swimming pools. Occup Environ Med 2003 Jun;60(6):385-94. 39. Lagerkvist BJ, Bernard A, Blomberg A, Bergstrom E, Forsberg B, Holmstrom K, et al. Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance. Environ Health Perspect 2004 Dec;112(17):1768-71. 40. Heir T, Aanestad G, Carlsen KH, Larsen S. Respiratory tract infection and bronchial responsiveness in elite athletes and sedentary control subjects. Scand J Med Sci Sports 1995;5:94-9. 41. Global Strategy for Asthma Mangement and Prevention. 2006. Ref Type: Internet Communication

42. Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: Challenges for diagnosis. J Allergy Clin Immunol 2002 Sep;110(3):374-80. 43. Carlsen KH, Engh G, Mrk M. Exercise induced bronchoconstriction depends on exercise load. Respir Med 2000 Aug 2;94:750-5. 44. Carlsen KH, Engh G, Mrk M, Schrder 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. 45. Dickinson JW, Whyte GP, McConnell AK, Harries MG. Screening elite winter athletes for exercise induced asthma: a comparison of three challenge methods. Br J Sports Med 2006 Feb;40(2):179-82. 46. Brannan JD, Anderson SD, Perry CP, Freed-Martens R, Lassig AR, Charlton B. The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline. Respir Res 2005;6:144. 47. Landwehr LP, Wood RP, Blager FB, Milgrom H. Vocal cord dysfunction mimicking exercise-induced bronchospasm in adolescents. Pediatrics 1996;98(5):971-4. 48. McFadden ERJ, Zawadski DK. Vocal cord dysfunction masquerading as exerciseinduced asthma. a physiologic cause for "choking" during athletic activities. Am J Respir Crit Care Med 1996 Mar;153(3):942-7. 49. Refsum HE, Fnstelien E. Exercise-associated ventilatory insufficiency in adolescent athletes. In: Oseid S, Edwards AM, editors. The asthmatic child in play and sports.London: Pitmann Books Limited; 1983. p. 128-39. 50. Williams JH, Powers SK, Stuart MK. Hemoglobin desaturation in highly trained athletes during heavy exercise. Med Sci Sports Exerc 1986 Apr;18(2):168-73. 51. Powers SK, Williams J. Exercise-induced hypoxaemia in highly trained athletes. Sports Med 1987 Jan;4(1):46-53. 52. Powers SK, Dodd S, Lawler J, Landry G, Kirtley M, McKnight T, et al. Incidence of exercise induced hypoxemia in elite endurance athletes at sea level. Eur J Appl Physiol Occup Physiol 1988;58(3):298-302. 53. Adir Y, Shupak A, Gil A, Peled N, Keynan Y, Domachevsky L, et al. Swimming-induced pulmonary edema: clinical presentation and serial lung function. Chest 2004 Aug;126(2):394-9. 54. Anderson SD, Sue-Chu M, Perry CP, Gratziou C, Kippelen P, McKenzie DC, et al. Bronchial challenges in athletes applying to inhale a beta2-agonist at the 2004 Summer Olympics. J Allergy Clin Immunol 2006 Apr;117(4):767-73.

55. Anderson SD, Fitch K, Perry CP, Sue-Chu M, Crapo R, McKenzie D, et al. Responses to bronchial challenge submitted for approval to use inhaled beta2-agonists before an event at the 2002 Winter Olympics. J Allergy Clin Immunol 2003 Jan;111(1):45-50. 56. Bonini S, Brusasco V, Carlsen KH, Delgado L, Del Giacco SR, Haahtela T, et al. Diagnosis of asthma and permitted use of inhaled beta2-agonists in athletes. Allergy 2004 Jan;59(1):33-6.
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