1. When Athletes Can’t Breathe: Exercise-Induced Asthma/Bronchospasm Mark A. Brown, M.D. Professor of Pediatrics Director, University of Arizona Pediatric Pulmonary Center mabrown@arc.arizona.edu + ++++9+=9+/+ +

2. If from running, gymnastic exercises, or any other work, the breathing becomes difficult, it is called “Asthma”. The symptoms of its approach are heaviness of the chest…, difficulty of breathing in running or on a steep road. Areteaus, The Cappadocian, First Century AD

3. Definitions EIB - Symptoms of chest tightness, shortness of breath, cough and/or wheezing following vigorous exercise EIA - chest tightness, shortness of breath, cough and/or wheezing - triggered by exercise in a patient with asthma (known or unknown)

4. Prevalence EIB –14% of collegiate cross country runners (Thole, et al. Med & Sci in Sports & Exer 2001; 33:1641-1646.) –50% of elite summer athletes had positive screening test (Holzer, et al. J Allergy Clin Immunol 2002; 101:374-380.)

5. Prevalence EIB affects approximately: 90% of asthmatics 35-40% of those with allergic rhinitis 12-15% of the general population 3-25% of athletes (higher percentages in younger age groups)

6. Olympians and Asthma 212% increase in β- agonist use from 1984 to 1996 151% increase in β- agonist use from 1996 to 2000 66% of athletes using β- agonists in 2004 were also using inhaled corticosteroid Fitch, KD. Clin Rev Allergy Immunol 31:259, 2006 Carlsen KH et al. Allergy 63:387, 2008

7. Typical EIB Time Course % Baseline Time (min) Exercise

8. Typical EIA Time Course % Baseline Time (min) Exercise

9. EIB Refractory period % Baseline Time (min) Exercise

10. Physical Factors Exercise: type, intensity, duration Bronchial hyper-responsiveness (BHR) Environmental factors –Direct: temperature, humidity –Indirect (through increase in BHR): air pollution, viral infections, allergen exposure

11. High Asthmagenic Activities High Minute Ventilation Activities –Long-distance running –Cycling –Basketball –Soccer –Rugby Activities associated with cool, dry conditions –Ice hockey –Speed skating –Cross country skiing –Scuba diving

12. Low Asthmagenic Activities Low minute ventilation activities –Football –Baseball –Downhill skiing –Karate –Wrestling –Boxing –Sprinting –Gymnastics –Racquet sports –Golf Activities associated with warm, humid conditions –Swimming –Diving –Water polo –Water skiing

13. Proposed Stimuli Respiratory (airway) heat loss Increased airway fluid osmolality Rapid airway cooling and rewarming

14. Respiratory Heat Loss Degree of bronchoconstriction is proportional to respiratory heat exchange Sufficient respiratory heat exchange induces bronchoconstriction in the absence of exercise »Deal, et al. J Appl Physiol 1979; 46:467-475

15. Respiratory Heat Loss Direct airway temperature measurements confirm fall with exercise/hyperventilation »McFadden, et al. J Appl Physiol 1985; 58:564-570. »McFadden, et al. J Appl Physiol 1985; 76:1007-1010. Bronchoconstriction induced following inhalation of hot dry air »Anderson, et al. Eur J Respir Dis 1985; 67:20-30.

16. Increased Airway Fluid Osmolality Bronchoconstriction induced following inhalation of hot dry air »Anderson, et al. Eur J Respir Dis 1985; 67:20-30. Level of minute ventilation necessary to induce bronchoconstriction same regardless of air temperature (humidity constant) »Eschenbacher & Shepherd. Am Rev Respir Dis 1985; 131:894-901.

17. Increased Airway Fluid Osmolality Osmolality of nasal secretions increases in response to cold dry air »Togias, et al. Am Rev Respir Dis 1988; 137:625-629. Osmolality of tracheal lining fluid is increased in tracheostomy patients »Potter, et al. Am Rev Respir Dis 1967; 96:83-87. Osmolality of tracheal lining fluid is increased in dog trachea exposed to air »Boucher, et al. J Appl Physiol 1981; 50:613-620.

18. Proposed Mechanisms Neuropeptide release Mediator release Vascular engorgement

19. Neuropeptide Release Hypertonic saline induces changes of neurogenic inflammation »Umeno, et al. J Clin Invest 1990; 85:1905-1908. Little evidence to support sympathetic/vagal mechanisms

20. Mediator Release Supported by studies of –Direct measurement of mediators released into lung fluid following hypertonic, hyperventilation and exercise stimuli; –Effects of specific mediator antagonists or synthesis inhibitors on induced bronchoconstriction

21. Mediator Release Histamine Prostaglandins ECP PAF Bradykinin Leukotrienes Neutrophil chemotactic activity (IL-8, LTB 4 ) Substance P/NEP

22. Diagnosis History alone is an unreliable indicator of EIB. –45.8% of adolescents who screened negative by history had EIB (Bukolic RE. J Peds 2002; 141:306-308.) –Poor correlation between reported symptoms and exercise challenge in collegiate cross-country runners/elite athletes (Thole, et al. Med & Sci in Sports & Exer 2001; 33:1641-1646. Rundell, et al. Med & Sci in Sports & Exer 2001; 33:208-213. Rundell, et al. Med & Sci in Sports & Exer 2000; 32:309-316.)

23. Diagnosis Diagnosis confirmed by >15-20% fall in PEFR or FEV 1 after –formal exercise challenge test taking into account the type of exercise, temperature and relative humidity (confirmed by a positive test, but not excluded by a negative test); –formal eucapnic hyperventilation challenge as an alternative (more sensitive; negative test usually excludes EIA).

24. Exercise Challenge Baseline spirometry or PEFR Exercise Challenge –Exercise to 80% calculated maximal heart rate or O 2 consumption of 30-35 ml/min/kg for 6-10 min –FEV 1 or PEFR every 3-5 min after exercise for 20-30 min

25. Eucapnic Hyperventilation Subject breathes 5% CO 2 /21% O 2 /74% N 2 at 30 x FEV 1 for 6 minutes Spirometry measured before and at regular intervals afterward At least comparable to, perhaps more sensitive than methacholine challenge

26. Exercise/Eucapnic Hyperventilation Response % Baseline Time (min) Exercise/EH

27. Inhaled Mannitol Inhalation of powdered mannitol increases lung lining fluid osmolality, perhaps mimicking changes associated with exercise. Compared to eucapnic hyperventilation, mannitol challenge was 96% sensitive and 92% specific for EIB. (Holzer, et al. Am J Respir Crit Care Med 2003; 167:534-537.)

28. Differential Diagnosis Poorly controlled asthma Poor conditioning Vocal cord dysfunction Cardiac disease

29. Vocal Cord Dysfunction

30. Exercise-associated respiratory symptoms Symptoms FOLLOWING exercise Symptoms DURING exercise Undiagnosed or poorly controlled asthma Further history, exam, spirometry Classification of severity, selection of appropriate therapy, patient education Follow-up 6-8 weeks Presumptive diagnosis of EIB Further history, exam,  spirometry Prophylaxis with  -agonist Optimal ResponseSuboptimal Response Exercise/EH Challenge Normal Reconsider Dx, Reassess Abnormal Escalate therapy

31. Prevention Careful sport selection –Low minute ventilation/warm humid conditions Simple Measures Prophylactic pharmacologic therapy –  -agonists –Inhaled anti-inflammatories: Cromolyn, Nedocromil, steroids –LABA –LTRA Induction of refractory period

32. Simple Preventive Measures Improve physical conditioning Exercise in warm humidified environment In cold weather cover mouth/nose with scarf or mask Gradually decrease intensity of exercise at end of work-out Avoid aeroallergens, pollutants

33. Therapeutic Sequence Simple Measures  -agonists Inhaled corticosteroids Inhaled long-acting  -agonists Ipratropium or leukotriene receptor antagonists

34. Medications approved by both the NCAA and USOC MedicationEffectiveness Albuterol*High Terbutaline*High Salmeterol*High CromolynModerate NedocromilModerate * Approval by the USOC is dependent on a previous notification and independent assessment by the Olympic Medical Commission. NCAA and USOC allow  - agonists by inhalation only.

35. Medications approved by both the NCAA and USOC MedicationEffectiveness Triamcinolone*Very Fluticasone*Very Budesonide*Very Flunisolide*Very Theophylline, SRModerate IpratropiumPossible * Approval by the USOC is dependent on a previous notification and independent assessment by the Olympic Medical Commission.

36. Alternative Medicine Approaches Omega-3 fatty acid supplementation »Mickleborough, et al. Am J Respir Crit Care Med 2003; 168:1181-1189. Buteyko Breathing Technique - relaxation? »Bowler, et al. Med J Australia. 1998; 169:575-578. »Cooper, et al. Thorax 2003; 58:674-679

37. May there never develop in me the notion that my education is complete, but give me the strength and leisure and zeal continually to enlarge my knowledge. Maimonides