Exercise-induced bronchoconstriction

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Exercise-induced bronchoconstriction

Presented by Suparat Sirivimonpan, MD.

June14, 2013

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Exercise-induced bronchoconstriction

  1. 1. Exercise-induced bronchoconstrictionSuparat Sirivimonpan,MD.14-6-13
  2. 2. Outline• Definition and overview• Prevalence• Pathogenesis• Diagnosis• Therapy• Take-home messages
  3. 3. Definition and overview
  4. 4. Definition and overview• Transient narrowing of the lower airways thatoccurs after vigorous exercise• It may be observed in patients who have or do nothave chronic asthma• EIA should no longer be used– Not all patients with EIB have asthma– Exercise does not induce asthma but rather isa trigger of bronchoconstrictionWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.Exercise-induced airway narrowingEexercise-induced asthma synonymous termsExercise-induced bronchospasmE.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th ed
  5. 5. Definition and overview• Exercise-induced bronchoconstriction (EIB)– is a manifestation of BHR– is often the first sign of asthma– the last to resolve with an asthma exacerbation• Diagnosis : decrease in FEV1 after exercise of 10-15% of the preexercise valueWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315
  6. 6. DefinitionReferences EIB EIAE.R. McFadden Jr. MiddletonsAllergy: Principles & Practice,7th edCondition in which vigorous physical activity triggers acute airwaynarrowing in people with heightened bronchial reactivityPRACTALL consensus report.Allergy 2008; 63:953–961.Same clinical presentation inindividuals without asthmaLower airway obstruction &symptoms of cough, wheezingor dyspnea induced by exercisein patients with underlyingasthma.AAAAI Work Group Report.J Allergy Clin Immunol 2007;119:1349–1358Airway obstruction that occursin association withexercise without regard to thepresence of chronic asthmaCondition in which exerciseinduces symptoms ofasthma in patients who haveasthmaNAEPP EPR-3 2007 Bronchospastic event that iscaused by a lossof heat, water, or both from thelung during exerciseNot statedGINA 2010 Physical activity is an importantcause of symptoms for mostasthma patients, and for someit is the only causeNot stated
  7. 7. Prevalance
  8. 8. Prevalance• In the general population : 7-20%• Asthma patients : occur in up to 90%– more frequently more severe or less well-controlled asthma• Competitive athletes :up to 50%– depending on the type of sport, environmental conditions inwhich the exercise is performed, and maximum exerciselevelDavid A. Khan.Allergy Asthma Proc 2012:33:1–6T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315prevalence of EIB-varies considerably based on the type of test andcriteria used for diagnosis-may also be influenced by age, sex, and ethnicity
  9. 9. Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  10. 10. In childrenLee So-Yeon et al. Expert Rev Clin Immunol. 2009;5(2):193-207.
  11. 11. David A. Khan.Allergy Asthma Proc 2012:33:1–6
  12. 12. EIB is more common in more strenuoussports particularly in cold airRandolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.
  13. 13. Pathogenesis
  14. 14. Pathogenesis• EIB occurs in response to heating and humidifying largevolumes of air during a short period• Heat and water move from mucosa to the inspired airdirectly due to local temperature and vapor-pressuregradientsWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315EIB : Depend on-ventilation rate-water content and temperature of the inspired air-temperature of the airway wall-availability of airway surface liquid (ASL) toprovide humidification
  15. 15. The greater the heat exchange, the more severe the obstruction.Relationship between the heat lost from the respiratory tract duringexercise & the severity of obstruction in asthmatic patientsE.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th ed
  16. 16. Pathogenesis• Theory– Osmotic theory– Thermal theory– Airway injuryWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  17. 17. T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315thermal theory osmotic theoryCooling and hyperosmolarity- act independently as stimuli for the airways to narrow- operate togetherThermal theory doesnot include BSMcontraction ormediator release
  18. 18. Mediator of EIB• Several mediators are involved• PGs, LTs, and histamineT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315↑ cysLTs , PGD2 in induced sputum↓ PGE2↑ ratio of cysLTs to PGE2↑ urinary excretion of LTE4 , 9 ,11β-PGF2(metabolite of PGD2) (also be found in sputum after exercise)Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  19. 19. Mediator of EIB• ↑sPLA2-X protein in induced sputum supernatant and inepithelial cells after exercise challenge thus providing an explanation for the high levels ofcysLTs and other eicosanoids in EIBT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315
  20. 20. Hallstrand TS et al. JACI 2005;116:586-93.•Mild intermittentasthma•18-59 years of age•Exercise challenge
  21. 21. Mediator : mast cell, eosinophil• Mast cells : PGD2, LTs, histamine• Eosinophils : LTs, ECP• PGD2 : major mast cell specific mediator in EIB• The amount of eosinophilia in induced sputum hasbeen correlated with the degree of EIB severity• Levels of histamine and tryptase are also elevatedafter exercise challengeT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315
  22. 22. Mediator : Epithelium• Epithelium : generation and regulation of mediators• Adenosine and adenosine triphosphate– key regulators of the depth of the airway surface fluid layer– via A2b receptors act on mast cells to release mediators• expresses 15-lipoxygenase-1– which synthesizes the bronchoconstrictive mediator 15S-hydroxyeicosatetraenoic acid• major source of PGE2– bronchoprotective ,inhibit EIB when administered by inhalationT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315Epithelium may regulate the balance betweenthe release of bronchoconstricting eicosanoidsand mechanisms, which reduce the synthesis ofPGE2
  23. 23. Mediator : sensory nerve• Additional mediators are released from sensoryairway nerves• activated by eicosanoids (ex.cysLTs), in the airway• Activated sensory nerves release– Neurokinins bronchoconstriction , mucous release• Mucin 5AC (MUC5AC) predominant gel-forming mucin of goblet cellsT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315
  24. 24. T. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315
  25. 25. Airway injury• important role in elite athletes• arise from conditioning large volumes of dry air overmonths of training• Epithelial repair microvascular leak and plasma exudation contractile properties of airway smooth muscle changeand become more sensitive to stimuli (repeatedexposure to plasma-derived products)  AHRT. Pongdee and J.T. Li. Ann Allergy Asthma Immunol 2013;110: 311-315This type of airway injury does not involveairway remodeling and likely does not predictchronic disease
  26. 26. Anderson SD, Kippelen P. J Allergy Clin Immunol 2008;122:225-35.
  27. 27. Diagnosis
  28. 28. Diagnosis• Self-reported symptoms alone are not reliable fordiagnosis of EIB• Optimal EIB management may require confirmation ofthe diagnosis using objective methodsWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  29. 29. Randolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.
  30. 30. History• Characteristic: develops within 5-10minutes after completing exercise• Rarely occurs during exercise• Spontaneous resolution: ≈ 30 minutes later• Undertake and finish vigorous activity, butwork achieved is lower than normal• Exertion needs to be sustainedE.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th edWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  31. 31. Lee So-Yeon et al. Expert Rev Clin Immunol. 2009;5(2):193-207.
  32. 32. Less common• Stomachache, Sore throat (youngchildren)• Fatigue with expected exercise for age• Abdominal pain• Exacerbation of allergens and asthmaseasonally particularly with exertion• Muscle cramping• Side ache• HeadacheLee So-Yeon et al. Expert Rev Clin Immunol. 2009;5(2):193-207.Randolph C. Clinic Rev Allerg Immunol. 2008;34:205–216.
  33. 33. Refractory period & EIB: 50% of patientsRepeated bouts ofwork within 40minutes or lessbronchial narrowingprogressivelydecreases(lasting 2-3 hours)• Mechanism : Unknown•Increase circulating catecholamines, increase inhibitory prostaglandins??**first doing warm-up**E.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th ed
  34. 34. Objective methods• Direct challenges• Methacholine challenge• Histamine challenge• Provoke bronchoconstriction,exclusive of airwayinflammation•Indirect challenges•Exercise challenge (Laboratory-based; sports-specific)•Eucapnic voluntary hyperpnea (EVH)•Hypertonic saline challenge•Inhaled powdered mannitol•Inhaled adenosine monophosphate (AMP)• More effective in identifying EIB• Reflect severity of inflammationWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  35. 35. Methacholine challengeAmerican Thoracic Society.AJRCCM 2000;161:309-29considered positive according to IOC-MC- PC20 ≤ 4 mg/mL when not taking ICS- or 4-16 mg/mL when taking ICS for ≥1 monthWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  36. 36. • Screening for asthma• Low sensitivity for EIB Notrecommended as screening toolfor EIBAmerican Thoracic Society.AJRCCM 2000;161:309-29
  37. 37. American Thoracic Society.AJRCCM 2000;161:309-29
  38. 38. American Thoracic Society.AJRCCM 2000;161:309-29Methacholine challenge
  39. 39. Exercise challengeBaseline spirometryPostprovocation spirometryExercise challengeCalculate target FEV1-Positive result: 10% decrease in FEV1-Severe bronchoconstriction: 50% decrease in FEV1-Recovery: 95% of baseline FEV1-At 1 to 3, 5,10, 15, 20, and 30 to 45 minutes-2 repeatable FEV1 within 3% of each otherat each time pointWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.Laboratory challenge-8-minute exercise in ambientcondition (20-25 c, RH<50%)-80-90% of estimated HRmax(95% in elite athlete) by 2 minutes maintain for remaining 6 minutes-Inhale dry air (<5 mg H2O/L)Field-based challenge-More sensitive than laboratory-challenge in elite winter athletesATS 2013 *  5,10,15, 30 minmore frequent if a severe response is expected*The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.
  40. 40. Criteria for EIB- 10% decrease in FEV1 after exercise (based on 2 SD from themean percentage decrease in FEV1 in healthy individuals)- ≥ 15% decrease in PEFR or an FEV1 of 15% afterchallenge with exercise- 10-15% decrease in FEV1 after exerciseWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.E.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th edThe American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.Joint Task Force of ERS & EAACI in cooperation with GA2LEN. Allergy 2008:63: 387–403.
  41. 41. Contraindications for exercise challengeThe American Thoracic Society. Am J Respir Crit Care Med 2000;161:309-29
  42. 42. Eucapnic Voluntary Hyperpnea (EVH)Challenge• High sensitivity to identify EIB• IOC MC: optimal test to identify EIB for athletes seekingapproval to inhaled β2–agonist before an event• Compare with exercise• Similarities : stimulus, time course of airwayresponse & recovery, mediators, inhibitory effectsof drugs• Differences : cardiovascular response orsympathetic driveWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.Rundell KW, Slee JB. J Allergy Clin Immunol 2008;122:238-46.
  43. 43. Eucapnic Voluntary Hyperpnea Challenge• Baseline FEV1 < 80% of predicted  performed withcaution• Baseline FEV1 < 70% of predicted  should not beperformedWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  44. 44. Hypertonic saline challenge• Effectiveness similar to exercise and EVH• Advantage : - More economical & easier to administer- Ability to collect sputum• Nebulize 4.5% hypertonic saline inhalation in 15-20 minutes• Exposure time: 30 & 60 sec, 2 & 4 & 8 min (total 15.5 mins)- FEV1 measurement: 1 min after everyexposure< 10% fall in FEV1  doubled exposure time> 10% fall in FEV1  same exposure•Termination: ≥ 15% fall in FEV1 or totalminimum dose of 23 g (15.5 mins)Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  45. 45. Inhaled powder mannitol challenge• Correlates well with other indirect challenges• Safe, ease of use, short time to perform, no requirement forspecialized and costly equipment• Inhalation of dry powder mannitol:• 5, 10, 20, 40, 80, 160, 160 and 160 mg (dry power inhaler)(a maximal total cumulative dose of 635 mg)• FEV1 measurement: 1 min after each doseSandra D. Anderson.CHEST 2010; 138(2):25S–30SWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.A positive response•15% fall in FEV1 at a total cumulative dose of 635 mg•Or 10% fall in FEV1 from baseline between doses
  46. 46. Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  47. 47. Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  48. 48. Indirect challenges• Standardized dry air exercise challenge and EVH– are effective in diagnosing EIB– equipment is expensive and may not be practical in many clinicalsettings.• Hypertonic saline challenge and inhaled powderedmannitol– require less equipment and space– can be easily performed in the office environmentWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  49. 49. Confounding factors in diagnosisE.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th ed
  50. 50. Treatment
  51. 51. EIB therapy• Primary aim is prophylaxis• Isolated EIA• Pretreatment before exercise• Underlying asthma• Anti-inflammatory therapyWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.E.R. McFadden Jr. Middletons Allergy: Principles & Practice, 7th edPRACTALL consensus report. Allergy 2008; 63:953–961.•EIB is an indication to start regularpreventive treatment and a marker ofinadequate asthma management
  52. 52. TherapyNonpharmacological• Warm-up 10-15 min• Warm-down; 10-15 min• Avoidance of triggers• Nasal breathing• Wearing a mask in cold environments• Avoiding exercise in conditions where air iscold and dryWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  53. 53. Therapy• Controller therapy• Pretreatment before exercise• β2-adrenergic receptor agonist• Leukotriene modifer• Mast cell stabilizer• Other: anticholinergic agent,xanthine, antihistaminePharmacologicalWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  54. 54. β2-Adrenergic Receptor Agonists• single most effective therapeutic group of agents for– acute prevention of intermittent EIB– accelerating recovery of FEV1 to baseline• Daily use of β2-adrenergic agents lead to “tolerance” monotherapy with adrenergic agents isrecommended for use only on intermittent basisfor preventionWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  55. 55. β2-Adrenergic Receptor Agonists• are usually effective– 2 to 4 hours for SABAs– up to 12 hours for LABAs• inhaled 5 to 20 minutes before exercise (salmeterol 15-30 minutes)Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  56. 56. Leukotriene receptor antagonist• Vary in effectiveness• 50% of patients being responders• Most patients do not experience completeprotection• Bronchoprotective activity & acceleratingrecovery• Has no use to reverse airway obstruction• Daily use does not lead to toleranceWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  57. 57. Leukotriene receptor antagonistMontelukast• acts within 1 to 2 hours of oral administration• bronchoprotective activity for 24 hoursWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.-The magnitude of effect may be smaller forLTRAs than either ICS or preexercise SABA- duration of action is longer  very useful forpatients or athletes engaging in physical activitythroughout the dayThe American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.
  58. 58. ICS• Controller• decrease the frequency and severity of EIB• symptomatic asthmatic patients : best controlled bymaintenance anti-inflammatory treatment alone or incombination with other short-term preventive treatment• Beta2-Adrenergic agonists can be added if necessary forshort-term prevention of EIBWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  59. 59. • The choice of whether to add daily ICS or daily LTRA toas-needed use of SABA in patients with EIB who do notrespond to intermittent SABA therapy alone made on a case-by-case basis– evidence supports efficacy of both types ofmedications in EIB– ICS therapy• may have a more potent anti-inflammatory effect inpatients with EIB associated with airwayinflammation• may work better in patient with asthma with EIB >elite athlete without asthma with EIB• baseline lung function is below normal  ICSinitiallyThe American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.
  60. 60. Mast cell stabillizers (MCS)• Cromolyn sodium and nedocromil• Bronchoprotective activity• No bronchodilator activity• Interference with mast cell mediator release ofPGD2• Daily use does not lead to tolerance• Vary in effectiveness:• Monotherapy or add-on therapy• Rapid onset but of short duration (1-2 hours)Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  61. 61. • attenuation of EIB by about 50%• no significant differences between sodium cromoglycateand nedocromil sodium• Effectiveness : SABAs >MCSAs > anticholinergic agentsMast cell stabillizers (MCS)The American Thoracic Society. Am J Respir Crit Care Med 2013;187:1016-1027.
  62. 62. Other agents• Anticholinergic(ipratropium), theophylline, antihistamines, calciumchannel blockers, -adrenergic receptorantagonists, inhaled furosemide, heparin, and hyaluronicacid  inconsistent resultsWeiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  63. 63. An Official American Thoracic Society Clinical Practice GuidelineAm J Respir Crit Care Med 2013;187: 1016–1027*Or surrogate challenge ex.hyperpnea or mannitol
  64. 64. Am J Respir Crit Care Med 2013;187:1016-1027.
  65. 65. Am J Respir Crit Care Med 2013;187:1016-1027.
  66. 66. Am J Respir Crit Care Med 2013;187:1016-1027.
  67. 67. Am J Respir Crit Care Med 2013;187:1016-1027.
  68. 68. Weiler JM et al. Ann Allergy Asthma Immunol 2010;105:S1-S47.
  69. 69. Take-home messages• EIB is a transient narrowing of the lower airwaysthat occurs after vigorous exercise• Reduction of FEV1 of 10% to 15% of thepreexercise value is a criteria for diagnosis• Symptoms develop within 5-10 minutes aftercompleting exercise & spontaneously disappearabout 30 minutes later• Self-reported symptoms alone are not reliable, soindirect challenge is recommended
  70. 70. Take-home messages• Prevention is the main approach to management• EIB is a marker of inadequate asthma control inpatient with asthma• Inhaled β2-agonists is an effective prophylacticmedication• Monotherapy with adrenergic agents isrecommended only on intermittent basis• Pre-exercise warm-up may be helpful
  71. 71. Thank you

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