Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes
2008; Elsevier BV; Volume: 122; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2008.06.014
ISSN1097-6825
AutoresKenneth W. Rundell, Joshua B. Slee,
Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoThe prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented. The prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: August 2008. Credit may be obtained for these courses until July 31, 2010.Copyright Statement: Copyright © 2008-2010. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Kenneth W. Rundell, PhD, and Joshua B. Slee, MSActivity Objectives1. To understand the role of indirect challenges in the diagnosis and monitoring of exercise-induced bronchoconstriction.2. To describe optimal conditions for exercise, eucapnic voluntary hyperpnea, hypertonic saline, and mannitol challenges.3. To improve interpretation of exercise, eucapnic voluntary hyperpnea, hypertonic saline, and mannitol challenges.Recognition of Commercial Support: This CME activity is supported by an educational grant from Merck & Co., Inc.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Kenneth W. Rundell has received honoraria as a speaker for Merck; has participated in clinical trials sponsored by Pharmaxis, Merck, Schering-Plough, and SkyePharma; and has received reserch grants from the World Anti-Doping Agency and Alta. Joshua B. Slee has no significant relationships to disclose.GlossaryAMPAMP is used as an indirect provocation agent by stimulating the degranulation of bronchial mast cells with subsequent release of histamine, leukotrienes, and other inflammatory mediators. As such, it measures the level of airway inflammation.CHLORAMINESThe interaction of chlorine with human pollutants (eg, sweat, urine) forms chloramines, which are respirable above swimming pools and include chloramide, chlorimide, and nitrogen trichloride. Inhalation of chloramines has been associated with asthma exacerbations, occupational asthma, and increased levels of tryptase, eosinophil cationic protein, and basophils in nasal lavage fluid.EUCAPNIC VOLUNTARY HYPERPNEA (EVH)An indirect provocation test that was developed as a surrogate marker for exercise-induced bronchospasm. Other indirect tests were developed to mimic the various airway insults that occur during exercise. Hypertonic saline and dry powders mimic airway dehydration associated with water loss with exercise. Indirect tests have the advantage of assessing the presence of inflammatory cells and their mediators compared with direct tests that directly provoke smooth muscle contraction.HIGH-EMISSION POLLUTANTSPollutants termed criteria pollutants are known to cause health effects at ambient air concentrations and consist of carbon monoxide, lead, nitrogen dioxide, ozone, particulate matter, and sulfur dioxide. Sulfur oxides, carbon monoxide, nitrogen oxides, and particulates are made by burning fossil fuels (coal, oil, and natural gas) and can contribute to the formation of tropospheric ozone. Chlorofluorocarbons cause depletion of stratospheric ozone. Particle pollution includes acids, organic chemicals, and aeroallergens.HIGH-VENTILATION SPORTSHigh-ventilation sports are defined as endurance sports in which ventilation is increased for prolonged periods—for example, during cross-country skiing or long distance running. Although the prevalence of exercise induced bronchospasm was thought to be higher in these endurance sports, this might not be the case.MAXIMAL VOLUNTARY VENTILATION (MVV)The maximum amount of air that can be breathed in a given period, often 1 minute. The maximal voluntary ventilation is effort-dependent and subject to variability.MINUTE VENTILATION (VE)Minute ventilation maintains the correct amounts of oxygen and carbon dioxide available to the alveoli and is defined as frequency of breathing multiplied by the volume of the breath—that is, respiratory pate per minute × tidal volume. In contrast, the alveolar ventilation takes into account only the gas that is available for alveolar gas exchange by subtracting the dead space from the tidal volume.PERICILIARY FLUID/AIRWAY SURFACE LIQUIDThe airway surface fluid is a bilayer composed of a superficial mucous layer and a periciliary fluid layer that bathes the airway epithelium up to the cilia. The mucous layer is composed of mucin glycoproteins made up mainly of Mucin (MUC) 5AC and MUC5B. The periciliary and mucous layers are separated from one another by a layer of surfactant. Water evaporation creates a hypertonic environment, and hyperosmolar fluid causes mast cell and basophil degranulation with histamine and leukotriene release. Eosinophils can also be stimulated by mannitol in vitro to cause the release of leukotriene C4.SENSITIVITY/SPECIFICITYSensitivity is the presence of a positive test among all patients with a disease and gauges the ability of finding true-positives among diseased states. Specificity is the presence of a negative test among all patients without a disease and gauges the finding of true-negatives among all healthy patients. By contrast, the positive and negative predictive values are parameters that assess the ability of a test to find true-positives and true-negatives among all patients with positive and negative tests, respectively.The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary.Exercise-induced bronchoconstriction (EIB) is the transient airway narrowing after1Anderson S.D. Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes?.J Allergy Clin Immunol. 2000; 106: 419-428Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 2McFadden Jr., E.R. Gilbert I.A. Exercise-induced asthma.N Engl J Med. 1994; 330: 1362-1367Crossref PubMed Scopus (366) Google Scholar or during3Beck K.C. Offord K.P. Scanlon P.D. Bronchoconstriction occurring during exercise in asthmatic subjects.Am J Respir Crit Care Med. 1994; 149: 352-357Crossref PubMed Scopus (95) Google Scholar, 4Suman O.E. Beck K.C. Babcock M.A. Pegelow D.F. Reddan A.W. Airway obstruction during exercise and isocapnic hyperventilation in asthmatic subjects.J Appl Physiol. 1999; 87: 1107-1113PubMed Google Scholar, 5Rundell K.W. Spiering B.A. Judelson D.A. Wilson M.H. Bronchoconstriction during cross-country skiing: is there really a refractory period?.Med Sci Sports Exerc. 2003; 35: 18-26Crossref PubMed Scopus (40) Google Scholar exercise. An estimated 90% of individuals with asthma6Anderson S.D. Connolly N.M. Godfrey S. Comparison of bronchoconstriction induced by cycling and running.Thorax. 1971; 26: 396-401Crossref PubMed Scopus (99) Google Scholar, 7Fitch K.D. Morton A.R. Specificity of exercise in exercise-induced asthma.BMJ. 1971; 4: 577-581Crossref PubMed Scopus (115) Google Scholar and 10% to 50% of a given elite athlete population experience EIB.6Anderson S.D. Connolly N.M. Godfrey S. Comparison of bronchoconstriction induced by cycling and running.Thorax. 1971; 26: 396-401Crossref PubMed Scopus (99) Google Scholar, 7Fitch K.D. Morton A.R. Specificity of exercise in exercise-induced asthma.BMJ. 1971; 4: 577-581Crossref PubMed Scopus (115) Google Scholar, 8Mannix E.T. Farber M.O. Palange P. Galassetti P. Manfredi F. Exercise-induced asthma in figure skaters.Chest. 1996; 109: 312-315Crossref PubMed Scopus (127) Google Scholar, 9Provost-Craig M.A. Arbour K.S. Sestili D.C. Chabalko J.J. Ekinci E. The incidence of exercise-induced bronchospasm in competitive figure skaters.J Asthma. 1996; 33: 67-71Crossref PubMed Scopus (85) Google Scholar, 10Rundell K.W. Wilber R.L. Szmedra L. Jenkinson D.M. Mayers L.B. Im J. Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge.Med Sci Sports Exerc. 2000; 32: 309-316Crossref PubMed Scopus (170) Google Scholar, 11Wilber R.L. Rundell K.W. Szmedra L. Jenkinson D.M. Im J. Drake S.D. Incidence of exercise-induced bronchospasm in Olympic winter sport athletes.Med Sci Sports Exerc. 2000; 32: 732-737Crossref PubMed Scopus (211) Google Scholar, 12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar, 13Rundell K.W. Jenkinson D.M. Exercise-induced bronchospasm in the elite athlete.Sports Med. 2002; 32: 583-600Crossref PubMed Scopus (154) Google Scholar In this review, EIB is considered synonymous to exercise-induced asthma, although some reserve the term exercise-induced asthma for individuals with known asthma who bronchoconstrict from exercise. The wide range in reported prevalence in the athlete population is in part a result of the variability of specific environmental demands.13Rundell K.W. Jenkinson D.M. Exercise-induced bronchospasm in the elite athlete.Sports Med. 2002; 32: 583-600Crossref PubMed Scopus (154) Google Scholar This high prevalence of EIB reported in specific elite sports brings into question whether all individuals with EIB have asthma to some degree, or whether EIB is an entity exclusive from asthma and a natural occurrence related to lung injury. The 20% to 35% prevalence of EIB in the ice rink athlete has been attributed to the inhalation of cold dry air and high-emission pollutants from fossil-fueled ice resurfacing machines.14Rundell K.W. High levels of airborne ultrafine and fine particulate matter in indoor ice arenas.Inhal Toxicol. 2003; 15: 237-250Crossref PubMed Scopus (73) Google Scholar, 15Rundell K.W. Spiering B.A. Evans T.M. Baumann J.M. Baseline lung function, exercise-induced bronchoconstriction, and asthma-like symptoms in elite women ice hockey players.Med Sci Sports Exerc. 2004; 36: 405-410Crossref PubMed Scopus (63) Google Scholar, 16Rundell K.W. Pulmonary function decay in women ice hockey players: is there a relationship to ice rink air quality?.Inhal Toxicol. 2004; 16: 117-123Crossref PubMed Scopus (55) Google Scholar The 30% to 50% prevalence among Nordic skiers is attributed to chronic inhalation of cold, dry air during training and competition,5Rundell K.W. Spiering B.A. Judelson D.A. Wilson M.H. Bronchoconstriction during cross-country skiing: is there really a refractory period?.Med Sci Sports Exerc. 2003; 35: 18-26Crossref PubMed Scopus (40) Google Scholar, 17Sue-Chu M. Larsson L. Moen T. Rennard S.I. Bjermer L. Bronchoscopy and bronchoalveolar lavage findings in cross-country skiers with and without “ski asthma.Eur Respir J. 1999; 13: 626-632Crossref PubMed Scopus (111) Google Scholar, 18Sue-Chu M. Henriksen A.H. Bjermer L. Non-invasive evaluation of lower airway inflammation in hyper-responsive elite cross-country skiers and asthmatics.Respir Med. 1999; 93: 719-725Abstract Full Text PDF PubMed Scopus (34) Google Scholar and the approximate 15% prevalence among distance runners is strongly associated with atopy, allergy, and asthma.19Helenius I.J. Tikkanen H.O. Haahtela T. Association between type of training and risk of asthma in elite athletes.Thorax. 1997; 52: 157-160Crossref PubMed Scopus (107) Google Scholar, 20Helenius I. Haahtela T. Allergy and asthma in elite summer sport athletes.J Allergy Clin Immunol. 2000; 106: 444-452Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Likewise, the high prevalence of asthma and EIB reported in competitive swimmers (11% to 29%)20Helenius I. Haahtela T. Allergy and asthma in elite summer sport athletes.J Allergy Clin Immunol. 2000; 106: 444-452Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar has been related to inhalation of chloramines in the air immediately above the water in indoor pools. Current literature suggests that the prevalence of EIB is higher in the elite athlete population than in the nonathlete population. Because of high β2-agonist use among elite athletes, the International Olympic Committee (IOC) requires objective evidence to demonstrate asthma or EIB as an indication for therapeutic use of β2-agonists during competition21Anderson S.D. Sue-Chu M. Perry C.P. Gratziou C. Kippelen P. McKenzie D.C. et al.Bronchial challenges in athletes applying to inhale a beta2-agonist at the 2004 Summer Olympics.J Allergy Clin Immunol. 2006; 117: 767-773Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar; documented falls in FEV1 from a specified indirect or direct challenge have been used since the 2002 Salt Lake City Olympic Games. This article reviews indirect challenges used to obtain an objective diagnosis of EIB. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: August 2008. Credit may be obtained for these courses until July 31, 2010. Copyright Statement: Copyright © 2008-2010. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members:Authors: Kenneth W. Rundell, PhD, and Joshua B. Slee, MS Activity Objectives 1. To understand the role of indirect challenges in the diagnosis and monitoring of exercise-induced bronchoconstriction. 2. To describe optimal conditions for exercise, eucapnic voluntary hyperpnea, hypertonic saline, and mannitol challenges. 3. To improve interpretation of exercise, eucapnic voluntary hyperpnea, hypertonic saline, and mannitol challenges. Recognition of Commercial Support: This CME activity is supported by an educational grant from Merck & Co., Inc. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Kenneth W. Rundell has received honoraria as a speaker for Merck; has participated in clinical trials sponsored by Pharmaxis, Merck, Schering-Plough, and SkyePharma; and has received reserch grants from the World Anti-Doping Agency and Alta. Joshua B. Slee has no significant relationships to disclose. AMP is used as an indirect provocation agent by stimulating the degranulation of bronchial mast cells with subsequent release of histamine, leukotrienes, and other inflammatory mediators. As such, it measures the level of airway inflammation. The interaction of chlorine with human pollutants (eg, sweat, urine) forms chloramines, which are respirable above swimming pools and include chloramide, chlorimide, and nitrogen trichloride. Inhalation of chloramines has been associated with asthma exacerbations, occupational asthma, and increased levels of tryptase, eosinophil cationic protein, and basophils in nasal lavage fluid. An indirect provocation test that was developed as a surrogate marker for exercise-induced bronchospasm. Other indirect tests were developed to mimic the various airway insults that occur during exercise. Hypertonic saline and dry powders mimic airway dehydration associated with water loss with exercise. Indirect tests have the advantage of assessing the presence of inflammatory cells and their mediators compared with direct tests that directly provoke smooth muscle contraction. Pollutants termed criteria pollutants are known to cause health effects at ambient air concentrations and consist of carbon monoxide, lead, nitrogen dioxide, ozone, particulate matter, and sulfur dioxide. Sulfur oxides, carbon monoxide, nitrogen oxides, and particulates are made by burning fossil fuels (coal, oil, and natural gas) and can contribute to the formation of tropospheric ozone. Chlorofluorocarbons cause depletion of stratospheric ozone. Particle pollution includes acids, organic chemicals, and aeroallergens. High-ventilation sports are defined as endurance sports in which ventilation is increased for prolonged periods—for example, during cross-country skiing or long distance running. Although the prevalence of exercise induced bronchospasm was thought to be higher in these endurance sports, this might not be the case. The maximum amount of air that can be breathed in a given period, often 1 minute. The maximal voluntary ventilation is effort-dependent and subject to variability. Minute ventilation maintains the correct amounts of oxygen and carbon dioxide available to the alveoli and is defined as frequency of breathing multiplied by the volume of the breath—that is, respiratory pate per minute × tidal volume. In contrast, the alveolar ventilation takes into account only the gas that is available for alveolar gas exchange by subtracting the dead space from the tidal volume. The airway surface fluid is a bilayer composed of a superficial mucous layer and a periciliary fluid layer that bathes the airway epithelium up to the cilia. The mucous layer is composed of mucin glycoproteins made up mainly of Mucin (MUC) 5AC and MUC5B. The periciliary and mucous layers are separated from one another by a layer of surfactant. Water evaporation creates a hypertonic environment, and hyperosmolar fluid causes mast cell and basophil degranulation with histamine and leukotriene release. Eosinophils can also be stimulated by mannitol in vitro to cause the release of leukotriene C4. Sensitivity is the presence of a positive test among all patients with a disease and gauges the ability of finding true-positives among diseased states. Specificity is the presence of a negative test among all patients without a disease and gauges the finding of true-negatives among all healthy patients. By contrast, the positive and negative predictive values are parameters that assess the ability of a test to find true-positives and true-negatives among all patients with positive and negative tests, respectively. The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary. Physician diagnosis of EIB is often based on self-reported symptoms without lung function tests.12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar, 22Weiler J.M. Layton T. Hunt M. Asthma in United States Olympic athletes who participated in the 1996 Summer Games.J Allergy Clin Immunol. 1998; 102: 722-726Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 23Weiler J.M. Ryan 3rd, E.J. Asthma in United States Olympic athletes who participated in the 1998 Olympic Winter Games.J Allergy Clin Immunol. 2000; 106: 267-271Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 24Parsons J.P. Kaeding C. Phillips G. Jarjoura D. Wadley G. Mastronarde J.G. Prevalence of exercise-induced bronchospasm in a cohort of varsity college athletes.Med Sci Sports Exerc. 2007; 39: 1487-1492Crossref PubMed Scopus (112) Google Scholar EIB in the athlete is most often accompanied by symptoms of cough, wheeze, chest tightness, dyspnea, or excess mucus production.12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar Although a clinical diagnosis of EIB based on self-reported symptoms may be marginally useful,12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar, 25Weiler J.M. Bonini S. Coifman R. Craig T. Delgado L. Capão-Filipe M. et al.Ad Hoc Committee of Sports Medicine Committee of American Academy of Allergy, Asthma & Immunology. American Academy of Allergy, Asthma & Immunology Work Group report: exercise-induced asthma.J Allergy Clin Immunol. 2007; 119: 1349-1358Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar recent studies have shown a lack of sensitivity and specificity of a symptom-based diagnosis in athletes.12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar Rundell et al12Rundell K.W. Im J. Mayers L.B. Wilber R.L. Szmedra L. Schmitz H.R. Self-reported symptoms and exercise-induced asthma in the elite athlete.Med Sci Sports Exerc. 2001; 33: 208-213Crossref PubMed Scopus (264) Google Scholar found that approximately half of elite athletes reporting EIB symptoms demonstrate normal airway function, whereas half of the athletes who reported having no symptoms tested positive for EIB. This study established the necessity of objective spirometry using a standardized challenge for appropriate diagnosis of EIB. Most recently, Parsons et al24Parsons J.P. Kaeding C. Phillips G. Jarjoura D. Wadley G. Mastronarde J.G. Prevalence of exercise-induced bronchospasm in a cohort of varsity college athletes.Med Sci Sports Exerc. 2007; 39: 1487-1492Crossref PubMed Scopus (112) Google Scholar confirmed that symptoms were not predictive of EIB in a study of 107 college athletes in whom eucapnic voluntary hyperpnea (EVH) challenge was performed. They defined a fall in FEV1 of 10% or greater as consistent with EIB and found the prevalence of EIB was 36% in athletes with no symptoms and 35% for those with symptoms of EIB. Moreover, the athletes in high-ventilation sports were significantly more symptomatic (48%) than athletes in low-ventilation sports (25%; P = .02), with no difference in EIB prevalence between the groups. It is therefore necessary to confirm a diagnosis of EIB through objective measures of lung function by using standardized testing procedures. The methods used to test for EIB are critical in making the correct diagnosis and developing a treatment strategy Indirect challenges such as exercise, EVH, inhaled powdered mannitol, nebulized hypertonic saline, or AMP appear to be more effective in identifying EIB in the elite athlete population than direct challenges such as methacholine or histamine.26Karjalainen E.M. Laitinen A. Sue-Chu M. Altraja A. Bjermer L. Laitinen L.A. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine.Am J Respir Crit Care Med. 2000; 161: 2086-2091Crossref PubMed Scopus (259) Google Scholar, 27Henriksen A.H. Tveit K.H. Holmen T.L. Sue-Chu M. Bjermer L. A study of the association between exercise-induced wheeze and exercise versus methacholine-induced bronchoconstriction in adolescents.Pediatr Allergy Immunol. 2002; 13: 203-208Crossref PubMed Scopus (20) Google Scholar Indirect challenges may be the preferred strategy for monitoring the effectiveness of asthma therapy, because airway hyperresponsiveness is associated with inflammation,28Brannan J.D. Koskela H. Anderson S.D. Chew N. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma.Am J Respir Crit Care Med. 1998; 158: 1120-1126Crossref PubMed Scopus (132) Google Scholar and inflammation is reduced by inhaled corticosteroid (ICS) treatment.29Roquet A. Dahlen B. Kumlin M. Ihre E. Anstrén G. Binks S. et al.Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.Am J Respir Crit Care Med. 1997; 155: 1856-1863Crossref PubMed Scopus (266) Google Scholar, 30National Heart, Lung, and Blood Institute Expert panel report 2: guidelines for the diagnosis and management of asthma.1st ed. NIH Publications, Bethesda (MD)1997Google Scholar, 31Boulet L.P. Becker A. Berube A. Beveridge R. Ernst P. Canadian asthma consensus report, 1999.Can Med Assoc J. 1999; 161: S1-S62Google Scholar The indirect challenge is thought to cause inflammatory cells to release mediators such as leukotrienes, prostaglandins, and histamine that provoke airway smooth muscle constriction.1Anderson S.D. Holzer K. Exercise-induced asthma: is it the right diagnosis in elite athletes?.J Allergy Clin Immunol. 2000; 106: 419-428Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar Thus, the indirect challenge reflects the level of inflammation in the airways,28Brannan J.D. Koskela H. Anderson S.D. Chew N. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma.Am J Respir Crit Care Med. 1998; 158: 1120-1126Crossref PubMed Scopus (132) Google Scholar whereas a direct challenge acts directly with airway smooth muscle receptors to cause constriction independent of airway inflammation. The lack of using a standardized exercise challenge for EIB may explain the wide range in reported prevalence within specific sports, whereas the variety of exercise challenges at different intensities with no control over challenge minute ventilation (VE) or water content of inhaled air may result in poor test-retest reliability. Therefore, diagnosis should be based on objective measurement of variable or partially reversible airflow obstruction using a standardized test with prespirometry and postspirometry.32Bye M.R. Kerstein D. Barsh E. The importance of spirometry in the assessment of childhood asthma.Am J Dis Child. 1992; 146: 977-978PubMed Google Scholar, 33Crapo R.O. Casaburi R. Coates A.L. Enright P.L. Hankinson J.L. Irvin C.G. et al.Guidelines for methacholine and exercise challenge testing—1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999.Am J Respir Crit Care Med. 2000; 161: 309-329Crossref PubMed Scopus (2160) Google Scholar, 34Carlsen K.H. Anderson S.D. Bjermer L. Bonini S. Brusasco V. Canonica W. et al.European Respiratory Society, European Academy of Allergy and Clinical Immunology. 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: 387-403Crossref PubMed Scopus (262) Google Scholar The use of spirometry to identify EIB includes baseline lung function measures followed by an EIB-provoking challenge and a series of lung function measurements after the provocation. Typical postprovocation spirometry times are at 5, 10, 15, and 30 minutes after the completion of the challenge with 2 reproducible maneuvers within 3% of each other performed at each time point, although variations with maneuvers at 1-minute, 3-minute, or 20-minute time points have been performed (Fig 1). However, IOC-Medical Commission recommendations dictate that FEV1 should first be recorded at least 3 minutes a
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