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Published in: Respiratory Research 1/2009

Open Access 01-12-2009 | Research

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

Authors: Sandra D Anderson, Brett Charlton, John M Weiler, Sara Nichols, Sheldon L Spector, David S Pearlman, A305 Study Group

Published in: Respiratory Research | Issue 1/2009

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Abstract

Background

Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.

Methods

509 people (6–50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 ≤ 16 mg/ml and to mannitol a 15% fall in FEV1 at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.

Results

Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.

Conclusion

In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.

Trial registration

This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).
Literature
1.
go back to reference Expert Panel Report: Update on Selected Topics 2002: National Asthma Education and Prevention Program. National Institutes of Health, National Heart, Lung and Blood Institute, 2003. NIH publication no. 02–5074. 2003. Expert Panel Report: Update on Selected Topics 2002: National Asthma Education and Prevention Program. National Institutes of Health, National Heart, Lung and Blood Institute, 2003. NIH publication no. 02–5074. 2003.
2.
go back to reference Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ: Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000, 161:309–329.CrossRefPubMed Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ: Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000, 161:309–329.CrossRefPubMed
3.
go back to reference Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW, O'Byrne PM, Anderson SD, Juniper EF, Malo J-L: Airway responsiveness: Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J Suppl 1993, 16:53–83.CrossRefPubMed Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW, O'Byrne PM, Anderson SD, Juniper EF, Malo J-L: Airway responsiveness: Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J Suppl 1993, 16:53–83.CrossRefPubMed
4.
go back to reference Van Schoor J, Pauwels R, Joos G: Indirect bronchial hyper-responsiveness: the coming of age of a specific group of bronchial challenges. Clin Exp Allergy 2005,35(3):250–261.CrossRefPubMed Van Schoor J, Pauwels R, Joos G: Indirect bronchial hyper-responsiveness: the coming of age of a specific group of bronchial challenges. Clin Exp Allergy 2005,35(3):250–261.CrossRefPubMed
5.
go back to reference Cockcroft DW: How best to measure airway responsiveness. Am J Respir Crit Care Med 2001, 163:1514–1515.CrossRefPubMed Cockcroft DW: How best to measure airway responsiveness. Am J Respir Crit Care Med 2001, 163:1514–1515.CrossRefPubMed
6.
go back to reference O'Byrne PM, Zamel N: Airway challenges with inhaled constrictor mediators. In Provocation Testing in Clinical Practice. Volume 5. Edited by: Spector SL. New York: Marcel Dekker; 1995:311–324. O'Byrne PM, Zamel N: Airway challenges with inhaled constrictor mediators. In Provocation Testing in Clinical Practice. Volume 5. Edited by: Spector SL. New York: Marcel Dekker; 1995:311–324.
7.
go back to reference 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):144.CrossRefPubMedPubMedCentral 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):144.CrossRefPubMedPubMedCentral
8.
go back to reference Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M: Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003,22(3):491–496.CrossRefPubMed Brannan JD, Gulliksson M, Anderson SD, Chew N, Kumlin M: Evidence of mast cell activation and leukotriene release after mannitol inhalation. Eur Respir J 2003,22(3):491–496.CrossRefPubMed
9.
go back to reference Brannan JD, Gulliksson M, Anderson SD, Chew N, Seale JP, Kumlin M: Inhibition of mast cell PGD 2 release protects against mannitol-induced airway narrowing. Eur Respir J 2006, 27:944–950.PubMed Brannan JD, Gulliksson M, Anderson SD, Chew N, Seale JP, Kumlin M: Inhibition of mast cell PGD 2 release protects against mannitol-induced airway narrowing. Eur Respir J 2006, 27:944–950.PubMed
10.
go back to reference O'Sullivan S, Roquet A, Dahlén B, Larsen F, Eklund A, Kumlin M, O'Byrne PM, Dahlén S-E: Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 1998, 12:345–350.CrossRefPubMed O'Sullivan S, Roquet A, Dahlén B, Larsen F, Eklund A, Kumlin M, O'Byrne PM, Dahlén S-E: Evidence for mast cell activation during exercise-induced bronchoconstriction. Eur Respir J 1998, 12:345–350.CrossRefPubMed
11.
go back to reference Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, Guerreiro D, Hendeles L: Increased urinary excretion of LTE 4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997,52(12):1030–1035.CrossRefPubMedPubMedCentral Reiss TF, Hill JB, Harman E, Zhang J, Tanaka WK, Bronsky E, Guerreiro D, Hendeles L: Increased urinary excretion of LTE 4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 1997,52(12):1030–1035.CrossRefPubMedPubMedCentral
12.
go back to reference Avital A, Springer C, Bar-Yishay E, Godfrey S: Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 1995, 50:511–516.CrossRefPubMedPubMedCentral Avital A, Springer C, Bar-Yishay E, Godfrey S: Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 1995, 50:511–516.CrossRefPubMedPubMedCentral
13.
go back to reference Tan RA, Spector SL: Exercise-induced asthma: diagnosis and management. Ann Allergy Asthma Immunol 2002,89(3):226–235.CrossRefPubMed Tan RA, Spector SL: Exercise-induced asthma: diagnosis and management. Ann Allergy Asthma Immunol 2002,89(3):226–235.CrossRefPubMed
14.
go back to reference Weiler JM, Nathan RA, Rupp NT, Kalberg CJ, Emmett A, Dorinsky PM: Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma. Ann Allergy Asthma Immunol 2005, 94:65–72.CrossRefPubMed Weiler JM, Nathan RA, Rupp NT, Kalberg CJ, Emmett A, Dorinsky PM: Effect of fluticasone/salmeterol administered via a single device on exercise-induced bronchospasm in patients with persistent asthma. Ann Allergy Asthma Immunol 2005, 94:65–72.CrossRefPubMed
15.
go back to reference Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, Hendeles L, Loeys T, Dass SB, Reiss TF: Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol 2006,97(1):98–104.CrossRefPubMed Pearlman DS, van Adelsberg J, Philip G, Tilles SA, Busse W, Hendeles L, Loeys T, Dass SB, Reiss TF: Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol 2006,97(1):98–104.CrossRefPubMed
16.
go back to reference Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, Gonda I, Walsh A, Clark AR: A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997, 156:758–765.CrossRefPubMed Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, Gonda I, Walsh A, Clark AR: A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997, 156:758–765.CrossRefPubMed
17.
go back to reference National Heart Lung and Blood Institute: Guidelines for the Diagnosis and Management of Asthma NIH. 1997. National Heart Lung and Blood Institute: Guidelines for the Diagnosis and Management of Asthma NIH. 1997.
18.
go back to reference Polgar G, Promadhat V: Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia: W.B. Saunders Co; 1971. Polgar G, Promadhat V: Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia: W.B. Saunders Co; 1971.
19.
go back to reference Crapo RO, Morris AH, Gardner RM: Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981,123(6):659–664.PubMed Crapo RO, Morris AH, Gardner RM: Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis 1981,123(6):659–664.PubMed
20.
go back to reference National Institute of Health: Guidelines for the Diagnosis and Management of Asthma. In National Institutes of Health, National Heart, Lung and Blood Institute. Bethesda MD NHLBI/WHO workshop report Publication No 08–4051; 2007. National Institute of Health: Guidelines for the Diagnosis and Management of Asthma. In National Institutes of Health, National Heart, Lung and Blood Institute. Bethesda MD NHLBI/WHO workshop report Publication No 08–4051; 2007.
21.
go back to reference 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 1998,158(4):1120–1126.CrossRefPubMed 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 1998,158(4):1120–1126.CrossRefPubMed
22.
go back to reference Munoz PA, Gomez FP, Manrique HA, Roca J, Barbera JA, Young IH, Anderson SD, Rodriguez-Roisin R: Pulmonary gas exchange response to exercise- and mannitol- induced bronchoconstriction in mild asthma. J Appl Physiol 2008,105(5):1477–1485.CrossRefPubMed Munoz PA, Gomez FP, Manrique HA, Roca J, Barbera JA, Young IH, Anderson SD, Rodriguez-Roisin R: Pulmonary gas exchange response to exercise- and mannitol- induced bronchoconstriction in mild asthma. J Appl Physiol 2008,105(5):1477–1485.CrossRefPubMed
23.
go back to reference Holzer K, Anderson SD, Chan H-K, Douglass J: Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003,167(4):534–547.CrossRefPubMed Holzer K, Anderson SD, Chan H-K, Douglass J: Mannitol as a challenge test to identify exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003,167(4):534–547.CrossRefPubMed
24.
go back to reference Riedler J, Reade T, Dalton M, Holst DI, Robertson CF: Hypertonic saline challenge in an epidemiological survey of asthma in children. Am J Respir Crit Care Med 1994, 150:1632–1639.CrossRefPubMed Riedler J, Reade T, Dalton M, Holst DI, Robertson CF: Hypertonic saline challenge in an epidemiological survey of asthma in children. Am J Respir Crit Care Med 1994, 150:1632–1639.CrossRefPubMed
25.
go back to reference Pattemore PK, Asher MI, Harrison AC, Mitchell EA, Rea HH, Stewart AW: Ethnic differences in prevalence of asthma symptoms and bronchial hyperresponsiveness in New Zealand schoolchildren. Thorax 1989,44(3):168–176.CrossRefPubMedPubMedCentral Pattemore PK, Asher MI, Harrison AC, Mitchell EA, Rea HH, Stewart AW: Ethnic differences in prevalence of asthma symptoms and bronchial hyperresponsiveness in New Zealand schoolchildren. Thorax 1989,44(3):168–176.CrossRefPubMedPubMedCentral
26.
go back to reference Salome CM, Peat JK, Britton WJ, Woolcock AJ: Bronchial hyperresponsiveness in two populations of Australian schoolchildren. I. Relation to respiratory symptoms and diagnosed asthma. Clin Allergy 1987, 17:271–281.CrossRefPubMed Salome CM, Peat JK, Britton WJ, Woolcock AJ: Bronchial hyperresponsiveness in two populations of Australian schoolchildren. I. Relation to respiratory symptoms and diagnosed asthma. Clin Allergy 1987, 17:271–281.CrossRefPubMed
27.
go back to reference Porsbjerg C, Brannan JD, Anderson SD, Backer V: Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients. Clin Exp Allergy 2008,38(1):43–50.PubMed Porsbjerg C, Brannan JD, Anderson SD, Backer V: Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients. Clin Exp Allergy 2008,38(1):43–50.PubMed
28.
go back to reference Koskela H, Hyvärinen L, Brannan JD, Chan H-K, Anderson SD: Sensitivity and validity of three bronchial provocation tests to demonstrate the effect of inhaled corticosteroids in asthma. Chest 2003,124(4):1341–1349.CrossRefPubMed Koskela H, Hyvärinen L, Brannan JD, Chan H-K, Anderson SD: Sensitivity and validity of three bronchial provocation tests to demonstrate the effect of inhaled corticosteroids in asthma. Chest 2003,124(4):1341–1349.CrossRefPubMed
29.
go back to reference Anderson SD, Brannan JD: Methods for 'indirect' challenge tests including exercise, eucapnic voluntary hyperpnea and hypertonic aerosols. Clin Rev Allergy Immunol 2003,24(1):27–54.CrossRefPubMed Anderson SD, Brannan JD: Methods for 'indirect' challenge tests including exercise, eucapnic voluntary hyperpnea and hypertonic aerosols. Clin Rev Allergy Immunol 2003,24(1):27–54.CrossRefPubMed
30.
go back to reference Holzer K, Anderson SD, Douglass J: Exercise in elite summer athletes: Challenges for diagnosis. J Allergy Clin Immunol 2002,110(3):374–380.CrossRefPubMed Holzer K, Anderson SD, Douglass J: Exercise in elite summer athletes: Challenges for diagnosis. J Allergy Clin Immunol 2002,110(3):374–380.CrossRefPubMed
31.
go back to reference Cockcroft DW, Davis BE: The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result. J Allergy Clin Immunol 2006,117(6):1244–1248.CrossRefPubMed Cockcroft DW, Davis BE: The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result. J Allergy Clin Immunol 2006,117(6):1244–1248.CrossRefPubMed
32.
go back to reference Global Initiative for Asthma. Revised 2007. Global strategy for asthma and management and prevention [http://www.ginasthma.org] N. H. National Institutes of Health, Lung and Blood Institute, editor. NHLBI/WHO workshop report Medical Communication Resources, Inc, Bethesda, Maryland; 16–19. Global Initiative for Asthma. Revised 2007. Global strategy for asthma and management and prevention [http://​www.​ginasthma.​org] N. H. National Institutes of Health, Lung and Blood Institute, editor. NHLBI/WHO workshop report Medical Communication Resources, Inc, Bethesda, Maryland; 16–19.
33.
go back to reference British Guideline on the Management of AsthmaThorax 2008,63(Suppl 4):iv1-iv121. British Guideline on the Management of AsthmaThorax 2008,63(Suppl 4):iv1-iv121.
Metadata
Title
Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma
Authors
Sandra D Anderson
Brett Charlton
John M Weiler
Sara Nichols
Sheldon L Spector
David S Pearlman
A305 Study Group
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2009
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-10-4

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