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

Sandra D Anderson, Brett Charlton, John M Weiler, Sara Nichols, Sheldon L Spector, David S Pearlman, A305 Study Group, Homer Boushey, Thomas Casale, Linda Ford, Leon Greos, Phillip Halverson, Frank Hampel, Phillip Korenblat, Anne-Marie Irani, Jonathon Matz, Anjuli Nayak, Nancy Ostrum, David Pearlman, Andrew Pedinoff, Bruce Prenner, Paul Qaqundah, Javier Quesada, Paul Ratner, Kenneth Rundell, Gail Shapiro, Christine Sorkness, Sheldon Spector, Ricardo Tan, Steven Weinstein, Robert Ziering, Sandra D Anderson, Brett Charlton, John M Weiler, Sara Nichols, Sheldon L Spector, David S Pearlman, A305 Study Group, Homer Boushey, Thomas Casale, Linda Ford, Leon Greos, Phillip Halverson, Frank Hampel, Phillip Korenblat, Anne-Marie Irani, Jonathon Matz, Anjuli Nayak, Nancy Ostrum, David Pearlman, Andrew Pedinoff, Bruce Prenner, Paul Qaqundah, Javier Quesada, Paul Ratner, Kenneth Rundell, Gail Shapiro, Christine Sorkness, Sheldon Spector, Ricardo Tan, Steven Weinstein, Robert Ziering

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 > or = 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 < or = 16 mg/ml and to mannitol a 15% fall in FEV1 at < or = 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.

Trial registration: ClinicalTrials.gov NCT00025229.

Figures

Figure 1
Figure 1
Subject disposition.
Figure 2
Figure 2
The maximum percentage fall in FEV1 for mannitol and methacholine in subjects in the per-protocol population.
Figure 3
Figure 3
The receiver operating curve for mannitol and methacholine to identify exercise-induced bronchoconstriction defined as ≥ 10% fall in FEV1 from baseline at one time point after exercise on at least one of two exercise tests.

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