Original articleAsthma, lower airway diseaseAccuracy of eucapnic hyperpnea or mannitol to diagnose exercise-induced bronchoconstriction: a systematic review
Introduction
Exercise-induced bronchoconstriction (EIB) is defined as “the airway obstruction that occurs in association with exercise without regard to the presence of chronic asthma,”1 and exercise-induced asthma (EIA) is defined as “the condition in which exercise induces symptoms of asthma in patients who have asthma.”1 An estimated 7% of Americans have asthma,2 and 60 to 90% of people with asthma demonstrate EIA.3, 4 The prevalence of EIB has been documented to be 6 to 13% in people with no history of asthma or allergy5, 6 and as high as 50% in athletes.4
Objective testing is essential for the valid diagnosis of EIA/EIB. Because the most common complaint in people with EIA/EIB is symptoms related to exercise, evaluating whether exercise provokes their symptoms,7 and correspondingly impairs lung function, seems appropriate. The most direct way to establish a diagnosis of EIA/EIB is to perform an exercise challenge.1 The American Thoracic Society (ATS) has published guidelines on exercise challenge testing (ECT) for the diagnosis of EIA/EIB.8 The standardized ECT requires the patient to exercise on a treadmill or cycle ergometer for 4 to 6 minutes at a heart rate or minute ventilation equivalent to 80 to 90% or 40 to 60% of age-predicted maximum, respectively. One-second forced expiratory volume (FEV1) is measured before and at set intervals after exercise, and the patient is deemed positive for EIA/EIB if FEV1 decreases by more than 10% after exercise. Despite standardization of the ECT protocol, the airway response to exercise testing has been shown to be variable.9, 10 In addition, some have suggested that surrogate tests such eucapnic voluntary hyperpnea (EVH) and mannitol provocation are actually more sensitive to detect EIA/EIB than the standard ECT.11, 12, 13
Several studies have focused on EVH and mannitol provocation to determine whether these tests are suitable alternatives to ECT. Like exercise, both are considered indirect challenges, because they are thought to cause inflammatory cells to release mediators such as leukotrienes, prostaglandin, and histamine, which provoke smooth muscle constriction and broncoconstriction.14 Although the pathological mechanisms may be similar to exercise, these tests do not expose the patient to increased cardiac risk and do not require the same amount of equipment or space as the ECT. Thus, EVH or mannitol provocation may be important non-exercise alternatives to the ECT. The purpose of this systematic review was to review the current literature comparing eucapnic EVH and mannitol with standard exercise challenge testing to determine whether either test is a suitable alternative to standard exercise testing for the diagnosis of EIA/EIB.
Section snippets
Methods
The review was conducted using valid systematic review methods15 that were outlined in an a priori protocol.
Literature Search
The search identified 5,318 citations. Ten cross-sectional studies were included (see e-Fig 1 in online supplement): 7 (138 participants) examined EVH,18, 19, 20, 21, 22, 23, 24 and 3 (423 participants) focused on mannitol.25, 26, 27
EVH
Seven studies18, 19, 20, 21, 22, 23, 24 compared EVH with a standardized ECT. See online supplement for description of study and participant characteristics (e-Table 1, e-Table 2). Overall, methodological issues limited the interpretation and generalizability of
Discussion
This systematic review summarizes the best available evidence on the use of either EVH or mannitol provocation tests as an alternative to ECT to detect EIA/EIB. To our knowledge, this is the first effort to summarize these tools in these settings. Using a comprehensive search strategy to avoid publication bias and multiple reviewers to avoid selection bias, we identified only 10 diagnostic cross-sectional studies to include in this review. Overall, the sensitivity and specificity of EVH as
Conclusions
Based on the current evidence, higher-quality studies are needed before either EVH or mannitol can be confirmed as alternative tests to ECT. The overall sensitivity and specificity of EVH data were heterogeneous, and EVH studies typically used an ECT that was not consistent with ATS guidelines. Sensitivity and specificity for mannitol provocation was more consistent; however, only 3 studies have compared mannitol with ECT. Finally, many of the studies reviewed suffered from spectrum bias,
Acknowledgments
We thank the Cochrane Airways Group for their assistance and providing access to their database of articles.
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Disclosures: Authors have nothing to disclose.
Funding Sources: This project was funded under contract no. 290-2007-10021-I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. M K Stickland is supported by a Canadian Institutes for Health Research (CIHR; Ottawa, ON) New Investigator Award. B H Rowe receives support as a Canada Research Chair from the CIHR through the Government of Canada (Ottawa, ON).