Review and Feature Article
Bronchial Provocation Testing for the Identification of Exercise-Induced Bronchoconstriction

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Exercise-induced bronchoconstriction (EIB) occurs in patients with asthma, children, and otherwise healthy athletes. Poor diagnostic accuracy of respiratory symptoms during exercise requires objective assessment of EIB. The standardized tests currently available are based on the assumption that the provoking stimulus to EIB is dehydration of the airway surface fluid due to conditioning large volumes of inhaled air. “Indirect” bronchial provocation tests that use stimuli to cause endogenous release of bronchoconstricting mediators from airway inflammatory cells include dry air hyperpnea (eg, exercise and eucapnic voluntary hyperpnea) and osmotic aerosols (eg, inhaled mannitol). The airway response to different indirect tests is generally similar in patients with asthma and healthy athletes with EIB. Furthermore, the airway sensitivity to these tests is modified by the same pharmacotherapy used to treat asthma. In contrast, pharmacological agents such as methacholine, given by inhalation, act directly on smooth muscle to cause contraction. These “direct” tests have been used traditionally to identify airway hyperresponsiveness in clinical asthma but are less useful to diagnose EIB. The mechanistic differences between indirect and direct tests have helped to elucidate the events leading to airway narrowing in patients with asthma and elite athletes, while improving the clinical utility of these tests to diagnose and manage EIB.

Introduction

Exercise-induced bronchoconstriction (EIB) describes the transient narrowing of the airways that occurs during or, most commonly, after vigorous exercise.1 EIB is common in patients with asthma who experience frequent respiratory symptoms (such as cough, wheeze, chest tightness, and mucus hypersecretion), and it is often an indicator of persistent asthma warranting treatment.2 EIB can occur in otherwise healthy people, including children and adolescents, and in those performing regular exercise (eg, army recruits and elite athletes).2,3

EIB is characterized by a transient fall in forced expiratory volume in 1 second (FEV1). Bronchial provocation tests that induce changes in FEV1 in response to exercise, or surrogates of exercise (eg, dry air hyperpnea and hyperosmotic stimuli), are recommended for EIB diagnosis.2,4 This approach is strengthened by observations that exercise symptoms are poor predictors of EIB.5

Understanding the mechanisms of EIB is important to select the most appropriate test to assess EIB, as well as to justify and guide therapy.6 This review is a summary of the pathophysiology of EIB, and describes the advantages and disadvantages of various diagnostic tests available for EIB assessment and management. In addition, this review demonstrates how discrepancies between “indirect” (eg, exercise and its surrogates) and “direct” (eg, methacholine) tests advanced our understanding of the pathophysiology of EIB, and how the development of surrogates for exercise helped to improve clinical practice. According to current guidelines, direct tests are not recommended for the assessment of EIB, because of discordance in the airway response in individuals with EIB alone and in those with mild clinical asthma with EIB.7,8

Section snippets

Mechanisms of EIB: What Have Mechanistic Studies Taught Us?

Water loss from the airway surface in response to conditioning large volumes of air to body conditions (ie, 37°C, 100% relative humidity) during exercise is regarded as the primary stimulus to EIB.1,9 Severity of EIB varies with the water content of inhaled air,9 and inhalation of fully conditioned air during exercise completely blocks EIB.10,11 Because cold air is always dry, EIB is usually more severe during winter12 and is common in winter athletes.13,14 In addition to the amplifying effect

Challenge Testing for the Diagnosis of EIB: An Historical Perspective

The development of tests for the diagnosis of EIB was derived from the understanding that exercise was a common stimulus for bronchoconstriction in patients with asthma. Assessing EIB is also useful and important in occupational settings where EIB could put individuals at risk of an attack of asthma (eg, army recruits and scuba divers) and/or impair exercise performance (eg, professional athletes). Prevalence of EIB in all these groups can differ significantly, as does the diagnostic

Measurement of Change in Airway Caliber

For all bronchial provocation tests it is essential that quality baseline spirometry be performed (ie, strictly using American Thoracic Society/European Respiratory Society recommendations).53 Baseline FEV1 should be greater than or equal to 70% to 75% of predicted normal value, and not less than 1.2 L.2 For both safety and efficacy reasons, the baseline FEV1 must be stable. FEV1 should be measured in duplicate at each time point during or after the challenge, with a difference of no more than

Exercise for bronchial provocation

Laboratory exercise tests (usually performed on treadmills or cycle ergometers) require participants to perform a 6- to 8-minute high-intensity effort.2,4 The warm-up period before reaching the target workload should be short (2-3 minutes maximum), and the remaining exercise (5-6 minutes) should be performed at 80% to 90% of predicted maximum heart rate (calculated as 220 minus age) or 17.5 to 21 times FEV1 (when ventilation is recorded). The rationale for such protocols is to permit high

Osmotic Stimuli (eg, Mannitol Challenge)

The methodology for the mannitol challenge arose from the need to make indirect tests more practical and accessible.67 The test is standardized and simpler to perform than exercise or EVH, which both require complex equipment. The mannitol test comes as a kit consisting of increasing doses of mannitol powder (5, 10, 20, and 40 mg in capsules) and a simple low-resistance inhaler.68 FEV1 is measured at baseline and 60 seconds after the inhalation of each dose. Because the response to mannitol is

Future Directions

Future directions in research in EIB have previously been discussed.84 The role of the small airways in EIB is still unclear, and few studies have used outcome measures other than FEV1 to quantify the change in airway caliber, such as impulse or forced oscillometry.85,86 It is still not clear whether these outcome measures can provide complementary information to FEV1. Future studies could investigate these methods on EIB, in particular those with mild EIB. The threshold for a positive EVH test

Conclusions

The development of surrogate tests for the diagnosis of EIB has assisted with the understanding of the mechanisms of EIB. EIB is an osmotically driven and inflammatory mediated condition that is primarily triggered by the loss of water from the airways during conditioning of inhaled air during exercise hyperpnea. In spite of some limitations, surrogate indirect bronchial provocation tests (in particular, EVH and mannitol) reproduce in a more standardized manner the osmotic changes that occur

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    Conflict of interest: J. D. Brannan receives a 10% portion of royalties for the sale of Aridol/Osmohaler that are paid to his previous employer, Royal Prince Alfred Hospital; holds a minimum number of shares in the manufacturer Pharmaxis Ltd; and in the past has acted as a consultant to Pharmaxis Ltd and the Nth American distributor of Aridol, Methapharm Pty Ltd. P. Kippelen has no relevant conflicts of interest.

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