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doi: 10.3810/psm.2010.12.1827
The Physician and Sportsmedicine: Volume 38: No.4
The Inflammatory Basis of Exercise-Induced Bronchoconstriction
John D. Brannan, PhD And James A. Turton, BSc(Hons), MBBS, MMedSc, FRACGP
Copyright 2010 All rights reserved. Cover and contents may not be reproduced in whole or in part without prior written permission. The Physician and Sportsmedicine is a registered trademark of JTE Multimedia, LLC. Sending and distribution of any document from this site is strictly prohibited either for free and or a service fee, and will be sited as a violation of copyright under the laws of THE UNITED STATES OF AMERICA

Abstract: Exercise-induced bronchoconstriction (EIB) is common in individuals with asthma, and may be observed even in the absence of a clinical diagnosis of asthma. Exercise-induced bronchoconstriction can be diagnosed via standardized exercise protocols, and anti-inflammatory therapy with inhaled corticosteroids (ICS) is often warranted. Exercise-related symptoms are commonly reported in primary care; however, access to standardized exercise protocols to assess EIB are often restricted because of the need for specialized equipment, as well as time constraints. Symptoms and lung function remain the most accessible indicators of EIB, yet these are poor predictors of its presence and severity. Evidence suggests that exercise causes the airways to narrow as a result of the osmotic and thermal consequences of respiratory water loss. The increase in airway osmolarity leads to the release of bronchoconstricting mediators (eg, histamine, prostaglandins, leukotrienes) from inflammatory cells (eg, mast cells and eosinophils). The objective assessment of EIB suggests the presence of airway inflammation, which is sensitive to ICS in association with a responsive airway smooth muscle. Surrogate tests for EIB, such as eucapnic voluntary hyperpnea or the osmotic challenge tests, cause airway narrowing via a similar mechanism, and a response indicates likely benefit from ICS therapy. The complete inhibition of EIB with ICS therapy in individuals with asthma may be a useful marker of control of airway pathology. Furthermore, inhibition of EIB provides additional, useful information regarding the identification of clinical control based on symptoms and lung function. This article explores the inflammatory basis of EIB in asthma as well as the effect of ICS on the pathophysiology of EIB.

Keywords: asthma; exercise-induced bronchoconstriction; bronchial hyperresponsiveness; inhaled corticosteroids

Introduction

The 2 key pathophysiological features of asthma are bronchial hyperresponsiveness (BHR) and airway inflammation. The Global Initiative for Asthma (GINA) guidelines state that chronic inflammation in association with BHR is responsible for recurrent symptoms of wheezing, breathlessness, chest tightness, and coughing.1 Airway narrowing can commonly occur during vigorous exercise in most patients with asthma, which is known as exercise-induced asthma (EIA).2,3 Exercise-induced asthma is the transient narrowing of the airways and the subsequent increase in airway resistance that can occur either during or (more commonly) following, vigorous exercise.3 It can also occur in individuals (eg, athletes) in the absence of other clinically recognized symptoms of asthma.4-6 It is for this reason that the term exercise-induced bronchoconstriction (EIB) is preferred. The mechanism of EIB in asthma suggests that the association of chronic inflammation and sensitive airway smooth muscle are important features of the response.7

Symptoms are known to be poor predictors of the presence and severity of EIB, and this has increased the need for standardized measures of EIB.4,8-10 It is common for primary care physicians to encounter individuals who report exercise-related respiratory symptoms.11 However, the testing facilities to assess EIB in primary care are limited. Measurement of lung function at rest and after a dose of bronchodilator is commonly used to assess the presence of reversible airway obstruction, which is a feature of asthma.11 The investigation of reversible airways obstruction is usually not helpful in those who present with normal lung function. Tests that assess BHR were developed to assist in the diagnosis of asthma in persons with normal lung function. Tests for BHR, including exercise protocols, are not commonly used in primary care and are more commonly used in tertiary care.12

Exercise-induced respiratory symptoms are associated with poor asthma control.13 There is evidence from a large survey of patients in primary care that up to 59% have uncontrolled asthma,14 indicating that the current methods for identifying asthma severity and the need for treatment are suboptimal. Exercise-induced bronchoconstriction can take longer to resolve using ICS compared with symptoms and lung function.15 Thus, EIB, which is a marker of BHR and active inflammation, may provide better evidence for the benefits of anti-inflammatory treatment using inhaled corticosteroids (ICS) when compared with symptoms and lung function.

The identification of EIB using an objective test for EIB provides evidence that an individual may benefit from ICS therapy.16 The objective reassessment of EIB with ICS therapy may provide an evidence-based marker of the control of airway inflammation, in addition to improvements in symptom and lung function.17 This may be important given evidence of persistent airway inflammation and BHR in asthmatics with documented symptom-controlled asthma.18 This article explores the inflammatory basis of EIB in individuals with asthma and the concept of using the inhibition of EIB after ICS therapy as an objective marker of asthma control.

The Inflammatory Basis of EIB in Asthma

Research investigating the mechanism of EIB has revealed that inflammation plays a key role in causing the airways to narrow. Initial studies demonstrated the importance of exercise intensity, exercise duration, inspired air temperature, and humidity on the airway response to exercise.19 During exercise, increases in ventilation and the cooling and/or drying of the airways were considered important determinants of respiratory water loss.19 The osmotic and thermal effects of respiratory water loss are now thought to be the primary factors for airway narrowing in response to exercise.3 The increase in the osmolarity of the airway surface liquid is considered to play a primary role in the release of bronchoconstricting mediators.20-22 These mediators act on specific receptors on bronchial smooth muscle causing contraction and airway narrowing. Thus, both airway inflammation and sensitive airway smooth muscle are important features of EIB (Figure 1).

View: (Figure 1 ) - A schematic demonstrating the key events leading to bronchial smooth muscle contraction in individuals with asthma as a result of dry air hyperpnea from an exercise or an EVH challenge.

Drugs used in the treatment of asthma are also effective at inhibiting EIB.23 Early studies investigating the effects of drugs highlighted the role of inflammation in the response to exercise. Inhaled β2-agonists were the first drugs used to inhibit EIB.24 When β2-agonists were administered orally, they were not effective at protecting against EIB even though they caused bronchodilation.25 This suggested that the superior efficacy of an inhaled β2-agonist against EIB was due to an added benefit on the airway surface. It was proposed that a dual mechanism of bronchoprotection occurred to account for this effect: β2 receptor-mediated relaxation of airway smooth muscle and stabilization of mast cells. Sodium cromoglycate was effective at inhibiting EIB; however, its action was thought to be confined to stabilization of the mast cell alone.26 Daily treatment with ICS decreased the severity of EIB, suggesting airway inflammation was an important determinant of disease severity.27 Subsequently, the inhibition of EIB with the use of leukotriene receptor antagonists suggested the involvement of another powerful inflammatory mediator important for sustaining airway narrowing to exercise.28

More recently, direct evidence for airway inflammation in EIB has been demonstrated. More eosinophils are seen in the sputum of asthmatic children with EIB compared with children without EIB.29,30 The severity of EIB is also related to the number of eosinophils in both sputum and blood.29,31,32 Exhaled nitric oxide (eNO), a nonspecific marker of inflammation, is also related to the airway response to exercise in asthmatics.33 However, eNO may only indicate the presence of atopy in asthmatics with EIB.34,35

There is increasing evidence that mast cell mediator release occurs in association with EIB. Early studies demonstrated exercise-related increases in arterial plasma histamine levels when measured during maximal airway narrowing.36 Histamine is thought to play a role, though not all studies have demonstrated that specific receptor antagonists for histamine are effective at inhibiting EIB.37,38

More recently, leukotriene E4 or the metabolite of prostaglandin D2 (9α, 11β-PGF2), a marker of mast cell release, has been measured in urine20,22,39 and sputum following EIB.40,41 This is supported by studies using sodium cromoglycate, which inhibits the airway responses to surrogate measures of EIB in association with the inhibition of the release of the mast cell marker 9α,11β-PGF2 in urine.42,43 These observations in vivo are supported by in vitro experiments demonstrating mast cell44,45 and eosinophil46 release of bronchoconstricting mediators when in a hyperosmotic environment.

Recently, it has been observed that nonasthmatics can release various bronchoconstricting mediators in the absence of any bronchoconstriction following either exercise or a challenge using the surrogate tests for EIB.39,47-49 These observations have highlighted the importance of airway inflammation and airway smooth muscle sensitivity in response to these stimuli. Although it has been shown that EIB is not a cause for airway inflammation,50 there may be an increased likelihood of airway injury, as seen by the release of columnar epithelial cells in association with the severity of EIB.40 It has been hypothesized that regular, high-intensity exercise may facilitate an epithelial airway injury via the effects of repeated high levels of ventilation and chronic airway dehydration.7

Tests to Identify EIB

The first exercise testing protocols to identify EIB were developed in the 1970s.51 Although exercise testing could be performed in both children and adults, the tests were often inaccessible. Thus, exercise testing was confined to either a pulmonary function laboratory test or a field test. Currently, exercise testing equipment is normally available in hospital laboratories or tertiary centers. Testing is difficult to perform in the primary care setting, where asthma is most commonly diagnosed and treated. In recent years, surrogate tests for EIB have been developed, making the assessment process more accessible.52

Because the major factors that determine the severity of EIB are pulmonary ventilation and inspired air water content, any exercise challenge test must be able to monitor ventilation and control the water content of inspired air. Exercise challenges have been standardized, and typically involve 6 to 8 minutes of exercise on a treadmill or cycle ergometer.8 Compressed, dry air should be used as a standard because it minimizes inhaled air water content and allows for effective airway drying. During exercise, a suitable level of intensity is assessed by maintaining 80% to 90% of the predicted maximal heart rate for at least 4 minutes. However, this may not be of sufficient intensity, as 1 study demonstrated that only 9 of 20 children with asthma tested positive from an exercise challenge at 85% estimated maximal heart rate, whereas all 20 tested positive at an intensity of 95% estimated maximal heart rate.53 It has been recommended that ventilation should also measured during exercise to achieve a rate of at least 40% to 60% of the predicted maximum voluntary ventilation (MVV).8

Forced expiratory volume in 1 second (FEV1) should be the primary outcome variable to assess airway response to exercise.8 It is recommended that subjects have normal to near-normal resting lung function to perform these tests (eg, FEV1 > 70% of predicted). As the maximum response often occurs following exercise, the FEV1 should be measured before exercise, at regular intervals during exercise, and for at least 20 to 30 minutes after exercise. Exercise-induced bronchoconstriction is identified if a 10% fall in FEV1 in adults and a 15% fall in FEV1 in children occurs.

Other stimuli that mimic the loss of water or increase the osmolarity of the airway surface have been used as surrogates for exercise challenge testing. The most widely used tests are eucapnic voluntary hyperpnea (EVH) or osmotic challenges (eg, hyperosmolar saline, inhaled dry powder mannitol). These tests are known as indirect bronchial provocation tests because (like EIB) they act via the release of the same contractile mediators from inflammatory cells within the airway.54 Eucapnic voluntary hyperpnea and the osmotic challenge tests overcome some of the practical and safety limitations of performing exercise testing at high intensity.9 The dose-response osmotic challenge tests using inhaled dry powder mannitol (Aridol™; Pharmaxis Ltd., New South Wales, Australia) has recently been approved by the US Food and Drug Administration (FDA) for the assessment of BHR.55 The diagnostic validity of the mannitol challenge test has been assessed in 3 large clinical trials,56-58 which have consistently shown that the rate of false-positive tests in nonasthmatics is very low, and the mannitol test has a high specificity for active asthma.

In selected groups of asthma patients, the inhaled dry powder mannitol test has been shown to be comparable with the exercise test. Inhaled dry powder mannitol has identified EIB in asthmatic adults,21 children,59 and athletes.60 The airway sensitivity to mannitol predicts the severity of EIB in steroid-naïve individuals with asthma.21,61 One large trial has compared inhaled powder mannitol with the exercise challenge test in a group of subjects with symptoms that were suggestive of asthma without a clinical diagnosis. Although the sensitivity of mannitol to identify EIB was lower than that observed in a group of known asthmatic subjects with EIB, an airway response to mannitol was found to be 1.41 times more frequent in identifying BHR than an initial exercise test where a 10% fall in FEV1 was the diagnostic criteria for EIB. This increased to 1.65 if a 15% fall in FEV1 was used.57 In this same subject group, when EIB was assessed using a standardized exercise challenge, the airway response was reproducible in most subjects who had mild symptoms.62 When EIB was assessed a few days apart in individuals without a definite diagnosis of asthma and good lung function, individuals with the mildest EIB were more likely to have 1 positive test compared with individuals with more severe responses. The reasons for this are unclear considering the exercise intensity of both test days was similar. However, the variability in those with mild EIB may be due to other factors that can influence the airway response to exercise. It is now recognized that dietary modification may modify the severity of mild EIB.39,63 Furthermore, environmental changes are also known to augment the airway response to exercise, such as exposure to allergen prior to testing.64 However, the variation could be due to the intrinsic reproducibility of the test itself.62

Measuring the Effects of ICS on EIB

Inhaled corticosteroids are the most effective anti-inflammatory treatment in asthma.15 The mechanism of action includes the attenuation of mast cells and eosinophils, which are both key inflammatory cells in asthma.65 A Cochrane Review has established that regular use of ICS for ≥ 4 weeks is effective in attenuating EIB in both adults and children.16 There is increasing evidence that the reduction in the severity in EIB occurs in association with reductions in markers of airway inflammation.32,66

There is a dose-response effect on the reduction in the percentage fall in FEV1 following exercise after 4 weeks of standard dosing with ICS (100–400 μg budesonide) in children.67 However, the dose effect on symptoms and lung function (peak expiratory flow rate) was observed to plateau after 100 μg budesonide, which challenges the clinical relevance of monitoring EIB using symptoms and lung function. In a study of similar design in adults, more rapid attenuation of EIB using higher ICS doses was confirmed using 320 μg ciclesonide over 3 weeks when compared with lower doses (40–160 μg).68

A recent study further demonstrated the effects of short-term ICS on the extent of sputum eosinophilia in association with improvements in EIB in adults.32 It was found that low doses of ciclesonide (40 or 80 μg) in those with more severe EIB who also had > 5% sputum eosinophilia only had modest reductions in EIB over a 3-week period. However, when the same subjects received a higher dose of ciclesonide (160 or 320 μg), a more rapid attenuation of EIB was achieved. Those with lower levels of eosinophils (< 5%) who also had milder EIB were found to have less rapid reductions in EIB in 3 weeks on either high- or low-dose ICS. In both groups, 3 weeks was not enough to treat all symptoms of EIB even though the mean level of sputum eosinophilia was in the normal range (< 2%).32 The data from this study suggest that the initial anti-inflammatory benefits of ICS may be due to the action on eosinophils, while the action on mast cells may require a longer duration of treatment.69 Few studies have evaluated the effects of longer treatment periods using ICS on EIB. In most children, low doses of ICS (100–200 μg budesonide) over 12 weeks effectively inhibit EIB (Figure 2).70 These studies suggest that if EIB is observed, those with more severe EIB before treatment may require longer treatment periods or higher doses of ICS before inhibition. Thus, complete inhibition of EIB using ICS may suggest that the contribution of mediators of both eosinophils and mast cells have been reduced because of a decrease in the number of these cells.71

View: (Figure 2 ) - Individual data of the effects of 12 weeks treatment with low doses of budesonide (100 μg or 200 μg once daily) on the percentage fall in FEV1 in children with asthma who have EIB.

Inhaled corticosteroids reduce both airway sensitivity to EVH72 and osmotic stimuli.73,74 It has been well documented that following both short- and long-term treatment with ICS, airway responses to osmotic stimuli are abolished.73-76 This is supported by studies demonstrating cells that are sensitive to the effects of ICS are associated with the degree of airway sensitivity to osmotic stimuli, such as the mast cell and eosinophil.77,78 Furthermore, improvements in the airway sensitivity to these stimuli in the presence of ICS occur in association with the expected improvements in symptoms and lung function.74,76 Conversely, airway sensitivity to mannitol returns or increases following withdrawal of ICS in asthmatics who are clinically stable.79 Increases in the airway reactivity (known as the response-dose ratio) to mannitol and increases in eosinophils were predictive of an exacerbation during down-titration of ICS dose.79 Additional studies need to establish if the abolition of the airway response to indirect stimuli other than exercise can be used to monitor ICS therapy.

Conclusion

Exercise-induced bronchoconstriction is common in asthma and is a marker of active disease, which responds to the use of ICS. Although there is limited clinical access to tests for EIB, there is a clear rationale of re-assessing a patient using a standardized exercise testing protocol to demonstrate the efficacy of ICS. This may provide a clinically relevant marker of optimal treatment using ICS that focuses on the interaction of the 2 key features of asthma: airway inflammation and BHR. The complete inhibition of EIB with ICS may provide an objective marker of asthma control. More studies are warranted to investigate the use of indirect tests for BHR to assess responses to ICS in persons with asthma who have EIB.



Conflict of Interest Statement
John D. Brannan, PhD and James A. Turton, BSc(Hons), MBBS, MMedSc, FRACGP disclose a conflict of interest with Pharmaxis Ltd.
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John D. Brannan, PhD 1
James A. Turton, BSc(Hons), MBBS, MMedSc, FRACGP 2

1Department of Respiratory and Sleep Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, New South Wales, 2050, Australia. [email protected] 2The Australian National University, Canberra, Australia

Correspondence: John D. Brannan, PhD, Department of Respiratory and Sleep Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Rd., Camperdown, New South Wales, 2050, Australia.,
Tel: 612-9515-6121,
Fax: 612-9515-8196,
E-mail: [email protected]
Disclaimer
In an effort to provide information that is scientifically accurate and consistent with accepted standards of medical practice, the editors and publisher of The Physician and Sportsmedicine routinely consult sources believed to be reliable. However, readers are encouraged to confirm this information with other sources. For example and in particular, physicians are advised to consult the prescribing information in the manufacturer's package insert before prescribing any drug mentioned.




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