Fractional exhaled nitric oxide in the assessment of exercise-induced bronchoconstriction: A multicenter retrospective analysis of UK-based athletes.

INTRODUCTION: Exercise-induced bronchoconstriction (EIB) is not only highly prevalent in people with asthma, but can also occur independently, particularly in athletes. Fractional exhaled nitric oxide (FeNO) is an indirect biomarker of type 2 airway inflammation that has an established role in the assessment and management of asthma. The aim was to evaluate the value of FeNO in the assessment of EIB in athletes. METHOD: Multicenter retrospective analysis. In total, 488 athletes (male: 76%) performed baseline FeNO, and spirometry pre- and post-indirect bronchial provocation via eucapnic voluntary hyperpnea (EVH). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for established FeNO thresholds-that is, intermediate (≥25 ppb) and high FeNO (≥40 ppb and ≥ 50 ppb)-and were evaluated against objective evidence of EIB (≥10% fall in FEV1 ). The diagnostic accuracy of FeNO was calculated using receiver operating characteristics area under the curve (ROC-AUC). RESULTS: Thirty-nine percent of the athletes had a post-EVH fall in FEV1 consistent with EIB. FeNO values ≥25 ppb, ≥40 ppb, and ≥ 50 ppb were observed in 42%, 23%, and 17% of the cohort, respectively. The sensitivity of FeNO ≥25 ppb was 55%, which decreased to 37% and 27% at ≥40 ppb and ≥ 50 ppb, respectively. The specificity of FeNO ≥25 ppb, ≥40 ppb, and ≥ 50 ppb was 66%, 86%, and 89%, respectively. The ROC-AUC for FeNO was 0.656. CONCLUSIONS: FeNO ≥40 ppb provides good specificity, that is, the ability to rule-in a diagnosis of EIB. However, due to the poor sensitivity and predictive values, FeNO should not be employed as a replacement for indirect bronchial provocation in athletes.

Ventilation Rates Achieved in Eucapnic Voluntary Hyperpnea Challenge and Exercise-Induced Bronchoconstriction Diagnosis in Young Patients with Asthma.

PURPOSE: Exercise-induced bronchoconstriction (EIB) affects approximately 50% of young asthma patients, impairing their participation in sports and physical activities. Eucapnic voluntary hyperpnea (EVH) is an approved surrogate challenge to exercise for objective EIB diagnosis, but the required minimum target hyperventilation rates remain unexplored in this population. This study aimed to evaluate the association between the achieved ventilation rates (VRs) during a challenge and EIB-compatible response (EIB-cr) in young asthma patients. METHODS: This cross-sectional study included 72 asthma patients aged 10-20 years. Forced expiratory volume in the first second (FEV1) was measured before and 5, 15, and 30 min after the EVH. The target VR was set at 21 times the individual's baseline FEV1. A decrease of > 10% in FEV1 after the challenge was considered an EIB-cr. The challenge was repeated after 48-72 h in those without an EIB-cr. RESULTS: Thirty-six individuals had an EIB-cr at initial evaluation. The median VRs achieved was not different between individuals with and without an EIB-cr (19.8 versus 17.9; p = 0.619). The proportion of individuals with an EIB-cr was nor different comparing those who achieved (12/25) or not (24/47) the calculated target VRs (p = 0.804). At the repeated EVH challenge an EIB-cr was observed in 14/36 individuals with a negative response in the first evaluation, with no differences in achieved VRs between the two tests (p = 0.463). CONCLUSION: Irrespective of the achieved VR, an EIB-compatible response after an EVH challenge must be considered relevant for clinical and therapeutic judgment and negative tests should be repeated.

Reproducibility of eucapnic voluntary hyperpnoea for exercise-induced bronchoconstriction diagnosis in asthmatic children and adolescents.

BACKGROUND: Respiratory symptoms after exercise are frequently reported by asthmatic patients, and exercise-induced bronchoconstriction (EIB) is a frequent cause, which requires objective testing for diagnosis. Eucapnic voluntary hyperpnea (EVH) is recommended as a surrogate stimulus for this purpose. Its short-term reproducibility is not yet established in children and young adolescents with asthma. OBJECTIVE: To evaluate the short-term test-retest agreement and reproducibility of FEV1 changes after EVH in this population. METHODS: Asthmatic patients aged between 10 and 20 years underwent EVH for EIB diagnosis on two occasions 2-4 days apart at a specialized university clinic. FEV1 was measured at 5, 15, and 30 min after EVH with a target ventilation rate 21 times the baseline FEV1 . EIB was diagnosed as a decrease ≥10% in FEV1 from baseline. RESULTS: A total of 26 of 62 recruited individuals tested positive for EIB on both visits (positive group) and 17 on one visit only (divergent group), while 19 tested negative on both visits (negative group). The overall agreement was 72.5% (95%CI 61.6%, 83.6%), and Cohen's kappa coefficient was 0.452. Low bias (0.87%) and high intra-class correlation coefficient (0.854, 95%CI 0.758,0.912; p < .001) for FEV1 response between test days were found, but with wide limits of agreement (±20.72%). There were no differences in pre-challenge FEV1 or achieved ventilation rate between visits either between groups (p = .097 and p = .461) or within groups (p = .828 and p = .780). There were no safety issues. CONCLUSIONS: More than one EVH test should be performed in children and young adolescents with asthma to exclude EIB and minimize misdiagnosis and mistreatment.

The effect of diurnal variation in exercise-induced bronchoconstriction.

Objective: Exercise-induced bronchoconstriction (EIB) is an acute, transient narrowing of the airway as a result of exercise. Diurnal variation in asthma is well-established, however, few studies have investigated diurnal variability in EIB; no study has used eucapnic voluntary hyperpnea (EVH). The aim of this study was to examine circadian variability in EIB using EVH.Methods: Fourteen recreationally-active males with mild to moderate asthma and nine healthy controls were randomized to first complete either an AM (07:00-08:00) or PM (17:00-18:00) EVH challenge, followed by the alternate test 34 h to 7 days later. The EVH protocol comprised of six-minutes of hyperventilation of a 5% CO2 gas at a minimum ventilation rate of 21 × FEV1 min-1. The primary outcome measure was FEV1 pre- and post-EVH.Results: We observed no diurnal effect on EIB in the asthma group. The minimum observed post-EVH FEV1 in the asthma cohort was 3.58 ± 0.95 L in AM and 3.62 ± 0.87 L in PM tests, corresponding to a 15.0 ± 15.3% vs. 14.9 ± 14.7% reduction from baseline, respectively. The asthma group showed similar baseline FEV1 before AM (4.21 ± 0.79 L) and PM (4.25 ± 0.65 L) tests. No difference was observed in minute ventilation between AM (26.1 ± 3.4 × FEV1 min-1) and PM (25.6 ± 3.8 × FEV1 min-1) tests for the asthma cohort. Controls displayed no significant changes in FEV1 or minute ventilation between tests.Conclusions: When baseline pulmonary function is similar, this study suggests that time-of-day has no effect on EIB in mild to moderate asthma.

Can EVH Results Predict Post-Exercise Changes in FEV1 Following Interval and Continuous Exercise?

The eucapnic voluntary hyperpnea (EVH) challenge is used to determine the presence of exercise-induced bronchoconstriction (EIBC) by monitoring changes in forced expiratory volume in 1 s (FEV1). However, the predictability of the post-EVH decline in FEV1 on post-exercise FEV1 remains unclear. Participants completed an EVH challenge to confirm EIBC and completed a continuous exercise (CONT; n = 21), high-intensity interval exercise (HI; n = 13), and sprint interval exercise (SPRT; n = 8) sessions on separate days. FEV1 was assessed pre- and post exercise. A 1% decline in FEV1, post EVH was associated with 0.44%, 0.85%, and 0.56% declines in FEV1 post CONT, post HI, and post SPRT, respectively. The decline in FEV1 following the EVH challenge was associated with the decline in FEV1 following all exercise conditions, with the strongest association being observed following HI. These findings may have implications for exercise prescription and asthma education for recreationally active adults with EIBC.

Is there cardiac autonomic dysfunction in children and adolescents with exercise-induced bronchospasm?

BACKGROUND: The pulmonary impairment in patients with bronchoconstriction induced by eucapnic voluntary hyperpnea(EVH) goes beyond the respiratory system, also impairing autonomic nervous modulation. This study aimed to evaluate the behavior of cardiac autonomic modulation in young asthmatics with and without EIB after the EVH test. RESEARCH DESIGN AND METHODS: A cross-sectional study design using 54 asthmatics(51.9% female), aged between 10 and 19 years, investigated with the EVH test. Forced expiratory volume in one second(FEV1) was measured at 5, 10, 15, and 30 min after EVH. Heart rate variability(HRV) measures of time were assessed pre and 30 min-post EVH. The diagnosis of Exercise-Induced bronchoconstriction with underlying clinical asthma(EIBA) was confirmed by a fall in FEV1 ≥10% compared to baseline. RESULTS: Thirty(55.5%) asthmatics had EIBA. Subjects with EIBA have reduced mean of the R-R intervals in relation to baseline until 15 minutes after EVH. Individuals without EIBA had increased parasympathetic activity compared to baseline(rMSSD) from 5 min after EVH(p < 0.05). This parasympathetic activity increase in relation to baseline was seen in individuals with EIBA after 25 minutes (rMSSD = 49.9 ± 5.3 vs 63.5 ± 7.2, p < 0.05). CONCLUSION: Young asthmatics with EIBA present a delay in the increase of the parasympathetic component after EVH when compared to asthmatics without EIBA.

Exercise-induced bronchoconstriction in university field hockey athletes: Prevalence, sex differences, and associations with dyspnea symptoms.

Introduction: Exercise-induced bronchoconstriction (EIB) is a prevalent condition in athletes. EIB screening studies identify many athletes with undiagnosed EIB. Moreover, there is a poor relationship between EIB and dyspnea symptoms recalled from memory. Purpose: This study investigated: (I) the prevalence of EIB in British university field hockey athletes; (II) the effect of sex and diagnostic criteria on EIB prevalence; and (III) the association between EIB and contemporaneous dyspnea symptoms. Methods: 52 field hockey athletes (age: 20 ± 2 years; height: 173 ± 9 cm; body mass: 72 ± 10 kg; male = 31; female = 22) completed a eucapnic voluntary hyperpnea (EVH) test with multi-dimensional dyspnea scores measured 3-10 mins post-EVH. A test was deemed positive (EIB+) if a fall index (FI) ≥10% in FEV1 occurred at two consecutive time points post-test (FIATS). Two further criteria were used to assess the effect of diagnostic criteria on prevalence: FI≥10%, determined by a pre-to-post-EVH fall in FEV1 of ≥10% at any single time-point; and FI≥10%-NORM calculated as FI≥10% but with the fall in FEV1 normalized to the mean ventilation achieved during EVH. Results: EIB prevalence was 19% and greater in males (30%) than females (5%). In EIB+ athletes, 66% did not have a previous diagnosis of EIB or asthma and were untreated. Prevalence was significantly influenced by diagnostic criteria (P = 0.002) ranging from 19% (FIATS) to 38% (FI≥10%-NORM). Dyspnea symptoms were higher in EIB+ athletes (P ≤ 0.031), produced significant area under the curve for receive operator characteristics (AUC ≥ 0.778, P ≤ 0.011) and had high negative prediction values (≥96%). Conclusion: Overall, 19% of university field hockey athletes had EIB, and most were previously undiagnosed and untreated. EVH test diagnostic criteria significantly influences prevalence rates, thus future studies should adopt the ATS criteria (FIATS). Contemporaneous dyspnea symptoms were associated with bronchoconstriction and had high negative prediction values. Therefore, contemporaneous dyspnea scores may provide a useful tool in excluding a diagnosis of EIB.

Bronchial Provocation Testing for the Identification of Exercise-Induced Bronchoconstriction.

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.

Management of Exercise-Induced Bronchoconstriction in Athletes.

Exercise-induced bronchoconstriction (EIB) is a phenomenon observed in asthma but is also seen in healthy individuals and frequently in athletes. High prevalence rates are observed in athletes engaged in endurance sports, winter sports, and swimming. The pathophysiology of EIB is thought to be related to hyperventilation, cold air, and epithelial damage caused by chlorine and fine particles in inspired air. Several diagnostic procedures can be used; however, the diagnosis of EIB based on self-reported symptoms is not reliable and requires an objective examination. The hyperosmolar inhalation test and eucapnic voluntary hyperpnea test, which involve indirect stimulation of the airway, are useful for the diagnosis of EIB. A short-acting ß-agonist is the first choice for prevention of EIB, and an inhaled corticosteroid is essential for patients with asthma. Furthermore, treatment should accommodate antidoping requirements in elite athletes. Tailoring of the therapeutic strategy to the individual case and the prognosis after cessation of athletic activity are issues that should be clarified in the future.

Testing for Exercise-Induced Bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is a form of airway hyperresponsiveness that occurs with or without current symptoms of asthma. EIB is an indicator of active and treatable pathophysiology in persons with asthma. The objective documentation of EIB permits the identification of an individual who may be at risk during a recreational sporting activity or when exercising as an occupational duty. EIB can be identified with laboratory exercise testing or surrogate tests for EIB. These include eucapnic voluntary hyperpnea and osmotic stimuli (eg, inhaled mannitol) and offer improved diagnostic sensitivity to identify EIB and improved standardization when compared with laboratory exercise.

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma.

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (DlCO), were conducted before and after three conditions: 1) 2 h of exercise in the heat with no fluid intake (dehydration), 2) 2 h of exercise with ad libitum fluid intake (control), and 3) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7-15)%, 11 (9-24)%, and 12 (7-20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in DlCO Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function.NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced dehydration appears to compromise small airway function.

A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes.

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled ß2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11ß-prostaglandin F2α (11ß-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11ß-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11ß-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Diagnosing exercise-induced bronchoconstriction with eucapnic voluntary hyperpnea: is one test enough?

BACKGROUND: In athletic individuals, a secure diagnosis of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Indirect bronchoprovocation testing is often used in this context and eucapnic voluntary hyperpnea (EVH) testing is recommended for this purpose, yet the short-term reproducibility of EVH is yet to be appropriately established. OBJECTIVE: The aim of this study was to evaluate the reproducibility of EVH in a cohort of recreational athletes. METHODS: A cohort of recreational athletes (n = 32) attended the laboratory on two occasions to complete an EVH challenge, separated by a period of 14 or 21 days. Spirometry and impulse oscillometry was performed before and after EVH. Training load was maintained between visits. RESULTS: Prechallenge lung function was similar at both visits (P > .05). No significant difference was observed in maximum change in FEV1 (ΔFEV1max) after EVH between visits (P > .05), and test-retest ΔFEV1max was correlated (intraclass correlation coefficient = 0.81; r(2) = 0.66; P = .001). Poor diagnostic reliability was observed between tests; 11 athletes were diagnosed with EIB (on the basis of ΔFEV1max ≥10%) at visit 1 and at visit 2. However, only 7 athletes were positive at both visits. Although there was a small mean difference in ΔFEV1max between tests (-0.6%), there were wide limits of agreement (-10.7% to 9.5%). Likewise, similar results were observed for impulse oscillometry between visits. CONCLUSIONS: In a cohort of recreational athletes, EVH demonstrated poor clinical reproducibility for the diagnosis of EIB. These findings highlight a need for caution when confirming or refuting EIB on the basis of a single indirect bronchoprovocation challenge. When encountering patients with mild or borderline EIB, we recommend that more than one EVH test is performed to exclude or confirm a diagnosis.