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Inconsistent calculation methodology for the eucapnic voluntary hyperpnoea test affects the diagnosis of exercise-induced bronchoconstriction

Introduction The eucapnic voluntary hyperpnoea (EVH) challenge is used to screen for exercise-induced bronchoconstriction. Several criteria have been proposed to determine the decrease in lung function (fall index, FI) following EVH. We compared three published FI calculation methods to determine if they affect the diagnostic classification. Methods The three FIs were calculated for 126 EVH tests. Spirometry was performed in duplicate at baseline and repeated 3, 5, 10, 15 and 20 min following 6 min of EVH. The higher of the two forced expiratory volume in 1 s (FEV1) measures at all time-points post-hyperpnoea was selected for the calculation of the FIs. The FIA was determined as the single lowest of the five postchallenge values, and a test was considered positive if FEV1 decreased ≥10 %. In FIB, a test was considered positive if FEV1 decreased ≥10% at two consecutive post-challenge time-points. The FIC was calculated identically to FIA, but was normalised to the achieved minute ventilation during the EVH challenge. Results Calculation method affected the raw FIs with FIB generating the smallest and FIC generating the highest values (p<0.001) and a within-subject range of 7%±10%. The number of positive tests differed between the calculation criteria: FIA: 62, FIB: 48 and FIC: 70, p<0.001. Nineteen participants (15%) tested positive in one or two FI methods only, indicating that the FI method used determined whether the test was positive or negative. Discussion Inconsistency in methodology of calculating the FI leads to differences in the diagnostic rate of the EVH test, with potential implications in both treatment and research outcomes.

Introduction The eucapnic voluntary hyperpnoea (EVH) challenge is used to screen for exercise-induced bronchoconstriction. Several criteria have been proposed to determine the decrease in lung function (fall index, FI) following EVH. We compared three published FI calculation methods to determine if they affect the diagnostic classification.
Methods The three FIs were calculated for 126 EVH tests. Spirometry was performed in duplicate at baseline and repeated 3, 5, 10, 15 and 20 min following 6 min of EVH. The higher of the two forced expiratory volume in 1 s (FEV 1 ) measures at all time-points post-hyperpnoea was selected for the calculation of the FIs. The FI A was determined as the single lowest of the five postchallenge values, and a test was considered positive if FEV 1 decreased ≥10 %. In FI B , a test was considered positive if FEV 1 decreased ≥10% at two consecutive post-challenge time-points. The FI C was calculated identically to FI A , but was normalised to the achieved minute ventilation during the EVH challenge. results Calculation method affected the raw FIs with FI B generating the smallest and FI C generating the highest values (p<0.001) and a within-subject range of 7%±10%. The number of positive tests differed between the calculation criteria: FI A : 62, FI B : 48 and FI C : 70, p<0.001. Nineteen participants (15%) tested positive in one or two FI methods only, indicating that the FI method used determined whether the test was positive or negative. Discussion Inconsistency in methodology of calculating the FI leads to differences in the diagnostic rate of the EVH test, with potential implications in both treatment and research outcomes.

IntroDuctIon
Exercise-induced bronchoconstriction (EIB) is defined as the transient narrowing of the airways resulting from exercise. 1 Mucosal dehydration caused by evaporation and mucosal cooling with subsequent hyperaemia are the stimuli thought to cause EIB, 2 affecting 5%-20% of individuals in the general population and 4%-55% of athletes, depending on the athletes' type of sport and the diagnostic test used. 1 The high prevalence of EIB in athletes, particularly in endurance trained athletes such as cross-country skiers, runners and cyclists is thought to be a result of the repeatedly sustained high minute ventilations over prolonged periods of time. 1 2 High minute ventilations can cause the above-described mucosal dehydration and mucosal cooling, ultimately resulting in EIB. The International Olympic Committee (IOC) considers the eucapnic voluntary hyperpnoea (EVH) test the best available laboratory-based challenge to screen for EIB. 3 In one of the first descriptions of the EVH challenge in 1985, Phillips et al. 4 asked individuals to hyperventilate dry air with 4.7% added CO 2 for 8 min at the minute ventilation they had generated during an exercise challenge on a previous test day. Spirometry was performed at baseline, 5, 10 and 20 min after the hyperpnoea period. The authors concluded that the EVH challenge was suitable to identify individuals with exercise-induced asthma due to the comparable decreases in forced expiratory volume in 1 s (FEV 1 ) between the exercise and the EVH challenges. One advantage of the EVH challenge compared with an exercise test is the high degree of standardisation Open access that can be achieved for athletes, independent of their sport. Standardised, sport-specific test protocols to screen for EIB that are recognised by major sporting agencies or by the IOC do not exist. Particularly in outdoor sports where athletes train and compete in varying terrain and meteorological conditions, such as cross-country skiing, standardisation for an exercise test is nearly impossible.
Since its introduction, the EVH test protocol has been continuously adjusted to minimise potential misdiagnoses. The determination of the fall index (FI) is one parameter that has evolved over time; however, some of the presented changes to the calculation of the FI have not yet been evaluated, and it is unclear if the FI criteria in previously published studies affect the diagnostic classification of the EVH challenge. The FI is defined as the difference in FEV 1 pre-EVH and post-EVH, expressed as a per cent of baseline. 5 An EVH challenge is considered positive (EVH+) and subsequently indicative of EIB, if the FI exceeds a predetermined cut-off. 6 In a landmark paper by Andersen et al 7 spirometry was performed in duplicate at baseline and repeated at 5, 10, 15 and 20 min post-EVH. The higher of the two values was recorded for every time point. Of the postchallenge values, the one showing the greatest decline from baseline was reported (in this manuscript referred to as FI A ). To minimise the risk of low readings due to technique error or poor effort, the current American Thoracic Society (ATS) Clinical Practice Guideline recommends the calculation of the FI based on two consecutive values with a decrease in FEV 1 ≥10% rather than one single value (in this manuscript referred to as FI B ). 8 9 Argyros et al. 10 and Hurwitz et al. 11 recommended using the criteria of FI A but normalising the calculated FI by the achieved minute ventilation during the EVH challenge (in this manuscript referred to as FI C ). Normalisation of FI is suggested because a dose-response relationship between the achieved minute ventilation during the EVH challenge and the experienced degree of bronchoconstriction has been previously shown; 10 12 therefore, a greater release of inflammatory mediators following higher relative minute ventilations during the EVH challenge are thought to increase the stimulus for bronchoconstriction. Recently, Price et al. 13 suggested a shift in the diagnostic cut-off from 10% to 15%. In their experience, the majority of competitive athletes with normal baseline lung function and no respiratory symptoms present with an FI after EVH close to or beyond 10%.
The aim of this retrospective analysis was to compare three previously published calculation methods of the FI (FI A , FI B and FI C ) in the EVH challenge. We calculated the FIs using the three methods and evaluated the resulting clinical classification (EVH+ vs EVH-). We hypothesised that the calculation method of the FI would significantly affect the diagnostic classification of the EVH challenges. To assess ecological validity of the FI calculation methods, we compared them to the change in FEV 1 induced by a short-duration, high-intensity exercise bout. Furthermore, we assessed if the change in the proportion of positive and negative tests following a shift in the cut-off from 10% to 15% varied between FI calculation methods.

MethoDs overview of included eVh tests
The EVH tests from five different projects were pooled, adding up to 165 data sets that were checked for eligibility. 14-18 A total of 39 data sets were removed from the analysis due to participants' repeated study participation within our laboratory (n=13) or due to spirometry measures that did not meet the repeatability criteria for duplicate measures as per the ATS guidelines (n=26). 19 For individuals who participated in several studies pooled for this analysis, only the data set from participants' first EVH test were included. Participants, whose EVH tests were included were non-smokers, not pregnant and free from cardiovascular and metabolic disease (except for EIB). Ethics approval for this study was granted by the University of British Columbia Clinical Research Ethics Board in accordance with the Helsinki Declaration. All study participants provided written, informed consent.

experimental protocol
All participants completed an EVH challenge to screen for EIB. Since participants only mimic the breathing of a high-intensity exercise bout without actually conducting any form of exercise, some researchers refer to the EVH challenge as a tool to screen for bronchial hyper-responsiveness instead of EIB. Due to the ATS and the IOC describing the EVH challenge as a validated test to screen for EIB, we will use this term for the purpose of this manuscript. A subset of 41 well-trained cyclists completed a 10 km cycle time trial (TT) on a separate test day with pre-TT and post-TT spirometry. The EVH challenge and the TT were completed in the same laboratory with a washout period of a minimum of 3 days, and a maximum of 2 weeks. Predicted spirometric values were obtained following Crapo et al. 20 For the EVH challenge and the TT, all participants were asked to withhold from short-acting and long-acting bronchodilators for 12 hours prior to testing, but were permitted to continue corticosteroid treatment. Participants did not exercise on either of the study days to avoid exercise-induced bronchodilation and abstained from caffeine.

eVh challenge and calculation of fall indices
Baseline lung function was determined as the highest FEV 1 from three manoeuvres using spirometry (TrueOne 2400; ParvoMedics, Sandy, Utah, USA). 19 The target minute ventilation for the EVH period was calculated as 30× baseline FEV 1 . Individuals breathed dry gas (5% CO 2 , 21% O 2 , balanced N 2 ) for 6 min wearing a nose clip, and repeated spirometry in duplicate 3, 5, 10, 15 and 20 min after completion of the hyperventilation. Real-time feedback of their minute ventilation was provided as 10 sec averages to ensure that the target was maintained. If the target ventilation was not met, participants were verbally encouraged to increase respiratory rate or tidal volume based on the test administrator's observations. The FI was calculated as: 21 To investigate how different calculation methods of the FI affect the diagnostic classification of the EVH challenge, we used FI A , FI B and FI C as summarised in table 1.
The severity of EIB was graded as mild (FI≥10%, but <25%), moderate (FI≥25%, but <50%) and severe (FI≥50%) for all FI calculation methods following the ATS guidelines. 9 spirometry precycling and postcycling time trials A subset of 41 trained cyclists performed a short-duration, high-intensity cycle bout in the form of a simulated 10 km TT on a cycle ergometer. Spirometry was performed in duplicate before and immediately after the completion of the TT, as soon as it was safe for the participant to get off the cycle ergometer. During the TT, a virtual course was displayed on a screen with distance, cadence and gearing information shown. Participants wore a facemask attached to a two-waynon-rebreathing valve (7450V2Mask, Hans Rudolph, Shawnee, Kansas, USA) during the TT. Of the 41 individuals who completed post-TT spirometry measures, seven (17%) had to be removed from the analysis because they did not meet ATS guidelines, most commonly because duplicate measures were not within 150 mL. 19 The change in FEV 1 between pre-TT and post-TT (FI TT ) was analysed for a total of 39 well-trained cyclists (18 men and 21 women). The highest of the two measures taken at baseline and on completion of the TT, respectively, were chosen, and FI TT was expressed as a per cent of baseline.
statistical analyses All data are presented as mean values (M) with standard deviations (SD). First, raw values of FI A-C and FI TT were compared with each other using repeated measures analyses of variance, with sex serving as the between-subject variable. If a main effect was found, a Sidak test was performed to test for significance.
In a second analysis, the number of EVH+ and EVHtests resulting from the three FI calculation methods were compared with each other using a 10% and a 15% cut-off, respectively, with the Friedman test. If a  significant main effect was found, posthoc analysis was performed using the Wilcoxon signed-rank test.
The changes in FEV 1 pre-TT and post-TT in the subset of 39 athletes were calculated using a repeated-measures T-test.
For all tests, the significance level was set at 0.05. Statistical procedures were completed using SPSS (V.24, IBM, Armonk, New York, USA).

results study participant characteristics
Of the 126 included individuals, 34 reported a previous asthma diagnosis. These 34 previously received asthma diagnoses could not be further classified by their mode of diagnosis, as the majority of participants could not recall how the diagnosis was made. Of the 34 individuals with a previous asthma diagnosis, 20 treated their symptoms with daily inhalations of corticosteroids and inhaled ß 2 -agonists on an as-needed basis. Two individuals relied on inhaled ß 2 -agonists on an as-needed basis only, and 12 did not take any medications to treat respiratory symptoms. All collected anthropometric, baseline lung function and fitness parameters are summarised in table 2.     comparison of eVh fall indices to the change in FeV 1 pre-time and post-time trial When using FI B following the current ATS guidelines to calculate the FI, 5 (13%) of the 39 athletes who completed spirometry pre-TT and post-TT, presented with a mild decrease in FEV 1 following the TT of on average 0.11L±0.09L (p=0.054) with the FI TT decreases ranging between −1.2% and −7.9%. Four athletes tested EVH+ when using all three FI calculation methods, but no one presented with a FI TT ≥10%. The remaining 33 (87%) athletes bronchodilated significantly with an average increase in FEV 1 of 0.2L±0.2L (p≤0.001) equalling an increase ranging from 1%-26% (see figure 1).

DIscussIon
In the past, studies have focused on optimising and standardising several components of the EVH challenge protocol such as the duration 10 22 and target minute ventilation 10  In this study, the FI calculation methods applied to determine the change in lung function following an individual's EVH challenge varied on average by 7%±11%, which affected the EVH interpretation in 15% of participants. Thus, the course of treatment and training advice given to those 15% could depend on the chosen calculation method. As a result, the calculation method of the FI needs careful consideration in clinical and research settings, and the chosen methodology should be clearly described. When the EVH+ tests were classified into categories, the number of moderate and severe diagnoses varied almost threefold between the FI calculation methods, with FI C leading to the highest number of moderate and severe EIB cases. Given the severity of their EIB, these are individuals who would need the most medical support in managing their respiratory symptoms to pursue sport or physical activity. Therefore, the calculation method of the FI appears to be more important for individuals with more severe EIB compared with individuals with an FI just above or below the 10% cut-off.
The FI C led to significantly higher FIs and a significantly greater number of EVH+ tests compared with FI A and FI B . These findings are in contrast to Hurwitz et al. 11 who investigated older participants and individuals with a history of smoking. They found only a 1% difference between raw and VE EVH-achieved -adjusted FIs. 11 The reasons for this disparity are unclear, however, the current study examined young, physically active non-smokers. As such, the average per cent predicted FEV 1 of participants in this study was greater compared with that of Hurwitz' study population (FEV 1 per cent predicted in healthy individuals and asthmatics=98.3 (1.9)% and 90.9 (1.6)%, respectively). 11 It appears that adjusting FI for VE EVHachieved in healthy individuals with high static lung volumes might give starkly different results compared with the raw FI values, and thus such a method should be used with caution.
The shift of the cut-off from 10% to 15% approximately halved the number of mild EVH+ tests. In our study, the FEV 1 of 16%-20% of the included participants fell between 10% and 15% when using FI A , FI B and FI C . This rate is comparable to that of Price et al. 13 with 20% of their asymptomatic individuals falling into this range. The high number of athletes presenting with bronchodilation following the TT, regardless of their FI, did not confirm our EVH test findings, making conclusions on the optimal cut-off for the EVH difficult. With 87% of the athletes showing bronchodilation regardless of the FI calculation method, the FI B following the current guidelines 8 9 appears to be the most cautious approach in the determination of the FI when compared with FI A and FI C . One potential concern when using FI B might be to falsely identify individuals with a late onset of bronchoconstriction as EVH-, as a decrease in FEV 1 in two consecutive measurements is needed. This analysis shows that the majority of individuals test EVH+ within the first 5 min. To avoid a potential misdiagnosis if an individual only starts to present with bronchoconstriction at the 20 min post-hyperpnoea time point, it might be advisable to add an extra spirometric assessment 25 min post-hyperpnoea to confirm a sustained bronchoconstriction induced by EVH.

limitations
We collected spirometric data up to 20 min following the EVH challenge, but performed just a single (duplicate) spirometry assessment immediately following the TT. Blackie et al. 22 concluded that the onset of bronchoconstriction was delayed with increasing duration of isocapnic hyperventilation in asthmatics. Hyperventilation itself may inhibit bronchoconstriction or the mechanisms inducing bronchoconstriction may be delayed in response to hyperventilation. 22 It would have been preferable to have spirometric data following the TT over a comparable 20 min time-period as for the EVH test. Furthermore, an analysis of the FI methods against experienced asthma symptoms during and following exercise might have helped to further characterise the FI calculation methods.
conclusIon The FI calculation method significantly affects the number of EVH+ and EVH-tests and the magnitude of the raw FI value used to classify the severity of EIB. Individuals with moderate and severe EIB are affected most by the FI calculation method. Careful consideration should be paid to the choice of calculation method since it affects the course of treatment and symptom management provided to physically active individuals. A 10 km cycling TT in this study acted as a powerful bronchodilator and did not accurately confirm the individuals' response to the EVH challenge. With FI B leading to the smallest decreases in FEV 1 following EVH and the lowest number of EVH+ tests, it appears to be the most conservative of the three calculation methods. The use of FI C may not be advisable in individuals with high per cent predicted FEV 1 at baseline as it may lead to unachievable target VEs in the EVH challenge. Further research is needed to better address the question of whether a shift from 10% to 15% for the FI-cutoff in the EVH challenge should be recommended. The symptoms and the degree of EIB Open access experienced in individuals with mild EIB, commonly observed in well-trained athletes, are variable. 24 Having individuals with mild EIB complete multiple exercise tests and multiple EVH challenges to compare the results between the exercise and EVH challenges would provide a better assessment. As previously recommended by Mastronarde 25 and Price et al., 13 minute ventilations for the exercise and the EVH challenges should be matched to further investigate the role of minute ventilation, and a comprehensive airway inflammatory profile should be included to provide a more detailed basis for a decision on the shift from 10% to 15%.