Discussion
Knowledge of the reproducibility of a test is paramount for understanding its clinical utility for diagnosis or evaluation of changes over time and responses to therapeutic interventions18. In a group of 62 children and adolescents with asthma, we found the EVH challenge test to have a short-term FEV1 reproducibility response of 72.5% for EIB diagnosis, with positive and negative agreement of 41.9% and 30.6%, respectively. It should be noted that, in 12 patients, EIB occurred only on the second challenge. This is relevant for the differential diagnosis of respiratory symptoms upon exercise in young asthmatics, in whom EIB is one of the most common but not the only triggering factor, with consequences for the individual patient and the choice and monitoring of treatment options6,7,30,31. Our study fills a gap in the literature, as published studies on the reproducibility of the EVH have been conducted only in athletes21,22 or in small numbers of asthmatic adults23,24. The presence of EIB is defined by a decrease in FEV1 > 10% from baseline, either for exercise or EVH challenges13,17. For research purposes, the dimensionless area under the FEV1fallmax% curve and ICC may contribute to general understanding of the bronchial response and repeatability but are difficult to interpret on clinical grounds. Despite a high ICC and low bias, we found wide limits of agreement (LOAs), both for FEV1fallmax% and AUC0-30min (Figure 1). As shown in Table 2, the overall LOAs were similar among those individuals with a positive response on two visits, irrespective of the magnitude of the FEV1fallmax%. In an earlier study comparing EIB response between EVH and treadmill running challenges in a similar population, we also observed wide LOAs between tests (+19.7%)32.
The overall LOAs are wider than those found by Anderson et al.19 in exercise tests in their group of children (+ 13.4%). This may be explained by the lower rate of negative agreement found in our study (30.6% compared to 56.8%) and may be a consequence of the difference in study populations, as Anderson’s study group had symptoms compatible with asthma, but no medical diagnosis. Despite these differences, the overall agreement for EIB diagnosis in our study varies little from that observed by these authors, who found 76% agreement between two exercise tests conducted one to four days apart. Price et al.21 found a 75% agreement between EIB responses to EVH tests on two occasions (14-21 days apart) in 32 adult athletes (19% with asthma) with a high proportion of negative agreement (55%). These authors considered the limits of agreement to be wide (+ 10.1%), although they were approximately 50% lower than in our study. This too may be explained by differences in study population.
Our population comprised young individuals receiving an asthma diagnosis at a tertiary university specialty care facility, most (95%) classified as having controlled or partially controlled asthma, with a score >18 on the ACT (Brazilian version26). There were no differences in asthma control score between EVH response groups (Table 3). No patient was regularly using inhaled corticosteroids capable of interfering with the EIB response33.
The recommended target ventilation rate during the six-minute EVH test for elite athletes is 85% of maximum voluntary ventilation (MVV), i.e., 30 times the baseline FEV1. For non-athletes, 60% of MVV is considered adequate (21 times baseline FEV1)13,34. We adopted this as the target ventilation rate to be achieved during the EVH challenge. Overall, there were no differences in the mean ventilation rate achieved between visits or between the three groups (Table 3). Most individuals (48/62) were able to achieve more than 80% of the target ventilation, but fourteen (22.5%) achieved values between 60% and 80%. This may be a weakness of our study. Detailed examination of these individuals reveals that four and eight were in the positive and negative EIB groups on both visits respectively, and two tested positive on one day only (p = 0.119, Chi Square).
No correlation was found between target ventilation and the FEV1falmax% for any visit (Visit 1: r = -0.20, p = 0.110, Visit 2: r = -0.12, p = 0.358 – Spearman’s rho). These findings are consistent with those of Brummel et al.16 and Stadelmann et al.22, who found the ventilation rate not to be related to FEV1fallmax% after EVH. More studies need to be conducted to evaluate this relationship. Unlike these authors, we found no differences in ventilation levels achieved during EVH between males and females (p=0.430).
Published guidelines recommend a baseline FEV1 of over 75% of predicted as a safety measure to avoid severe bronchospastic responses35,36. Brannan and Kippelen34 recommend that individuals known to be asthmatic be excluded from performing EVH. Parsons et all.13 do not provide specific safety recommendations. The experience in our laboratory, as reported by other publications14,16,17,23, is that a safe EVH test can be conducted in asthmatics with a baseline FEV1 as low as 60% of predicted. Of course, the test must be conducted by trained personnel with resources available for a possible emergency event. On Visits 1 and 2, 11 and 14 patients respectively had baseline FEV1 <75% but >60% of predicted; only one presented a severe EVH response (FEV1fallmax% > 50%) but had no severe respiratory symptoms or hemoglobin oxygen saturation below 94%.
Different from Hurwitz et al.37, who observed a weak but statistically significant correlation between baseline FEV1 and the FEV1fallmax%, we were unable to detect such a correlation on either of the two visits (Visit 1 r = 0.165, p = 0.201; Visit 2 r =0.178, p =0.166. Spearman’s rho).
The limits of agreement between repeated tests allow us to evaluate the magnitude of response that can be considered to lie outside expected variations in the parameter29. For a treatment to be considered of benefit in individuals with a FEV1falmax% greater than 20%, using the LOAs for this study population with a mean drop of 37.5%, the FEV1fallmax% after administration of the drug would need to be less than 18%. On the other hand, the narrow LOAs observed for those individuals with negative response on both visits (Table 2) agree with the results of Burman et all.17 that found a 10% fall in FEV1as a good cutoff value for EIB diagnosis after EVH.
Bias in a test repeatability evaluation may be related to the execution of the test itself (measurement error), changes in environmental conditions or in individual factors, such as medication use, severity of disease, and exposure to triggering factors. The patients in our study were a homogeneous group in terms of asthma diagnosis, disease control level and medication use. The EVH tests were repeated within a short period of time to avoid any time-related changes in airway responsiveness, disease conditions or environmental exposure. No statistical differences were observed in baseline FEV1% of predicted between visits. Although patients were coached to achieve the target ventilation rate (60% of MVV), some did not reach this level. However, comparison of individuals with divergent EIB responses to EVH on separate days revealed no differences in the mean ventilation rates achieved suggesting that this relationship deserves more investigation. Although undetected factors may have interfered with the short-term reproducibility of response to the EVH stimulus in 17 patients that presented a different EIB response on each visit, our previous findings33, like those of Price et al.21 and Anderson et al.19, suggest that there may be an inherent individual variability in bronchial response to EVH or exercise test, even between short term evaluations.
Our study was conducted in young asthmatics, most with well controlled disease and with a short interval between tests. The findings cannot, thus, be extrapolated to other populations or to larger intervals between tests, for which specifically designed studies should be conducted. It remains intriguing, however, that the same bronchial stimulus elicits different bronchial responses in different individuals with the same condition and, in the same individuals, on different occasions.
In conclusion, it is clear that, for the moment, there are no diagnostic tests that can be considered a “gold standard” for EIB diagnosis, either in athletes38 or in asthmatic individuals19. Without a repeated EVH test, 28% of our patients with EIB diagnosis would have been missed. There is a need for cautious interpretation of a negative EVH challenge for EIB diagnosis and two or more tests should be performed in those patients in whom EIB is to be excluded. Keen clinical judgment needs to be exercised, especially in cases of diagnosis and therapeutic intervention in patients with exercise-related respiratory complaints and mild or no decrease in FEV1 after EVH challenge.
Table 1. Baseline characteristics of patients