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