Correspondence

Bronchodilator
reversibility in patients
with asthma and
persistent airflow
limitation
Authors’ reply
We read with great interest the
Correspondence by Ernesto Crisafulli
and colleagues on our Article.1 They
correctly point out the importance
of bronchodilator reversibility and
show that greater bronchodilator
reversibility is strongly associated
with the presence of persistent airflow
limitation (PAL), both with respect
to flow (FEV1) and volume (forced
vital capacity [FVC]) response. Based
on their findings, we reanalysed
available data in the ATLANTIS
study, not only cross-sectionally,
but also longitudinally in relation to
exacerbations.
In line with Crisafulli and colleagues’
analyses, we did a univariable analysis
that showed that patients with PAL had
bronchodilator reversibility significantly
more often than did those without PAL.
This was the case for all definitions of
bronchodilator reversibility used by
Crisafulli and colleagues. For example,
Flow response
Change in FEV1 % predicted (continuous variable)
Change in FEV1 of ≥12% from baseline
Change in FEV1 of ≥10% predicted
Change in FEV1 of ≥12% and increase in absolute volume of
≥200 mL from baseline
Volume response
Change in FVC % predicted (continuous variable)
Change in FVC of ≥10·5% from baseline
Change in FVC ≥9·2% predicted
Change in FVC of ≥10·5% and increase in absolute volume of
≥320 mL from baseline
Data are hazard ratios, with 95% CIs and p values in parentheses, for the risk of exacerbation with the addition
of each bronchodilator reversibility variable in the multivariable Cox regression model. The multivariable Cox
regression model includes the variable as in the original Article, consisting of: PAL, age, sex, current smoking,
ex-smoking, GINA steps 4 and 5, blood neutrophils, blood monocytes, blood eosinophils. FVC=forced vital
capacity. PAL=persistent airflow limitation.
Table: Hazard ratios for exacerbations in patients in the ATLANTIS study in multivariable Cox
regression model (n=744)
149 (60%) of 248 patients with PAL had
an increase of at least 12% from baseline
after bronchodilator use, compared
with 144 (28%) of 512 patients without
PAL (p<0·0001). In this context,
notably, patients with PAL on average
have a lower FEV1 and FVC than do
those without PAL. Therefore, they
have more room for improvement
when given a bronchodilator and are
more likely to pass a threshold based on
baseline FEV1 or FVC. For that reason, we
also did an analysis of the association
between bronchodilator reversibility
and PAL, adjusting for baseline FEV1 or
FVC. Using this multivariable analysis,
we did not find flow reversibility to
be associated with PAL anymore. For
instance, in a model with baseline
FEV1 as a covariate, change in FEV1 of
at least 12% had an odds ratio of 1·04
(95% CI 0·97–1·11; p=0·25). This finding
suggests that the correlation observed
in the univariable analysis might reflect
baseline dependency and perhaps
so-called regression to the mean. By
contrast with flow reversibility, volume
reversibility remained a significant
predictor for PAL. For example, in a
model for PAL including baseline FVC
% of predicted, FVC change of at least
10% had an odds ratio of 1·64 (95% CI
1·50–1·80; p<0·0001).
Hazard ratio for exacerbation
1·00 (0·98–1·03; p=0·78)
1·07 (0·75–1·54; p=0·70)
1·00 (0·69–1·44; p=0·99)
1·04 (0·72–1·50; p=0·84)
1·01 (0·98–1·03; p=0·65)
1·34 (0·86–2·08; p=0·19)
1·07 (0·69–1·67; p=0·75)
1·23 (0·77–1·94; p=0·38)
A key finding of our study1 was
the observation that the presence of
PAL is associated with an increased
risk of exacerbations, not only
in those with severe asthma but
also in those with mild asthma.
Therefore, we also analysed this
association as described in our
Article while including parameters
of bronchodilator reversibility in the
model. None of the six definitions
of bronchodilator reversibility were
independently associated with
exacerbations when combined in the
model with PAL, neither in the full
group of patients with asthma (table),
nor in patients with milder asthma
(GINA steps 1 and 2; data not shown).
In all these models, PAL remained a
significant predictor of exacerbations.
In summary, we replicated the
finding of Crisafulli and colleagues
that patients with PAL more often
have bronchodilator reversibility
than do those without PAL, an
observation that might be attributable
to baseline dependency. With regards
to exacerbations, we found that PAL,
but not bronchodilator reversibility,
was an independent risk factor for
exacerbations not only in severe
asthma, but also in mild asthma (GINA
steps 1–2).
HAMK reports grants from Chiesi Farmaceutici,
GlaxoSmithKline, and Novartis; and consulting fees
paid to their institution from GlaxoSmithKline and
Novartis. MvdB reports research grants paid to their
institution from GlaxoSmithKline, Chiesi
Farmaceutici, AstraZeneca, Novartis, Genentech,
and Roche. TMK declares no competing interests.
*Tessa M Kole, Huib A M Kerstjens,
Maarten van den Berge, on behalf of
ATLANTIS, UBIOPRED, and CADSET
contributors
t.m.kole@umcg.nl
Department of Pulmonary Disease and Groningen
Research Institute for Asthma and COPD, University
of Groningen, University Medical Center Groningen,
Groningen 9713GZ, Netherlands
1 Kole TM, Vanden Berghe E, Kraft M, et al.
Predictors and associations of the persistent
airflow limitation phenotype in asthma:
a post-hoc analysis of the ATLANTIS study.
Lancet Respir Med 2022; published online
July 27. https://doi.org/10.1016/S2213-
2600(22)00185-0.

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