Results:
Between 2009 and 2019, 249 spirometry tests with bronchodilator response
were reported for 102 patients during days 4-10 of admission for PEx. 46
patients had one admission with BD testing, 22 patients had 2 tests, and
34 had 3 or more tests. The median (IQR) of tests per patient was 2
(1,3). Median (IQR) age at BD response testing was 14.3 (11.7, 16.2)
years. Additional characteristics of the study population are described
in Table 1. The characteristics where not significantly different
looking exclusively at the first admission with BD response testing
(Table 1). Medians (IQR) of FEV1 at baseline (best
FEV1 over 6 months prior to admission), at admission, at
day 4-10 (prior to bronchodilators) and at end of treatment are
presented in Table 2.
The median (IQR) (range) absolute change in FEV1 from
pre to post BD testing was 0.064 liters (0.018, 0.124) (-0.217, 0.496).
The median (IQR) (range) of relative percent change in
FEV1 from pre to post BD was 4.3% (1.4, 7.8%) (-13.7,
44.2%) (Figure 1). The relative change in FEV1 from pre
to post BD was not different when comparing those prescribed inhaled
steroids (ICS) (n=104/249) to those not prescribed ICS (4.9% (1.8,
7.3%), 4.1% (1.0, 7.9%); p=0.58). A total of 23/249 (9%) tests in
17/102 (17%) patients resulted in significant BD responses as defined
by ATS/ERS guidelines (12% or greater change with increase of 200 ml or
more in FEV1)15. Significant BD
response remained rare (33/249, 13%) also when defining BD response
using a 12% change without the need for 200 ml increase.
To assess whether the proportion of patients with significant BD
response was different from what is observed in an outpatient setting,
we analysed all PFTs of CF patients who underwent BD response testing in
our center as outpatients in the same time period (2009 to 2019). 2544
BD tests were performed on a total of 319 outpatient children with CF.
Of these 240 (9.4%) showed a significant BD response according to
ATS/ERS criteria.
Patients with significant BD response did not differ from those without,
in terms of gender, ethnicity, CFTR mutation class, use of ICS,
pathogens detected in airway cultures, age, BMI or baseline
FEV1 (table 1). There was no significant difference in
the proportion of patients with at least 90 % recovery to baseline
after treatment, between those with a significand BD response and those
without (table 1).
The relative change in FEV1 from pre to post BD was
poorly correlated to the severity of lung disease as indicated by
baseline pulmonary function (r=-0.16, p=0.02) (Figure 2). Similarly, a
poor correlation was seen between the relative change in
FEV1 from pre to post BD around day 7 and the recovery
of FEV1 from admission to end of treatment (r=0.14,
p=0.03) (Figure 3). The change in FEV1 from pre to post
BD around day 7 did not correlate with recovery to baseline as estimated
by end of treatment FEV1 divided by the best
FEV1 in 6 months prior to admission (R = 0.08, p=0.22)
(Figure 4).
Further investigating the subgroup of patients with a significant BD
response, we reviewed their clinical charts to detect if any change in
clinical management was initiated as a result of the BD test results. Of
17 patients with a total of 23 events, two were initiated on ICS
therapy, and another two on combination ICS / long acting beta agonist
(LABA) medications. For the majority of patients (13/17, 76.5%) no
immediate change in management was encountered.
Discussion :
The goal of this study was to summarize the results and to review the
clinical value of BD response testing in children treated for a CF PEx
at the Hospital for Sick Children between 2009 and 2019. We found
changes from pre to post bronchodilator FEV1 to be
generally low, and a significant BD response in this setting, as defined
by ATS/ERS criteria, was a rare finding. We did not identify any
significant differences in patient characteristics between the group of
responders versus non responders. Furthermore, only 4/17 patients from
the responders group encountered an immediate change in management as a
result of the significant BD response. Furthermore, BD response poorly
correlated with baseline pulmonary function prior to admission, or with
percent recovery in FEV1 from initiation to end of
treatment. No correlation was found between BD response and recovery to
baseline FEV1 and the proportion of patients recovering
to at least 90% of baseline FEV1 was similar in both
the BD responder and non-responder groups. Overall, BD testing appears
to be of limited clinical value in this setting.
Although airway reactivity does exist in individuals with CF, the
pathophysiology and the frequency of this phenomenon in the CF
population is an area of controversy. Historically, Mellis and Levison
showed that CF patients with lower lung function were more likely to
have a positive histamine challenge test17. They
concluded that the heightened bronchial reactivity in patients with CF
reflects the severity of their underlying lung disease rather than an
underlying asthmatic component. Eggleston et al. showed that CF patients
with positive methacholine challenge tests, suffered from more frequent
PEx and experienced a more rapid decline in FEV1 over
time compared to patients with negative methacholine
challenges18. Comparing CF to asthma, Mitchel et al.
showed that only 51% of CF patients had a positive methacholine
challenge test compared to 98% of asthmatic patients. The latter had
different dose–response curves and time courses, suggesting different,
or disease specific pathophysiologic mechanisms leading to a positive BD
response19. In a more contemporary study, Levin et al.
showed that in clinically stable patients with CF, BD response was not
associated with more severe lung disease as indicated by
FEV1<40% of predicted3.
Notably, many changes in CF standard of care have been implemented over
the years possibly explaining differences between older and more recent
studies.
The proportion of patients with a significant BD response in our study
was low (23/249, 9%), similar to pediatric patients tested in the
ambulatory setting 240/2544 (9.4%), and using a more sensitive
definition for BD response i.e., 12% without the need of 200 ml change,
the proportion of responders was not largely different (33/249, 13%).
On a cellular level, it has been shown that inflammation can cause
impairment of β adrenergic-induced relaxation of CF airway smooth
muscle20. However, many factors can lead to a
discrepancy between in vivo and in vitro findings, and the fact that we
did not quantify inflammatory markers in the airways of the patients
included in our analysis limits the ability to properly investigate the
influence of inflammation on airway responsiveness. Moreover, while PEx
is most probably associated with increased inflammation, these patients
also received intravenous antibiotic therapy, and there may have been
higher adherence to mucus clearance therapies including physiotherapy
during the time of admission. It is possible that some of these
circumstances impact lung function changes after bronchodilator
inhalation.
Interestingly, the proportion of patients with significant BD response
in this study, is significantly lower compared to the 39% reported by
Levin et al. in clinically stable patients3. However,
in that study, information is given only for the fraction of patients
with significant BD response, and the proportion of test events with
significant BD response is not reported. In an analysis of BD tests for
outpatients seen at our CF clinic over the same time period of this
study, we found the rate of significant BD response to be 240/2544
(9.4%). Overall, we found that at our center, the proportion of
significant BD response tests was similar for out and inpatients.
Inhaled corticosteroid (ICS) therapy is not considered a routine for CF
patients, and can be safely discontinued in most patients21,22. Despite that, 42% of the patients in this
study were treated with ICS. This is similar to the 40% seen in the CF
Foundation patient registry23. Interestingly, there
was no difference in the proportion of patients receiving ICS in the
responder group compared with the non-responders, nor was there a
significant difference in BD response for those receiving ICS compared
with those not receiving ICS. This suggests that the possibility of ICS
masking BD response in treated CF patients is less likely, although
adherence to ICS treatment was not monitored in this study. We also
found that in only 4 cases, the finding of significant BD response
during the admission resulted in addition of ICS or ICS + LABA,
medications typically used to treat asthma.
We found no significant relationship between airway microbiology results
upon admission and BD response. Aspergillus is a common pathogen in CF
airways, and known to cause ABPA in up to 9% of children with
CF24. Despite the fact that most CF patients with
positive aspergillus cultures will not develop ABPA, the finding that
there was no increase in BD responsiveness in aspergillus positive
patients treated for PEx is in keeping with our recent finding that
patients with diagnosed ABPA did not tend to have higher rates of BD
responses compared to other causes of deterioration in lung
function14.
To our knowledge, this is the first study to investigate BD
responsiveness in pediatric CF patients during treatment for PEx. One
strength of this study is the relatively large number of patients
tested. One of the study’s limitation is the retrospective analysis.
Also, while patients in this study underwent spirometry testing to
evaluate lung function after 1 week of therapy, a clear indication to
justify BD response testing was not documented. While we did not find
any proof that this selection was not random, we cannot exclude a
selection bias could affect the results of this study.