Discussion
This study provides a first insight into the association between extent
of structural damage in the lungs and airways in people with CF and the
FEV1 response to treatment with CFTR modulators during
real life follow up. There is no previous literature about this
association.
Unsurprisingly, our data confirm the correlation between baseline
ppFEV1 and Brody score derived from chest CT, as has
been established before by Helbich et al. for an earlier CT score in
adult and pediatric CF patients, and by Brody et al. for Brody score in
children with CF. 12,13
This study shows different findings concerning the correlation between
Brody score and lung function change for treatment with ivacaftor versus
lumacaftor/ivacaftor: we find a positive correlation between Brody score
and ppFEV1 response to ivacaftor treatment, whereas we
do not find any correlation between these same parameters for treatment
with lumacaftor/ivacaftor.
This contrast in findings could be explained by the differences in
treatment efficacy of the CFTR modulating drug; lumacaftor/ivacaftor for
F508del homozygous patients is known to be far less effective compared
to ivacaftor for patients with a gating mutation5,14.
This difference adds to the difficulties in the assessment of factors
correlated with magnitude of response.
Notably, the ivacaftor group consisted of patients with a relatively
well-preserved lung function and low Brody scores, reflecting only
minimal structural changes in the lungs. This may explain why a positive
correlation between Brody scores and lung function change on treatment
was found; in patients whose lungs are not severely affected by the
disease, an increase in lung function cannot be expected after the start
of treatment; the goal of treatment would be to preserve lung function
and to prevent lung damage rather than to reverse it. In a group of
patients with more severely affected lungs, it is possible that the
correlation would be absent or even negative, if extensive structural
damage proves to be irreversible by CFTR modulating therapy.
Also the fact that the timing of the CT scans was just before start of
therapy in the ivacaftor group, while this was anywhere in the 18 months
before or after start of therapy for the lumacaftor/ivacaftor group,
could in part account for the difference in findings. The decision to
include scans within the time span of 18 months before or after start,
was based on literature about the progression of structural damage
visible on CT scan in CF, showing no relevant progression in 18 months
on most parameters15.
This study faced several limitations, most of these concerning the group
of patients who had started lumacaftor/ivacaftor, as we use clinically
indicated CT scans in this group. Firstly, this implicates that
differences in scanning protocol occurred with variation of the clinical
indications that warranted the chest CT. This resulted in missing air
trapping scores in 5 patients in this group. We therefore used Brody
score excluding air trapping score for this analysis. As air trapping
(together with mucus plugging) would be the aberrance most likely to
improve on treatment, also influencing FEV1, this could
decrease the potential of the Brody score to pick up a possible
correlation between baseline CT anomalies and FEV1change on therapy. Another consequence of using indicated CT scans, is
that the timing of the scans is imperfect in comparison with CT scans in
the ivacaftor group (where CT was timed just before start of the
treatment as part of the regular follow up protocol). This might lead to
differences in the findings, as theoretically, some anomalies (such as
air trapping, mucus plugging) might improve quickly after initiation of
therapy. No information about short term effects of CFTR modulators on
CT findings is available in literature however.
A third limitation that the use of clinically indicated scans brings
along, is the fact that these scans may show more (possibly reversible)
abnormalities than would be present in a stable situation, as the scan
is carried out due to respiratory complaints. Also purely based on CT
scan it is not easy to discriminate between reversible and irreversible
structural abnormalities. For example, a CT scan could show
consolidations or increased bronchial thickening, reflecting an
exacerbation, in a patient undergoing CT scan because of hemoptysis. The
ivacaftor group on the other hand is small, making the data more prone
to be influenced by outliers, troubling calculation of partial
correlations, and making it impossible to tell if the correlation found
is in fact linear, or curved. An advantage was that in this group CT
scans were timed optimally and included expiration slides for air
trapping analysis.
Verification and closer analysis of this correlation in a larger patient
cohort would be favorable. Another additional approach could be to
evaluate if Brody scores from follow up CT scans improve in patients
while they are using CFTR modulators, and whether or not this
improvement is in line with the change in ppFEV1.