DISCUSSION
In this mixed cohort of retrospectively and prospectively collected iPFT
data from CF NBS infants, we found that hyperinflation was more common
than diminished FEV0.5 and FEF. Furthermore, RR was
elevated and correlated with increased FRC. These results suggest that
FRC is a more sensitive measure of early CF lung disease and that
measurement of RR may be a simple, non-invasive clinical marker to
identify CF NBS infants with hyperinflation.
Although there have been several iPFT studies in CF NBS infants, few
have reported FRC data. Some of the FRC measurements in previous studies
were performed using multiple breath washout (MBW), which may
underestimate hyperinflation compared to plethysmography29. In a multicenter iPFT study of CF infants
primarily diagnosed clinically, hyperinflation was more common than
diminished FEV0.5 16. Our results are
similar, suggesting that early diagnosis of CF through NBS does not
prevent hyperinflation. The only other study to report
FRCpleth in CF NBS infants has been from the London
Cystic Fibrosis Collaboration 7,9,11. FRC was elevated
in this Collaborative, but hyperinflation was less common and
obstruction, as measured by FEV0.5, was more common in
this group when compared to our cohort. Our finding that hyperinflation
was much more common than decreased FEV0.5 in CF NBS
infants highlights that small airway obstruction is present in early
life. It is also consistent with chest computed tomography findings that
demonstrate that air trapping is the earliest and most prevalent sign of
lung disease in CF NBS infants 2.
Very few studies have reported RVRTC and FRC data in CF NBS infants in
the USA. In our study, there was no significant difference in
FEV0.5 or FEF compared to normal reference values7,8,30. Britton, et al reported normal
FEV0.5 and FEF in CF NBS infants born in the USA31. Further, Pollak, et al reported that a large
proportion of infants had normal FEV0.5 and FVC in
infancy and these parameters did not predict abnormal lung function in
early school-age spirometry 32. This further suggests
that forced expiratory flows and volumes are less sensitive measures of
early CF lung disease.
Elevated RR in children and infants with CF has been described
previously 33-35. These studies have not shown an
association between RR and FEF or tidal breathing indices, although one
study did report an association between elevated RR and increased lung
clearance index (LCI) in infants with CF 35. However,
this study did report an association between RR and FRC obtained via
MBW, which may underestimate FRCpleth. They also did not
define RR thresholds associated with abnormal LCI. With a cutoff RR of
36, we demonstrated a high sensitivity for identifying infants with
hyperinflation as measured through FRCpleth, a sign of
early lung disease. In contrast to measurement of
FRCpleth in infants, which requires a high degree of
technical skill and expensive equipment, measurement of RR is much
simpler, non-invasive and does not require sedation, suggesting it may
be a clinically useful marker of infants at an increased risk of more
severe early lung disease.
Similar to previous studies, we found that wheezing and second-hand
smoke exposure were associated with worse lung function3,28. A history of Pa infection was also associated
with lower lung function, but this was not statistically significant in
our cohort. Several studies have shown a relationship between early
nutritional status and lung function at 6-12 years5,6,36, and similar to other iPFT studies we observed
lower WFA z-scores in our cohort 7,8. However, we were
unable to demonstrate that lower nutritional indices in early infancy
were associated with lower lung function later in infancy. Potential
reasons for this include the possibility that FEF and
FRCpleth are not sensitive enough to detect a
significant association or that 6 months was an insufficient time
between lung function and the measured outcomes to detect a significant
association.
Our results have potential implications for clinical care and research.
Hyperinflation was significantly more common than decreased FEF and
FEV0.5, suggesting that it may be a more sensitive
measure of early lung disease and could serve as an additional sensitive
measure for research studies evaluating early infant CF lung disease.
FRCpleth requires less technical skill compared to FEF.
RR correlated significantly with hyperinflation. Since RR can easily be
obtained without the need for specialized equipment, our results suggest
that RR could serve as a clinical marker for early CF lung disease.
However, the role of RR monitoring in CF infants needs further study
before it can be used in routine clinical practice.
There are several limitations to our study. This is a single-center
study, which could limit generalizability. However, our cohort had
similar clinical characteristics compared to other CF NBS studies. Our
sample size was also comparable to other iPFT studies in CF infants7-9,32. Some of our iPFT data came from clinically
indicated tests, which may have biased our study cohort towards greater
disease severity. To help reduce selection bias, we recruited a cohort
of clinically mild infants and asymptomatic infants who had iPFTs as
part of other research studies. Although the cohort may still have been
biased towards more severe disease, this would not have affected the
association between RR and FRC. RR was measured during sedation with
chloral hydrate. While this may have altered the actual respiratory rate
numbers, it should not have affected the correlation we demonstrated. As
with all iPFT studies, there is a paucity of normal reference data and
we relied on the same data utilized by other studies. Although our
reference values for FRC were obtained from a different study from which
we obtained our FVC, FEV0.5, FEF25-75,
and FEF75 reference values, they were all performed on
the same equipment using the same methods and sedation protocol.
In summary, this study of lung function in CF NBS infants found that
hyperinflation is more common than decreased FEF, and that RR correlated
with FRC. These results have potential implications for the care and
study of early CF lung disease in infants. Further research is needed to
evaluate the role of RR measurement as a non-invasive, simple and
clinically useful marker of early CF lung disease.