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.