Table 2.
LCI2.5 assessed by MBW was completed in 48 children ages 4 to 13 years. Median (IQR) values were comparable between the two diagnostic groups (Table 1 ). LCI2.5 data were classified based on two different upper limit of normal (ULN) cut-offs: one defined by 26 healthy volunteers from CHLA ages 3 to 19 years and of the same race/ethnicity distribution as study subjects (ULN = 8.02;Figure 1 ); and the other defined from the literature (ULN = 7.91, Supplemental Figure 2 ).13 There is no statistical difference in distribution between above and below cutoff among CF, CRMS/CFSPID, and CF-classified based on healthy volunteers from CHLA (p=0.140) and reference literature (p=0.345).
CFTR function was assessed by HNE assay in 10 selected subjects (8 CRMS/CFSPID, 2 re-classified to CF, Figure 2 ). In the CRMS/CFSPID group, wild type (WT)-CFTR (wtCFTR) function ranged from 27% to 67% (5.75 to 14 µA/cm2; reference is 21 µA/cm2 for healthy controls), while their sw[Cl-] varied from 28 to 49 mmol/L. In the two CF-reclassified subjects, CFTR function varied from 7% to 30% of wtCFTR (1.52 to 6.25 µA/cm2) while sw[Cl-] values were above the diagnostic threshold of 60 mmol/L. There was no linear relationship between the HNE assay and sw[Cl-].
Per California CF centers standard of practice, sites are encouraged to perform sw[Cl-] testing on the day of referral and to repeat at 6 months, 1 year, and yearly thereafter if values are <60 mmol/L. Repeated values (median [IQR] = 4 [2, 5] repeated measures per participant) analyzed by quantile mixed-effects showed distinct trajectories between children who retained the CRMS/CFSPID designation compared to those who reclassified to CF (p-value for difference between slopes = 0.013; Figure 3 ). Initial sw[Cl] values were also significantly different between groups (Intercept difference, <0.0001). The CF-reclassified population had an increase of 4.71 (95% CI 2.45-6.97) mmol/L/year, compared to 1.21 (95% CI 0.4-2.02) mmol/L/year among those who did not reclassify.
Firth logistic regression was used to detect factors associated with CRMS/CFSPID-to-CF reclassification among 71 participants. On univariate analysis, children with CRMS/CFSPID who reclassified had significantly higher rates of respiratory cultures positive for PSA, crackles detected on physical exam, respiratory symptoms, pneumonia, hospitalization for respiratory illness, use of antibiotics in the previous 12 months, growth concerns, and increasing (higher slope) sw[Cl-] (Table 3 ). The multivariate Firth logistic regression model included respiratory culture positive for PSA, sw[Cl-] trajectory (slope), history of pneumonia, and study site. Children with CRMS/CFSPID who had a respiratory culture positive for PSA were more likely to reclassify (adjusted OR [95% CI] = 6.43 [1.15 – 36.07], p=0.034). Increase in sw[Cl-] over time remained significantly associated with the risk of reclassification (adjusted OR [95% CI] = 1.21 [1.02 – 1.45], p=0.033). A history of pneumonia was not significantly associated with reclassification (adjusted OR [95% CI] = 1.87 [0.33 – 10.63], p=0.48). The conclusion of modeling was that sw[Cl-] increase and history of PSA were independently associated with CF reclassification.