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.