(140) Lung Function and Airway Inflammatory Markers in Children with CFTR-Related Metabolic Syndrome

Background: Newborn screening for cystic fibrosis (CF) has led to an increased diagnosis of children with CFTR-related metabolic syndrome (CRMS) who are at risk for developing CF. There is limited literature on stratifying children with CRMS who are at risk for progression to CF.

Methods: We conducted a cross-sectional study of children with CRMS and age-matched CF controls with measurement of FEV₁, lung clearance index (LCI), and inflammatory markers using exhaled breath condensate (EBC). LCI and functional residual capacity (FRC) were measured by sulfur hexafluoride multiple breath washout (MBW) using the Innocor® LCI. At least 2 acceptable LCI and FRC values were recorded. EBC samples were collected using the R-Tube method. Analysis of the EBC metabolites was conducted using liquid chromatography coupled to high-resolution mass spectrometry covering 472 validated metabolites and detection of novel molecules using data-dependent ion fragmentation. Methionine sulfoxide, a metabolite associated with inflammation in early CF bronchoalveolar lavage, was used to test our hypothesis that it is increased in CRMS patients who progress to CF. Other EBC metabolites were used for untargeted analysis to assess risk for progression to CF diagnosis.

Results: Seven children with CRMS (aged 4-14 years) and 26 children with CF (aged 5-15 years) were enrolled. In CRMS, CFTR variants included F508del and R117H;7T/9T (n=4), 2 siblings with 2789+2insA and R117H;7T/7T, and 2789+5G- >A and R117H;(TG)12-5T (n=1). In the CRMS group, the mean LCI and FRC were 6.55±0.56 and 1.35±0.91L, respectively. One child with CRMS had an abnormal LCI ( >7) of 7.39. In the CF group, mean LCI and FRC were 6.9±0.88 and 1.15±0.35L, respectively. Nine (35%) children with CF had abnormal LCI between 7.1-9.2. There was insufficient evidence to conclude that LCI differed between the CRMS and CF groups (p=0.32). Similarly, there was insufficient evidence to conclude that mean ppFEV₁ differed between the CRMS (102.2±6.4) and CF (96.6±11.6) groups (p=0.23).

Conclusions: There was no significant difference in LCI and ppFEV₁ between the CF and CRMS groups. However, we identified one CRMS child with an abnormal LCI suggesting the potential utility of MBW to stratify children with CRMS at risk for developing CF. Ongoing EBC analysis and correlation with lung function tests may be an additional modality of assessing lower airway inflammation in children with CRMS and assessing risk for progression to CF.

Acknowledgements: This work was supported by the Warshaw Fellows Research Grant.

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