Introduction: Early cystic fibrosis (CF) lung disease monitoring is crucial for understanding responses to therapy and preventing progressive pulmonary decline. Structural lung disease (SLD) is a major cause of pulmonary decline in CF. We aimed to identify metabolites in CF bronchoalveolar lavage (BAL) associated with and predictive of SLD.
Methods: We applied untargeted metabolomics to 84 BAL samples from a cross-sectional cohort of 67 clinically stable children with CF aged 1-5 years across two sites. We used a linear mixed-effects model to select metabolites associated with SLD, BAL neutrophils, and myeloperoxidase (MPO) and neutrophil elastase (NE) activities. An independent longitudinal cohort of infants who either did or did not exhibit bronchiectasis by age 9 years was analysed to determine whether metabolites associated with SLD could also predict future lung disease.
Results: In the cross-sectional cohort, 10 BAL metabolites, including methionine sulfoxide (MetO), ornithine and N-acetylmethionine (NAcMet), were associated with SLD, neutrophils, MPO and NE. The percentage of methionine oxidation (%OxMet) and the arginine-ornithine ratio were also associated with these outcomes. In the longitudinal cohort, MetO, %OxMet, ornithine and NAcMet predicted bronchiectasis development, and MetO plus ornithine was a more sensitive predictor than either alone. At age 0-2 years, these metabolites outperformed established biomarkers such as NE, MPO and interleukin-8.
Conclusions: We identified BAL metabolites associated with SLD, MPO and NE, detectable in the earliest stages of CF. MetO, %OxMet, NAcMet and ornithine predicted bronchiectasis development, outperforming established biomarkers. These metabolites reflect oxidising, proteolytic and other enzymatic activities of neutrophils, highlighting potential therapeutic avenues.
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