CLAD_sequence_files

Background Progression of chronic lung disease often leads to the requirement for a lung transplant (LT). Despite improvements in short-term survival after LT, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the relationship between the metabolome of bronchoalveolar lavage fluid (BALF) from subjects post-LT with underlying lung disease and CLAD severity.
Methods Untargeted LC-MS/MS metabolomics was performed on 960 BALF samples collected over 10 years from LT recipients with alpha-1-antitrypsin disease (AATD, n=22), cystic fibrosis (CF, n=46), chronic obstructive pulmonary disease (COPD, n = 79) or pulmonary fibrosis (PF, n=47). Datasets were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and final CLAD severity.
Results. BALF metabolomes varied by underlying disease state, with AATD LT recipients being particularly distinctive (PERMANOVA, p= 0.001, F= 3.91). We also found a significant association with the final CLAD severity score (RF variance explained = 11.08%, PERMANOVA, p=0.001), especially those with underlying CF. Association with CLAD severity was driven by changes in phosphoethanolamine and phosphocholine lipids that increased and decreased, respectively, and metabolites from the bacterial pathogen Pseudomonas aeruginosa. P. aeruginosa siderophores, quorum-sensing quinolones, and phenazines were detected in BALF, and 4-hydroxy-2-heptylquinoline (HHQ) was associated with the final CLAD stage in samples from CF patients (R= 0.34; p ≤ 0.01, CI 95% = 3.61e+06; -6.95e+05). Relationships between CLAD stage and P. aeruginosa metabolites were especially strong in those with CF, where 61% of subjects had at least one of these metabolites in their first BALF sample after transplant.
Conclusions: BALF metabolomes after LT are distinctive based on the underlying disease and reflect the final CLAD stage. In those with more severe outcomes, there is a lipid transition from phosphocholine to phosphoethanolamine. The association of P. aeruginosa metabolites with CLAD stages in LT recipients with CF indicates this bacterium and its metabolites may be drivers of allograft dysfunction.