Multi-omics biomarkers of endothelial dysregulation preceding chronic lung allograft dysfunction: A prospective cohort study

by Giulia Iacono, Christina Begka, Bailey Cardwell, Carmel Daunt, Roxanne Chatzis, Celine Pattaroni, Alana Butler, Matthew Macowan, Bronwyn Levvey, Gregory I. Snell, Glen P. Westall, Benjamin J. Marsland

Background Long-term survival of lung transplant recipients remains limited by chronic lung allograft dysfunction (CLAD). CLAD is only diagnosed following a persistent and substantial decline in lung function, after which irreversible damage to the lungs has occurred, limiting opportunities to effectively intervene at an early stage. There is a critical need for earlier detection prior to its clinical manifestation. The immunological drivers of CLAD remain unclear, limiting the development of predictive biomarkers and new therapies.

Methods and findings In this hypothesis-generating, prospective cohort study, we profiled the microbial, metabolic, lipidomic, and gene expression dynamics of longitudinally collected broncho-alveolar lavages (BALs) from 56 CLAD-free lung transplant recipients up to 30 months post-transplant, and compared BALs from 13 CLAD-free patients to BALs from 13 patients who developed CLAD. In CLAD-free patients, the first 6 months post-transplant were hallmarked by diminished microbial diversity and increased abundance of Staphylococcus and Candida, coupled with upregulated innate and adaptive immune responses, and elevated nitric oxide metabolism (FDR CD3, GZMA, IL2RB, CD28, CD40LG, and LCK, after tapering of maintenance immunosuppression (FDR HAPLN3, HS3ST3B1, SULF2, CHST2, CSGALNACT1, CXCR1, CSF3R, SELL, CXCL2, and CEACAM1 (FDR We have identified immunological processes, metabolites, lipids, and genes associated with the onset of CLAD. Our findings are to be considered associative and not aimed at establishing causality. Future studies employing a targeted approach in independent validation cohorts, using, for example, quantitative polymerase chain reaction (PCR) and targeted mass-spectrometry, will be required to confirm these findings.