The Early Post-Transplantation Lung Microbiome and CXCL10 are Associated with Chronic Lung Allograft Dysfunction: A...

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term lung transplantation success. Microbial factors have been linked to CLAD risk, and sequence-based methods have been applied recently to identify potential microbial drivers, though patient heterogeneity and follow-up time have been limitations. We undertook a longitudinal cohort study of 186 patients transplanted for diseases other than cystic fibrosis. Dense lung sampling was done over the first-year and patients were followed for 6.04 (median) years. Bronchoalveolar lavage (BAL) was analyzed by bacterial 16S rRNA gene sequencing and quantification. Post-implantation BAL was assayed for cytokines and metabolomics. Seventy patients (38%) developed CLAD. CLAD development and shorter time-to-CLAD were associated with higher lung bacterial burden particularly 6-months post-transplant, low Streptococcus/Prevotella ratio in lung six-weeks post-transplant, and elevated lung IP10/CXCL10 immediately post-implantation. Each factor associated with distinct CLAD timing. These factors, together with previously-recognized clinical features, stratify patients into groups differing by >3-fold CLAD risk. Thus, increased lung bacteria and altered composition during the first-year post-transplantation and immediate post-implantation IP10/CXCL10 associate with CLAD after transplantation for non-CF lung disease. Early events in the allograft may establish conditions impacting later graft failure, identify potentially modifiable mechanisms of injury, and provide biomarkers of CLAD risk.