The early posttransplant lung microbiome and IP10/CXCL10 are associated with chronic lung allograft dysfunction: A prospective study with 5-year follow-up

Chronic lung allograft dysfunction (CLAD) is a 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, although 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 carried out over the first year, and patients were followed for a median of 6.04 years. Bronchoalveolar lavage was analyzed by bacterial 16S ribosomal RNA gene sequencing and quantification. Postimplant bronchoalveolar lavage was assayed for cytokines and underwent metabolomics analysis. Seventy patients (38%) developed CLAD. CLAD development and shorter time to CLAD were associated with higher lung bacterial burden, particularly 6 months posttransplant, low Streptococcus/Prevotella ratio in lung 6 weeks posttransplant, and elevated lung IP10/CXCL10 immediately after implantation. Each factor was associated with distinct timing of CLAD onset. These factors, together with previously recognized clinical features, stratified patients into groups differing by >3-fold CLAD risk. Thus, increased lung bacteria and altered composition during the first year posttransplant and of IP10/CXCL10 immediately after implantation are associated with CLAD after transplantation for non-cystic fibrosis lung disease. Early events in the allograft may establish conditions affecting later graft failure, identify potentially modifiable mechanisms of injury, and provide biomarkers for CLAD risk.