The Lung Allograft Microbiome Associates with Pepsin, Inflammation, and Primary Graft Dysfunction.

RATIONALE: Primary graft dysfunction (PGD) is the principal cause of early morbidity and mortality after lung transplantation. The lung microbiome has been implicated in later transplantation outcomes but has not been investigated in PGD.

OBJECTIVES: To define the peri-transplant bacterial lung microbiome and relationship to host response and PGD.

METHODS: Single-center prospective cohort study. Airway lavage samples from donor lungs before organ procurement and recipient allografts immediately post-implantation underwent bacterial 16S rRNA gene sequencing. Recipient allograft samples were analyzed for cytokines by multiplex array and pepsin by ELISA.

MEASUREMENTS AND MAIN RESULTS: We enrolled 139 transplant subjects and obtained donor lung (n=109) and recipient allograft (n=136) samples. Severe PGD (persistent grade 3) developed in 15 subjects over the first 72 hours while 40 remained without PGD (persistent grade 0). The microbiome of donor lungs differed from healthy lungs, and recipient allograft microbiomes differed from donor lungs. Development of severe PGD was associated with enrichment in the immediate post-implantation lung of oropharyngeal anaerobic taxa, particularly Prevotella. Elevated pepsin, a gastric biomarker, and a hyperinflammatory cytokine profile were present in recipient allografts in severe PGD, and strongly correlated with microbiome composition. Together, immediate post-implantation allograft Prevotella/Streptococcus ratio, pepsin, and indicator cytokines associated with development of severe PGD during the 72-hour post-transplantation period (AUC=0.81).

CONCLUSIONS: Lung allografts that develop PGD have a microbiome enriched in anaerobic oropharyngeal taxa, elevated gastric pepsin, and hyperinflammatory phenotype. These findings suggest a possible role for peri-transplant aspiration in PGD, a potentially actionable mechanism that warrants further investigation.