Bronchoalveolar Lavage Lipopolysaccharide is Associated with Aspiration, Acute Rejection, and Chronic Lung Allograft Dysfunction in Lung Transplant Recipients

PurposeOur recent work has shown that bronchoalveolar lavage (BAL) lipopolysaccharide (LPS) is associated with increased risk of chronic lung allograft dysfunction (CLAD) in the absence of infection. Moreover, BAL LPS was associated with aspiration and reduced by anti-reflux surgery. As aspiration may increase CLAD risk by potentiating acute rejection (AR), we investigated whether BAL LPS is associated with AR in lung transplant recipients (LTRs). Moreover, we wanted to validate our previously identified BAL LPS cut-off that predicted CLAD in LTRs in an independent cohort.MethodsLPS was measured in BAL samples in a case control cohort of 120 adult bilateral LTRs from 2010-2015 with a transbronchial biopsy within the first-year post-transplant without concurrent infection. Lung function was characterised as either spirometrically significant or stable based on the presence or absence of ≥10% concurrent drop in FEV1. AR was based on A-grade ≥ 1. Reflux episodes were measured with 24h pH-impedance testing, bile acids were measured using mass spectrometry. Cox-PH models were used to assess the relationship between BAL LPS, using our previously reported cut-off >0.48 EU/mL, and outcomes.ResultsLTRs with spirometrically significant AR had higher levels of BAL LPS than those with stable AR or stable no AR (Figure 1A). BAL LPS was positively associated with total reflux episodes (r=0.39; p=0.004), proximal reflux episodes (r=0.51; p<0.001), and BAL bile acid levels (r=0.25; p=0.007). BAL LPS>0.48 EU/mL was associated with an increased risk of CLAD [HR: 2.27 (1.16-4.45); p=0.02] (Figure 1B) and death/retransplantation [HR: 2.45 (1.24-4.84); p=0.01].ConclusionWe demonstrate independent validation that BAL LPS predicts CLAD. LPS mediated immune activation may explain the link between aspiration, acute rejection, and CLAD. Anti-reflux surgery in LTRs with BAL LPS>0.48 EU/mL may help reduce BAL LPS levels and prevent CLAD. Our recent work has shown that bronchoalveolar lavage (BAL) lipopolysaccharide (LPS) is associated with increased risk of chronic lung allograft dysfunction (CLAD) in the absence of infection. Moreover, BAL LPS was associated with aspiration and reduced by anti-reflux surgery. As aspiration may increase CLAD risk by potentiating acute rejection (AR), we investigated whether BAL LPS is associated with AR in lung transplant recipients (LTRs). Moreover, we wanted to validate our previously identified BAL LPS cut-off that predicted CLAD in LTRs in an independent cohort. LPS was measured in BAL samples in a case control cohort of 120 adult bilateral LTRs from 2010-2015 with a transbronchial biopsy within the first-year post-transplant without concurrent infection. Lung function was characterised as either spirometrically significant or stable based on the presence or absence of ≥10% concurrent drop in FEV1. AR was based on A-grade ≥ 1. Reflux episodes were measured with 24h pH-impedance testing, bile acids were measured using mass spectrometry. Cox-PH models were used to assess the relationship between BAL LPS, using our previously reported cut-off >0.48 EU/mL, and outcomes. LTRs with spirometrically significant AR had higher levels of BAL LPS than those with stable AR or stable no AR (Figure 1A). BAL LPS was positively associated with total reflux episodes (r=0.39; p=0.004), proximal reflux episodes (r=0.51; p<0.001), and BAL bile acid levels (r=0.25; p=0.007). BAL LPS>0.48 EU/mL was associated with an increased risk of CLAD [HR: 2.27 (1.16-4.45); p=0.02] (Figure 1B) and death/retransplantation [HR: 2.45 (1.24-4.84); p=0.01]. We demonstrate independent validation that BAL LPS predicts CLAD. LPS mediated immune activation may explain the link between aspiration, acute rejection, and CLAD. Anti-reflux surgery in LTRs with BAL LPS>0.48 EU/mL may help reduce BAL LPS levels and prevent CLAD.