Large Airway Bronchial Wash Lipidomics As Novel Biomarkers for Chronic Lung Allograft Dysfunction

PurposeChronic lung allograft dysfunction (CLAD) is the primary cause of long-term mortality after lung transplantation. Aspiration of bile acids has been associated with CLAD and lipidomic dysregulation. This study evaluates the role of large airway bronchial wash (LABW) lipidomics and diagnosis of CLAD.MethodsLABW (n=611) samples were obtained from 305 lung transplant recipients at different timepoints. Concentrations of 26 specific lipid subfamilies were obtained using liquid chromatography mass spectrometry. Lipid percentages where stratified by highest tertiles. The primary outcome of interest was development of CLAD from sampling time. Time-to-event analysis was done using Kaplan-Meier functions and a multivariable Cox proportional hazards model adjusting for baseline comorbidities.ResultsSamples with CLAD at the time of collection showed higher percentages of hexosylceramides (HEXCER), CE, sphingomyelin (SM) and lactosylceramide (LACCER). A high percentage of bismethyl-phosphatidic acid (BMP), CE, phosphatidylethanolamine (PEP), dehydrosphingosine (DHSM), lysophosphatidylethanolamine (LPE), ganglioside (GM3), phosphatidyl-serine (PS) were associated with an increased hazards of CLAD by univariable analysis. A high percentage of CE (HR: 1.48, 95% CI: 1.09-2.03, P=0.013) were independent predictors of CLAD by multivariable analysis. High percentages of CER (HR: 0.49, 95% CI: 0.36-0.66, P<0.001) and a high LACCER:CER ratio (HR: 0.45, 95% CI: 0.34-0.62, P<0.001) were independently associated with decreased hazards of CLAD.ConclusionAirway lipidomic qualititative changes show a distinct phenotype that associate with the presence and risk of development of CLAD. Percentages of CE, CER and LACCER:CER ratios correlate independently with increased risk of development of CLAD. Changes in LABW lipids may serve as biomarkers for CLAD and elucidate pathophysiologic changes after transplant. Chronic lung allograft dysfunction (CLAD) is the primary cause of long-term mortality after lung transplantation. Aspiration of bile acids has been associated with CLAD and lipidomic dysregulation. This study evaluates the role of large airway bronchial wash (LABW) lipidomics and diagnosis of CLAD. LABW (n=611) samples were obtained from 305 lung transplant recipients at different timepoints. Concentrations of 26 specific lipid subfamilies were obtained using liquid chromatography mass spectrometry. Lipid percentages where stratified by highest tertiles. The primary outcome of interest was development of CLAD from sampling time. Time-to-event analysis was done using Kaplan-Meier functions and a multivariable Cox proportional hazards model adjusting for baseline comorbidities. Samples with CLAD at the time of collection showed higher percentages of hexosylceramides (HEXCER), CE, sphingomyelin (SM) and lactosylceramide (LACCER). A high percentage of bismethyl-phosphatidic acid (BMP), CE, phosphatidylethanolamine (PEP), dehydrosphingosine (DHSM), lysophosphatidylethanolamine (LPE), ganglioside (GM3), phosphatidyl-serine (PS) were associated with an increased hazards of CLAD by univariable analysis. A high percentage of CE (HR: 1.48, 95% CI: 1.09-2.03, P=0.013) were independent predictors of CLAD by multivariable analysis. High percentages of CER (HR: 0.49, 95% CI: 0.36-0.66, P<0.001) and a high LACCER:CER ratio (HR: 0.45, 95% CI: 0.34-0.62, P<0.001) were independently associated with decreased hazards of CLAD. Airway lipidomic qualititative changes show a distinct phenotype that associate with the presence and risk of development of CLAD. Percentages of CE, CER and LACCER:CER ratios correlate independently with increased risk of development of CLAD. Changes in LABW lipids may serve as biomarkers for CLAD and elucidate pathophysiologic changes after transplant.