Large airway bronchial wash lipidomics as novel biomarkers for chronic lung allograft dysfunction.

Abstract

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 evaluated the role of lipidomics in the diagnosis of CLAD. Large airway bronchial wash (n = 596) samples were obtained from 304 lung transplant recipients at different time points. Concentrations of 26 specific lipid subfamilies were obtained using liquid chromatography-mass spectrometry. Lipid percentages were stratified by the highest tertiles. The primary outcome of interest was the 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 greater percentages of hexosylceramides, ceramide (CER), sphingomyelin (SM), and lactosylceramide (LACCER). A high percentage of bismethyl-phosphatidic acid, CE, phosphatidylethanolamine, dehydrosphingosine, lysophosphatidylethanolamine, ganglioside, and phosphatidyl-serine was associated with an increased hazards of CLAD by univariable analysis. High ratios of CER:LACCER (hazard ratio, 0.53; 95% CI, 0.36-0.8, P = .002) and CER:SM (hazard ratio, 0.5; 95% CI, 0.33-0.76, P = .001) were independently associated with decreased hazards of CLAD. Samples with low CER:LACCER and CER:SM ratios were associated with high airway BA levels. Airway lipidomic qualitative changes show a distinct phenotype that associate with the presence and risk of development of CLAD. A high CER:LACCER and CER:SM ratio is independently associated with freedom from CLAD and associated with airway bile acid levels.