Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature. Issue 1 (22nd September 2020)

• Record Type: Journal Article
• Authors: Dugger, Daniel T.; Fung, Monica; Hays, Steven R.; Singer, Jonathan P.; Kleinhenz, Mary E.; Leard, Lorriana E.; Golden, Jeffrey A.; Shah, Rupal J.; Lee, Joyce S.; Deiter, Fred; Greenland, Nancy Y.; Jones, Kirk D.; Langelier, Chaz R.; Greenland, John R.
• Is Part Of: American journal of transplantation. Volume 21:Issue 1(2021)
• Page Start: 362
• Page End: 371
• Publication Date: 2020-09-22
• Subjects: lung (allograft) function/dysfunction -- lung transplantation/pulmonology -- microbiomics -- monitoring: immune -- rejection: chronic -- translational research/science; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.16293
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : Chronic lung allograft dysfunction (CLAD) is the major barrier to long‐term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine‐learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes ( p = .002) and improved prediction of graft failure ( p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha‐diversity ( p ≤ .04), neither infection nor alpha‐diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts. Abstract : RNA sequencing of small airway cytology brushings may facilitate the diagnosis of chronic lung allograft dysfunction or airway infection and provide pathogenesis insights.