Abstract
Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.
Highlights
Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX)
Before CLAD can be diagnosed, allograft-related (e.g. persistent acute rejection, Azithromycin Responsive Allograft Dysfunction (ARAD), infection/colonization, anastomotic stricture) and extra-allograft-related confounding factors leading to non-chronic rejection with Forced Expiratory Volume in one second ( FEV1) decline have to be excluded[6]
The lowest inter-assay %Coefficients of Variability (CV) was calculated for Matrix Metalloproteinases (MMPs)-9, while the highest inter-assay %CV was measured for Tissue Inhibitors of Metalloproteinases (TIMPs)-1
Summary
Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedomfrom-CLAD in Stable-LTX patients. Abbreviations ARAD Azithromycin-responsive allograft dysfunction BAL Bronchioalveolar lavage BOS Bronchiolitis obliterans syndrome BO Bronchiolitis obliterans CLAD Chronic lung allograft dysfunction CF Cystic fibrosis ELISA Enzyme-linked immunosorbent assay FEV1 Forced expiratory volume in one second IPF Idiopathic pulmonary fibrosis LTX Lung transplantation MMP-9 Matrix metalloproteinase-9 OS Overall survival RAS Restrictive allograft syndrome TIMP-1 Tissue inhibitors of metalloproteinase-1 TLC Total lung capacity. Chronic Lung Allograft Dysfunction (CLAD) remains the main limiting factor for reduced life expectancy after LTX occurring in approximately 50% of transplant recipients within 5 years after primary L TX1,2. The etiologies of IPF, CF and CLAD significantly differ, the pathophysiology of these diseases show overlapping characteristics, including epithelial cell injury, increased production and deposition of extracellular matrix, immune cell activation, and fibroblast proliferation[10]
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