Quantitative CT Correlates with Local Inflammation in Lung of Patients with Subtypes of Chronic Lung Allograft Dysfunction.

Sundaresh Ram,Robin Vos,Alexander J Bell,Bart M Vanaudenaerde,Geert M Verleden,Susan Murray,Charles R Hatt,Stefanie Galbán,Meilan K Han,Benjamin A Hoff,Stijn E Verleden,Wassim W Labaki,Vibha N Lama,Ella A Kazerooni,Craig J Galbán

doi:10.3390/cells11040699

Abstract

Chronic rejection of lung allografts has two major subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), which present radiologically either as air trapping with small airways disease or with persistent pleuroparenchymal opacities. Parametric response mapping (PRM), a computed tomography (CT) methodology, has been demonstrated as an objective readout of BOS and RAS and bears prognostic importance, but has yet to be correlated to biological measures. Using a topological technique, we evaluate the distribution and arrangement of PRM-derived classifications of pulmonary abnormalities from lung transplant recipients undergoing redo-transplantation for end-stage BOS (N = 6) or RAS (N = 6). Topological metrics were determined from each PRM classification and compared to structural and biological markers determined from microCT and histopathology of lung core samples. Whole-lung measurements of PRM-defined functional small airways disease (fSAD), which serves as a readout of BOS, were significantly elevated in BOS versus RAS patients (p = 0.01). At the core-level, PRM-defined parenchymal disease, a potential readout of RAS, was found to correlate to neutrophil and collagen I levels (p < 0.05). We demonstrate the relationship of structural and biological markers to the CT-based distribution and arrangement of PRM-derived readouts of BOS and RAS.

Highlights

Transplanted lungs have one of the highest rejection rates among all solid organ transplantations, and approximately 50% of lung transplant recipients suffer from chronic lung allograft dysfunction (CLAD) within five years of transplantation [1,2]
We previously demonstrated using a combination of computed tomography (CT) and microCT that obstruction of pre-terminal airways is common in both bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), while in RAS there is parenchymal destruction leading to further distortion and remodeling of terminal bronchioles [7,8]
We extend topological analysis of PRM (tPRM) to analysis of CLAD, as we investigate the relationship between topological features of Parametric response mapping (PRM)-derived classifications and structural and biological markers obtained from core samples extracted from explants of lung transplant recipients diagnosed with BOS and RAS who underwent re-transplantation or autopsy

Summary

Introduction

Transplanted lungs have one of the highest rejection rates among all solid organ transplantations, and approximately 50% of lung transplant recipients suffer from chronic lung allograft dysfunction (CLAD) within five years of transplantation [1,2]. The main subtypes of CLAD are (a) bronchiolitis obliterans syndrome (BOS), which is characterized by persistent spirometric airflow obstruction and mostly air trapping on expiratory X-ray computed tomography (CT), with or without bronchiectasis, and (b) restrictive allograft syndrome (RAS), which is defined by decreased total lung capacity ≤90% of baseline and persistent radiographic opacities [3–5]. The underlying pathology of both subtypes of CLAD is irreversible fibroproliferation, either strictly airway-related in BOS, or involving both the airways and the parenchyma in RAS. In RAS, fibroproliferation leads to fibrotic remodeling of the lung, which is preceded by immune-mediated graft injury. Once persistent lung function loss occurs, prognosis is poor, with most patients demonstrating ongoing decline [6]. Prognosis is significantly better for BOS than for RAS patients (3–5 years post-diagnosis versus 6–18 months)

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