Chronic lung allograft dysfunction phenotypes and treatment

Abstract

Chronic lung allograft dysfunction (CLAD) remains a major hurdle limiting long-term survival post lung transplantation. Given the clinical heterogeneity of CLAD, recently two phenotypes of CLAD have been defined [bronchiolitis obliterans syndrome (BOS) vs. restrictive allograft syndrome (RAS) or restrictive CLAD (rCLAD)]. BOS is characterized by an obstructive pulmonary function, air trapping on CT and obliterative bronchiolitis (OB) on histopathology, while RAS/rCLAD patients show a restrictive pulmonary function, persistent pleuro-parenchymal infiltrates on CT and pleuroparenchymal fibro-elastosis on biopsies. Importantly, the patients with RAS/rCLAD have a severely limited survival post diagnosis of 6-18 months compared to 3-5 years after BOS diagnosis. In this review, we will review historical evidence for this heterogeneity and we will highlight the clinical, radiological, histopathological characteristics of both phenotypes, as well as their risk factors. Treatment of CLAD remains troublesome, nevertheless, we will give an overview of different treatment strategies that have been tried with some success. Adequate phenotyping remains difficult but is clearly needed for both clinical and scientific purposes.

Keywords: Lung transplantation; bronchiolitis obliterans syndrome (BOS); chronic lung allograft dysfunction (CLAD); chronic rejection; restrictive allograft syndrome (RAS).

Figure 1

A patient underwent heart lung transplantation for Eisenmenger’s syndrome with an initial uneventful follow-up post discharge who developed BOS. 5 years post-transplantation (pulmonary function evolution in A), but without decrease in TLC (B). However 10 years post-transplantation there was a sudden TLC drop (red line indicates 10% decrease) and therefore diagnosis was changed to rCLAD/RAS. CT evolution is shown in panel 1C-D-E-F. Initially, the patient had a normal CT (C), which remained unchanged after BOS diagnosis (D). However, when the decrease in TLC was found, persistent apical infiltrates were seen on CT (E), which deteriorated at the last CT before successful redo transplantation (F). The histological analysis of this explant lung confirmed rCLAD diagnosis as a pattern of pleuroparenchymal fibro-elastosis and OB was observed.

Figure 2

Comparison between BOS and rCLAD. Gross image of a BOS lung (A), with the CT showing typical hyperinflation (B), while the explant lung specimen shows obliterative bronchiolitis (arrow) (C). Gross lung image of RAS/rCLAD lung (D), with the CT showing ground glass and reticulation (E) and the pathology showing newly formed fibrosis (arrows). H&E stainings are used in C and F.