Prediction of Survival after Chronic Lung Allograft Dysfunction in Lung Transplant Recipients by Blood Profiling Using a Predefined 52 Gene Signature

Purpose
Long term survival after lung transplantation (LTx) is still determined by the occurrence of chronic lung allograft dysfunction (CLAD). Early identification of high risk patients for CLAD is a large clinial unmet need. Previously, we used genome scale transcript profiling of peripheral blood mononuclear cells (PBMCs) and identified an outcome predictive 52-gene signature using a high risk and low risk score in idiopathic pulmonary fibrosis (IPF) patients. The aim of this study was to investigate whether this 52-gene signature may also be predictive for survival in CLAD, given the shared common fibrotic mechanisms between CLAD and IPF.

Methods
We collected blood from LTx recipients post-transplantation prior to diagnosis of CLAD and from a matched non-CLAD control group. RNA was isolated from PBMCs and we measured the 52-gene signature using Nanostring Ncounter. Risk Score was calculated using significance analysis microarrays (SAMs). Primary outcome was survival, expressed by time to death after transplantation in patients with a diagnosis of CLAD using Kaplan-Meier analyses. Secondary analysis was time to onset of CLAD in both groups.

Results
CLAD was diagnosed in 37 (33%) out of 112 LTx recipients (53 Male/59 Female). Thirty-five CLAD patients could be used for analyses. Four patients had a high risk and 31 patients a low risk 52-gene signature. A significant difference in overall survival was found between those two patient groups (time to death: 3.21 vs 6.84yrs; overall: p=0.04). Time to onset of CLAD was significantly different for the high risk group (time to CLAD 1.37 vs.4.30 yrs; p<0.0001) compared to the low risk group. The groups were not different in terms of sexe, prior diagnosis, or age. Interestingly, patients with gradual onset CLAD were characterized by significant upregulation of Haptoglobin and S100 Calcium Binding Protein A12 mRNA.

Conclusion
High risk gene profile of a predefined 52-gene signature showed a decreased survival after diagnosis of CLAD and earlier CLAD onset. Further analysis is needed to evaluate whether this 52-gene signature can predict survival after CLAD in a larger cohort and which specific genes are up- or downregulated in rapid or gradual onset CLAD.