Assessment of DQ Risk Epitope Mismatch in Lung Transplantation as a Predictor of Chronic Lung Allograft Dysfunction

Abstract

Chronic lung allograft dysfunction (CLAD) is a major contributor to reduced survival after lung transplantation. Specific HLA-DQ risk epitope mismatches (REM) predict the development of de novo DQ donor specific antibodies (dn-DSA). We hypothesise that the presence of DQ REM would be associated with an increased risk of CLAD. A retrospective cohort analysis was conducted of all bilateral lung recipients at a single centre between Jan-2014 and Jan-2019. DQ REM was defined as donor-recipient mismatch at DQA1*05-DQB1*02 (DQ2) and/or DQA1*05-DQB1*03:01 (DQ7). De novo REM DSA (DQ2 and/or DQ7) were defined as MFI >1000 on surveillance Luminex testing. Multivariate Cox proportional hazards models were used for time-to-event analyses. Complete molecular typing was available on 241/248 (97.2%). 156 (64.7%) recipients had no DQ REM, 37 (15.4%) had a DQ7 REM, 42 (17.4%) had a DQ2 and 6 (2.5%) had both. The median follow-up time was 3.2 years. A significantly higher proportion of recipients with DQ REM developed dn-REM-DSA compared to those without, 38/86 (44.7%) vs 0/156 (0%) p<0.01. In univariate analysis, DQ REM status was not significantly associated with CLAD (HR 1.38, p=0.17) [Panel A]. In multivariate analysis, recipients with DQ REM who developed dn-REM-DSA had a significantly increased risk of CLAD (HR 2.08, p=0.02) adjusted for native lung disease. There was a significant difference in the cumulative incidence of CLAD for recipients with DQ REM who developed DSA compared with those with DQ REM who did not develop dn-REM-DSA, and those without DQ REM, p=0.02 [Panel B]. DQ REM status alone was not significantly associated with an increased risk of CLAD within the follow-up period. Patients with DQ REM who developed dn-REM-DSA, however, had a shorter time to CLAD. Avoidance of DQ REM at allocation represents a strategy to reduce dn-REM-DSA and the risk of CLAD in this subgroup. Transplantation across DQ REM still may be an acceptable risk for urgent recipients.