Increased Eplet Mismatch Load and Reduced Immunosuppressive Exposure Elevate the Risk of Baseline Lung Allograft Dysfunction

<b>Background/Objectives:</b> Some lung transplant (LungTx) recipients do not achieve the expected lung function within the first year, a condition known as baseline lung allograft dysfunction (BLAD). Our objective was to analyze the risk factors associated with BLAD, focusing on the variables associated with a higher risk of developing a more intense alloimmune response. <b>Methods</b>: We carried out a prospective study including 88 LungTx recipients. BLAD was defined as failure to reach 80% of the predicted value for forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC) on two tests conducted at least three weeks apart. Tacrolimus time in therapeutic range (TTR) and mycophenolic acid area under the curve (MPA AUC_0-12h) were measured at the third month. Donor-recipient compatibility was assessed using HLA eplet mismatch analysis, performed via HLA Matchmaker 3.1. <b>Results</b>: BLAD patients showed greater eplet mismatch burden (67, IQR 20 vs. 55, IQR 22, <i>p</i> = 0.018) and had been exposed to a lower TTR (26.6%, IQR 14.0% vs. 39.6%, IQR 24.3%, <i>p</i> = 0.039) and less frequently to an adequate third-month MPA AUC_0-12 > 30 mg × h/L (57.1% vs. 89.2%, <i>p</i> = 0.020). DR/DQ eplet mismatches (β = -0.348, <i>p</i> = 0.002) and third-month MPA AUC_0-12 (β = 0.285, <i>p</i> = 0.009) were independently associated with six-month predicted FEV1%. <b>Conclusions</b>: Among other variables, BLAD and initial lung graft function are associated with greater eplet discordance and lower immunosuppressive drug exposure, suggesting a potential role of underlying alloimmune responses in their pathogenesis.