Increased Hazard of Chronic Lung Allograft Dysfunction in the Presence of Persistent and Complement Fixing Donor-Specific Antibodies

Purpose Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. Methods This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. Results 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p<0.001). This difference was maintained on multivariable analysis (HR:2.10 95%CI: 1.34-3.31) controlling for age, single vs double, and acute cellular rejection. Similar findings were observed in multivariable analyses for BOS (HR:2.02 95%CI: 1.26-3.25) and RAS (HR: 2.15 95% CI: 1.30-3.57). Conclusion Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes. Long-term survival in lung transplant recipients (LTR) is limited in large part due to chronic lung allograft dysfunction (CLAD). Donor-specific antibodies (DSA) have been previously associated with more rapid high-grade rejection and mortality. Characteristics of these DSA may predict which antibodies are more harmful than others. The purpose of this investigation was to determine if C1q+ DSA is associated with increased CLAD in LTRs versus no DSA and C1q- DSA. This was a single-center, retrospective cohort study of adult LTRs. Clinical data was extracted from the electronic medical record and laboratory systems. Patients were tested by Luminex Single Antigen Bead (SAB) IgG and C1q. IgG-SAB MFI > 1000 and C1q-SAB MFI > 500 were considered positive. DSA that were positive at more than one time point were classified as persistent, while those that were not were considered transient. Patients were grouped as no DSA, C1q- DSA, or C1q+ DSA. The primary outcome was CLAD. Secondary outcomes included CLAD subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Outcomes were assessed using Kaplan-Meier methods and multivariable Cox regression with a time-dependent covariate. 582 LTRs were analyzed. 335 (57.6%) had no DSA, 194 (33.3%) were DSA+ C1q-, and 53 (9.1%) were DSA+ C1q+. Of 247 LTRs who developed any DSA, Class II DSA (206 LTRs, 84%) were more common than Class I DSA (106, 43%), including those with both classes. 177 LTRs (72%) had persistent DSA, including all 53 with C1q+ DSA . There was no difference in time to CLAD for any DSA vs no DSA (p=0.26). Patients with persistent DSA had shorter time to CLAD vs no DSA and transient DSA (p=0.04) and trended towards significance on multivariable assessment (HR: 1.70 95%CI: 1.00-2.92, p=0.05). DSA+ Cq1+ had shorter time to CLAD vs no DSA and DSA+ C1q- (p<0.001). This difference was maintained on multivariable analysis (HR:2.10 95%CI: 1.34-3.31) controlling for age, single vs double, and acute cellular rejection. Similar findings were observed in multivariable analyses for BOS (HR:2.02 95%CI: 1.26-3.25) and RAS (HR: 2.15 95% CI: 1.30-3.57). Persistent DSA were associated with shorter time to CLAD. C1q+ DSA were associated with increased hazard of CLAD, BOS, and RAS. Larger cohorts are needed to evaluate other clinical outcomes.