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Pretransplant sensitization to human leukocyte antigens (HLA) increases waiting list time and mortality in lung transplantation (LTx). Instead of awaiting crossmatch-negative donors, since 2013, our recipients with preformed anti-HLA donor-specific antibodies (pfDSA) have been managed peri-transplant with a combination of repeated IgA/IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion 2g/kg, then 0.5g/kg every 4 weeks (wk) to max. 6 months), preceded by repeated plasmapheresis (PE), and a single dose of anti-CD20 antibody (375mg/m2, Rituximab) after the first IgGAM infusion. We hypothesized that the composition of plasma cytokines/chemokines was altered in pfDSA patients due to this treatment compared to DSA-free patients without this peri-transplant immunomodulation. Plasma cytokines and chemokines of subgroups of LTx patients with pfDSA (n=8 of 65) were compared to patients without preformed or de novo DSA (n=26 of 780) before and after LTx. 50 cytokines/chemokines in recipient plasma were quantified before, directly after, 24h, 3, 6wk and 12 months after LTx in these pfDSA+/- subgroups using multiplex assays. Clinical follow-up of all LTx patients was 51 (22-80) months. Of the 1072 LTx patients, 65 (6%) patients exhibited pfDSA, primarily against HLA class II (n=42, 65%), followed by HLA class I (n=19, 29%) and both classes (n=4, 6%), while 780 (73%) did not develop pf or early DSA (control group). In pfDSA vs. control patients, prevalence of primary graft dysfunction grade 3 at 72 hours was 10.8% vs. 4.5% (p=0.036). Graft survival and freedom from chronic lung allograft dysfunction did not differ between groups (9 years, 75% vs. 66%, p=0.41; 65% vs. 65%, p=0.59). The pfDSA treatment protocol resulted in significant changes in the plasma cytokine/chemokine composition with significantly reduced concentrations of several pro-inflammatory factors such as TNF-α, IFN-a2, IL-12p70, CXCL8/9 and FGF-β continuously from pre-Tx to at least 6 months later (all p< 0.05). A treatment protocol based on IgG/AM with PE allowed transplantation of patients with preformed DSA with a 9-year graft survival similar to non-DSA-control patients. The pfDSA treatment caused consistent reduction of multiple cytokines, thereby, potentially contributing to this improved graft survival. [ABSTRACT FROM AUTHOR]

Experience with treatment of early detected donor specific anti-HLA antibodies (eDSA) after lung transplantation in children is very limited. At our institution, since 2013, we have treated patients with eDSA with successive infusions (first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks for a maximum of 6 months) of IgA and IgM-enriched human intravenous immunoglobulins G (IgGAM), combined in some cases with plasmapheresis (PE) or immunoabsorption (3 or 5 sessions) before IgGAM and a single dose of anti-CD20 antibody (Rituximab) after the first IgGAM infusion. Aim of this study was to present the 9-year results of the IgGAM-based therapy in pediatric lung recipients. Records of pediatric (<18 years old) patients transplanted at our institution between 01/2013 and 10/2022 were reviewed. Outcomes of patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA (control group) were compared using the product-limit method of Kaplan-Meier and the log-rank test. Median (IQR) follow-up amounted to 53 (26-86) months. During the study period, among the 87 lung-transplanted pediatric patients (median age, 13 years), 38 (44%) formed the IgGAM group and 47 (%) the control group. One (1%) patient treated only with PE and Rituximab and 1 (1%) patient who was not treated at all were excluded from analysis. Among the 38 IgGAM patients, 19 (50%) showed only eDSA (possible subclinical antibody-mediated rejection, AMR) and 19 (50%) patients graft dysfunction concomitant with eDSA (possible clinical AMR). Three (8%) patients showed preformed DSA. Median time to eDSA detection was 21 days after transplantation. In addition to IgGAM, 18 (47%) patients received PE and 29 (76%) patients Rituximab. As of October 2022, treatment was completed in 37 (97%) patients (one patient still under treatment). Under treatment, eDSA cleared in 35 (94.5%) patients. The same eDSA recurred in 4 (11.4%) patients at a median of 6 months after treatment end. At 8 years, graft survival (%) was 76 vs. 67 (p=0.97) and freedom (%) from chronic lung allograft rejection (CLAD) was 76 vs. 58 (p=0.31), in IgGAM vs. control patients, respectively. After pediatric lung transplantation, an IgGAM-based treatment for eDSA yielded high eDSA clearance. IgGAM patients showed 8-year CLAD-free survival at least as good as control patients without eDSA. [ABSTRACT FROM AUTHOR]

ransplantsensitization to human leukocyte antigens (HLA) increases the recipient waiting list time and mortality in lung transplantation. Instead of awaiting crossmatch-negative donors, since 2013, recipients with preformed anti-HLA donor specific antibodies (pfDSA) have been managed peri-transplant at our institution with a combination of repeated IgA- and IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks thereafter to a maximum of 6 months), preceded by repeated plasmapheresis (PE), and a single dose of anti-CD20 antibody (375mg/m2, Rituximab) after the first IgGAM infusion. This study presents preliminary 7-year results of this protocol in patients transplanted with pfDSA. Records of patients transplanted at our institution between 02/2013 and 10/2020 were reviewed. Outcomes were compared between patients with pfDSA (pfDSA group) and those without any DSA (control group). Patients without pfDSA who developed de-novo DSA only post transplantation (n=205) were excluded from the study. Median follow-up was 42 (18-65) months. he 913 transplanted patients, 41 (4%) patients exhibited pfDSA and 667 (73%) did not develop any DSA (control group). Among these 41 patients, 27 (66%) patients possessed pfDSA against class II HLA antigens, 12 (29%) patients against class I antigens, and 2 (5%) patients against both classes. Ten (24%) patients showed a positive retrospective CDC crossmatch and 15 (37%) patients developed additional de-novo DSA after transplantation. Thirty (73%) patients were treated with PE and 35 (85%) patients with Rituximab. At follow-up end, treatment was completed in 33 (80%) patients (still on treatment, n=3; in-hospital deaths, n=2; treatment interrupted earlier as intended by protocol, n=3). In these 30 patients, IgGAM treatment cleared eDSA in 18 (60%) patients, with 3 (17%) patients showing eDSA recurrence. In pfDSA vs. control patients and at 7-year follow-up, respectively, graft survival (%) was 83 vs. 73 (p=0.61) and freedom from chronic lung allograft dysfunction (%, CLAD) was 85 vs. 65 (p=0.44). In lung transplantation, a treatment protocol based on IgGAM allowed transplanting patients with preformed DSA with good 7-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]

Pretransplant sensitization to human leukocyte antigens (HLA) increases the recipient waiting list time and mortality in lung transplantation. Instead of awaiting crossmatch-negative donors, since 2013, recipients with preformed anti-HLA donor specific antibodies (pfDSA) have been managed peri-transplant at our institution with repeated IgA- and IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks thereafter to a maximum of 6 months), usually in combination with plasmapheresis (PE) before IgGAM and a single dose of anti-CD20 antibody (375mg/m2, Rituximab) after the first IgGAM infusion. This study presents the 8-year results of this protocol in patients transplanted with pfDSA. Records of patients transplanted at our institution between 02/2013 and 10/2021 were reviewed. Outcomes were compared between patients with pfDSA (pfDSA group) and those without any early DSA (control group). Patients without pfDSA who developed DSA only post transplantation (n=219) were excluded from the analysis. Median follow-up was 47 (21-73) months. Of the 994 transplanted patients, 55 (5%) patients exhibited pfDSA and 721 (73%) did not develop any early DSA. Among these 55 patients, 40 (73%) patients possessed pfDSA against class II HLA antigens and 17 (31%) patients against class I antigens (2 patients against both classes). Twelve (22%) patients showed a positive retrospective CDC crossmatch and 21 (38%) patients developed additional de-novo DSA after transplantation. Forty-four (80%) patients were treated with PE and 45 (82%) patients with Rituximab. At follow-up end, treatment was completed in 45 (82%) patients (still on treatment, n=4; in-hospital deaths, n=2; treatment interrupted earlier as intended by protocol, n=4). In these 45 patients, IgGAM treatment cleared DSA in 33 (73%) patients, with 4 (12%) patients showing the same DSA recurrence. In pfDSA vs. control patients and at 5-year follow-up, respectively, graft survival (%) was 83 vs. 76 (p=0.40) and freedom from chronic lung allograft dysfunction (%) 72 vs. 72 (p=0.62). In lung transplantation, a treatment protocol based on IgGAM allowed transplanting patients with preformed DSA with good 5-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]