Search

Although use of extended-criteria donor organs (ECD) has increased in lung transplantation, their impact on outcomes remains unclear. The Eurotransplant (ET) lung donor score (ELDS) was designed to classify lung donor quality, taking into account donor history, tobacco exposure, age, arterial blood gases, chest x-ray and bronchoscopic findings. This retrospective single-center study evaluates the impact of ECD on graft function and survival. Records of lung allograft recipients transplanted at our institution between 01/2010 and 07/2022 were reviewed. Individual ELDS were calculated from the corresponding ET donor reports. Outcomes were compared between recipients of ideal donors (ELDS 6, Group 1), of intermediate-risk donors (ELDS 7-8, Group 2), and of extended-criteria donors (ELDS 9-15, Group 3). Median (IQR) follow-up was 56 (25-94) months. In total, 273 (19%) out of 1,428 lung-transplanted patients received Group 1 donor organs, 708 (50%) patients Group 2 donor organs, and 447 (31%) patients Group 3 donor organs. Group 2 and 3 recipients were older than group 1 recipients (median age, 53 and 54 vs. 44 years, p<0.001). The need for intraoperative ECMO support (29% vs. 30% vs. 29%, p=0.94), occurrence of primary graft dysfunction grade 3 at 72 hours after transplantation (4.8% vs. 4.7% vs. 6.3%, p=0.47), duration of mechanical ventilation (median 13 vs. 14 vs. 13 hours, p=0.12), and in-hospital mortality (4.4% vs. 4.8% vs. 4.0%, p=0.82) did not differ between Groups 1, 2 and 3, respectively. At 1-year follow-up, no difference in median forced expiratory volume in one second (% predicted) existed between groups 1, 2 and 3 (90 vs. 86 vs. 84, p=0.15), respectively. At 5 and 9 years, graft survival (%) did not differ significantly between groups 1, 2 and 3 (5-year: 74 vs. 69 vs. 71; 9-year: 65 vs. 57 vs. 53, p=0.065), respectively. Freedom from CLAD did not differ between groups 1, 2 and 3 (5-year: 73 vs. 71 vs. 65; 9-year: 63 vs. 58 vs. 54, p=0.077), respectively. At the Cox´s analysis, donor smoking history was associated with worse survival (HR=1.373; 95%CI 1.134-1.662, p=0.001) and with CLAD (HR=1.500; 95%CI 1.225-1.836, p<0.001). ECD lungs constituted one third of our donor pool and their use did not negatively impact the recipient survival and CLAD-free survival. [ABSTRACT FROM AUTHOR]

Patients with end-stage lung diseases on the MHH waiting list for lung transplantation (LTx) have been vaccinated against the SARS-CoV-2 spike protein with usually three doses of the mRNA vaccine. Hence, they are supposed to develop robust antibody and T cell responses when immunized prior to LTx without the influence of immunosuppression. Therefore, we hypothesized the induction of high spike-specific IgG levels and protection against SARS-CoV-2 infection and severe COVID-19. To proof this, we aimed to analyze the IgG levels specific for the spike S1-, RBD- and S2-domains in patients on a waiting list (WL-LTx) longitudinally before and after their transplantation. Plasma obtained pre (n=70) and post LTx (n=28) of WL-LTx patients was analyzed for spike-specific IgG by Luminex-based multiplex assays. The threshold for positivity was set separately for each spike domain based on the median MFI +2σ in a healthy, unexposed pre-pandemic control group. Patients with previous SARS-CoV-2-infection were excluded. 95.7% of WL-LTx patients had seroconverted for either RBD-, S1- or S2-specific IgG pre LTx and still 92.86% were positive post LTx. Overall, S1-, S2- and RBD-specific IgG MFI values did not significantly differ between pre vs. post LTx. A subanalysis of matched plasma samples (n=25) revealed that 52% of the WL-LTx patients showed a higher IgG response pre than post LTx for all three spike protein domains and 28% showed even elevated antibody levels post LTx. Interestingly, S2-specific IgG MFI values were significantly elevated compared to RBD-specific IgG MFI values, both pre (S2 vs. RBD p<0.0001) and post LTx (S2 vs. RBD p=0.0225). The majority of WL-LTx patients mounted high SARS-CoV-2 spike-specific IgG responses following vaccination pre LTx. Based on the more efficient antibody production against the S2-domain compared to RBD- and S1-domains, S2-specific IgG responses should be included also in the general evaluation of humoral immune responses to SARS-CoV-2. As expected, WL-LTx patients showed a superior antibody response to vaccination compared to LTx-recipients vaccinated only after LTx, which could even be maintained after LTx in some patients. Therefore, both patients on waiting list and LTx recipients may benefit from additional booster vaccinations after LTx. [ABSTRACT FROM AUTHOR]

There is less known about short- and long-term outcomes when sex-mismatched lung allografts are transplanted. Here, we performed a retrospective analysis comparing sex-mismatched with sex-matched patients. Records of patients were reviewed at our institution between May 2011 and September 2022. Four groups were formed: Female to female (F=>F group), male to female (M=>F group), female to male (F=>M group) and male to male (M=>M group) transplanted patients. Categorical variables were analyzed using Chi-square test. Graft survival and freedom from chronic lung allograft dysfunction (CLAD) were compared using Kaplan-Meyer analysis with the log-rank test. During the study period, 1415 patients were transplanted at our institution. 528 patients, 141 patients, 193 patients and 553 patients were in the F=>F group, M=>F group, F=>M group and M=>M group, respectively. There was no statistically significant difference regarding the incidence of primary graft dysfunction (PGD) grade 3 within the first 72 hours after transplant in the different groups (6% vs. 7% vs. 4% vs. 4%; p=0.184). Furthermore, the groups showed no differences in 1-, 6- and 12-year survival (89% vs. 89% vs. 94% vs. 92%; 67% vs. 70% vs. 70% vs. 70%; 51% vs. 55% vs. 57% vs. 46; p=0.67) as well as incidence of CLAD (97% vs. 98% vs. 99% vs. 95%; 66%; vs. 67% vs. 66% vs. 66%; 57% vs. 51% vs. 62% vs. 52%; p=0.565). Donor-recipient sex mismatch does not affect mortality and incidences of PGD grade 3 and CLAD after lung transplantation. [ABSTRACT FROM AUTHOR]

The development of anti-HLA donor specific antibodies detected early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. At our institution, since 2013, successive infusions of IgA- and IgM-enriched human intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) formed the backbone of eDSA therapy. Actually, patients with only evidence of eDSA (possible subclinical AMR) are treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or preformed DSA (positive virtual crossmatch) receive additionally plasmapheresis (PE) or immunoabsorption before the first IgGAM dose, and a single dose of anti-CD20 antibody (Rituximab) thereafter. Aims of this study were to present the 9-year results of the IgGAM-based therapy. Records of patients transplanted between 02/2013 and 10/2022 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA (control group). Median (IQR) follow-up was 51 (23-79) months. During the study period, among the 1,078 transplanted patients, 270 (25%) patients formed the IgGAM group and 785 (73%) the control group. The remaining 23 (2%) patients (14 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Sixty-five IgGAM patients (24%) showed pre-formed eDSA and 43 (16%) patients showed possible clinical AMR. Median time to eDSA detection was 14 days. At follow-up end, treatment was completed in 246 (91%) patients (still on treatment, n=9; in-hospital deaths, n=4; treatment interrupted earlier as intended by protocol, n=11). In these patients, IgGAM treatment cleared eDSA in 220 (89%) patients, 38 (17%) patients showing eDSA recurrence a median of 15 months after treatment end. In IgGAM vs. control patients and at 5- and 9-year follow-up, respectively, graft survival (%) was 77 vs. 76 and 60 vs. 64 (p=0.83), and freedom from CLAD was 76 vs. 74 and 65 vs. 66 (p=0.74), respectively. After lung transplantation, an IgGAM-based treatment protocol for eDSA yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 9-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]

At our institution, patients with severe pulmonary arterial hypertension (sPAH) undergo lung transplantation using a protocol based on postoperative extension of intraoperatively initiated veno-arterial extracorporeal membrane oxygenation (vaECMO) support. Here we present our 12-year experience with this protocol. Records of patients transplanted at our institution between May 2010 and September 2022 were retrospectively reviewed. Outcomes were compared between sPAH patients and patients transplanted for all the other indications. Prevalence of primary graft dysfunction (PGD) grade 3 and intensive care unit (ICU) stay time were compared using Chi-squared test and Mann-Whitney-U test, respectively. Graft survival and freedom from chronic lung allograft dysfunction (CLAD) were compared using Kaplan-Meyer analysis with the log-rank test and were further analysed by propensity score analysis. Among the 1419 lung transplanted patients, 90 (6.3%) were transplanted for sPAH and 1329 (93.6%) for other indications. Patients with sPAH were younger (33 vs. 53 years, p<0.0001) and prevalence of PGD grade 3 was higher at 24h (21% vs. 5%; p<0.0001), 48h (22% vs 5%; p<0.0001) and 72h (22 vs. 4%; p<0.0001) in comparison to control patients. Median postoperative ICU stay time was longer in sPAH patients (13 vs. 2 days; p<0.0001). 1-, 6- and 12-year survival (86.5% vs. 90.8%, 61.2% vs. 67.9%, 52% vs. 48.1% p=0.347), freedom from CLAD during follow up (96.8% vs. 96.6%, 65.8% vs. 66.1%, 57.3% vs. 54.9% p=0.955) and survival conditioned to hospital discharge (94.9% vs. 95.1%, 73% vs. 73.3%, 65.5% vs. 53% p=0.556) did not differ in sPAH vs. control patients. According to propensity score analysis, sPAH did not appear be associated with increased mortality, CLAD or mortality conditioned to hospital discharge. A protocol based on postoperatively extended intraoperative vaECMO support allows safe transplantation of patients with sPAH. Despite increased morbidity in the early postoperative period, long-term survival and freedom from CLAD were not reduced and negatively affected by sPAH. [ABSTRACT FROM AUTHOR]

Combined lung and liver transplantation is an uncommon procedure and poses several management challenges. At our institution, since 2005, we have been performing liver transplantation before lung transplantation (liver first strategy), because this strategy might improve the liver coagulopathy thus reducing the risk of bleeding, and spare the successively transplanted lung allograft from the liver reperfusion fluid. Aim of this study was to present our 15-year experience with the liver first strategy for combined lung-liver transplantation. Records of lung-transplanted patients between 01/2005 and 10/2021 at our institution were retrospectively reviewed. Outcomes were compared between patients undergoing combined lung-liver vs. patients undergoing lung-only transplantation. Median (IQR) follow-up was 53 (22-93) months. During the study period, among the 1822 lung-transplanted patients, 17 (0.9%) patients required combined lung-liver transplantation (male sex, n=15; median age, 30 years; lung transplant indication: cystic fibrosis, n=15; lung fibrosis, n=1; porto-pulmonary hypertension, n=1), the remaining 1805 (99.1%) patients undergoing lung-only transplantation. While median lung cold ischemic time (min.) was longer (first lung, 610 vs. 401, p<0.01; second lung, 692 vs. 510, p<0.01) and the intraoperative need for packed red blood cells greater (10 vs. 2 units, p<0.01) in the combined group, only one patient in this group showed primary graft dysfunction (PGD) grade 3 at 72 hours after transplantation (5.9% vs. 5.4%, p=0.61). Prevalence of rethoracotomy for bleeding (18% vs. 10%, p=0.41), temporary dialysis (24% vs. 11%, p=0.12), anti-HLA donor-specific antibodies (DSA, 12% vs. 19%, p=0.35), and in-hospital mortality (12% vs. 7%, p=0.32) did not differ in the lung-liver vs. lung-only transplantation group. Median and hospital stay time (33 vs. 23 days, p<0.01) was longer in the lung-liver group. At-5 years, lung graft survival (62% vs. 66%) and freedom from chronic lung allograft dysfunction (62% vs. 63%) did not differ between the lung-liver vs. lung-only groups (p=0.74 and p=0.71, respectively). Notwithstanding the longer ischemic times and the complexity of the procedure, the liverfirst strategy for combined lung-liver transplantation did not impair lung graft survival and function. [ABSTRACT FROM AUTHOR]

Donor shortage have led transplant centers in the past to extend acceptable criteria for lung donors, accepting older and more marginal donor organs for transplantation. Accepting donors ≥70 years of age as lung donors has shown good short-term outcomes in the past, however, no mid- and long-term outcome data on these extended criteria donors exists thus far. All patients undergoing lung transplantation between 06/2010 and 12/2019 at our institution were included into the analysis, that compared outcomes between patients transplanted with donors <70 years of age vs. patients transplanted with donors ≥70 years old. Outcome parameters included pre-, peri- and postoperative clinical parameters as well as recipient overall survival and CLAD-free survival. Median follow-up was 8.9 years. Between 06/2010 and 12/2019, among the 1168 lung-transplanted patients, 62 (5.3%) patients received lungs from donors ≥70 years old. Recipient age of the patients receiving older organs was significantly higher as compared to recipients of <70 years old lungs (56.2±7.8 vs. 48.7±38.9 yrs; p<0.0001) and more patients with an obstructive disease pattern prior to transplantation received a donor lung ≥70 years old (40.3% vs. 27.6%; p=0.04). Mean donor age was 73.4±2.9 years in the ≥70 years old group as compared to 44.3±15.8 yrs in the other cohort (p<0.0001). Older donors were significantly shorter on mechanical ventilation prior to donation (4.0±3.6 vs 5.7±5.1 days; p=0.0007), had a higher median Horowitz index (412.5 (356;469) vs. 384 (316; 448); p=0.01) and fewer history of smoking (12.9% vs. 42.1%; p<0.0001).Primary graft dysfunction scores at 24 (p=0.99), 48 (p=0.60) and 72 (p=0.94) hours after transplant showed no significant difference between both groups. Similarly, time on mechanical ventilation (p=0.68), time on ICU (p=0.65) as well as total hospital stay (p=0.58) were comparable in both groups. One-, five- and 7-year survival in both groups showed no significant difference (1yr: 95.1 vs. 90.2%, 5yr: 77.8 vs. 73.2%, 7yr: 69.1 vs. 68.1%, p=0.71). CLAD-free survival showed no difference between both groups in the follow-up period (p=0.76). Utilization of donor lungs ≥70 years of age leads to excellent mid- and long-term results that are similar to younger donor organs when carefully preselecting these older donor organs. [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]

The development of anti-HLA donor specific antibodies (DSA) after lung transplantation has been associated poor graft survival. DSA may develop early after lung transplantation or later, usually when chronic lung allograft dysfunction (CLAD) ensues. Early DSA have recently been considered a product of a memory rather than a de-novo reaction after alloantigen exposure. Aim of this study was to analyse the risk factors for the development of early DSA after lung transplantation. Records of patients transplanted at our institution between 01/2013 and 10/2021 were retrospectively reviewed. Patients were controlled for eDSA every two weeks after transplantation until hospital discharge, using the Luminex single-antigen test (mean fluorescence index threshold, 1000). Multivariable binary logistic regression analysis, including variables with univariable p-value <0.10, was performed to identify factors associated with eDSA. Goodness-of-fit of the model was tested using the Hoshmer and Lemeshow (H-L) test. During the study period, among the 1007 lung-transplanted patients, 275 (27%) patients showed early detectable DSA (preformed, n=56; de-novo, n=254; class I, n=71; class II, n=239). Median (IQR) time to DSA detection was 14 (11-21) days. The binary logistic regression analysis showed that pediatric (<18 years old) transplantation (OR: 2.2, 95%CI: 1.8-2.8, p=0.001), presence of pretransplant HLA antibodies (OR: 2.1, 95%CI: 1.6-2.8, p<0.01), donor lung preservation with Organ Care System (OR: 0.37, 95%CI: 0.14-0.97, p=0.04), and primary graft dysfunction (PGD) score grade 2-3 at 72 hours after transplantation (OR: 1.8, 95%CI: 1.2-1.8, p=0.007) were associated with eDSA detection (H-L statistic, p=0.92). The graft damage and donor antigen exposure provoked by primary graft dysfunction may lead to eDSA production, that should not be considered only a product of a memory but also of a de-novo reaction (Figure 1). [ABSTRACT FROM AUTHOR]

The development of anti-HLA donor specific antibodies early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. At our institution, since 2013, successive infusions of IgA- and IgM-enriched human intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) formed the backbone of eDSA therapy. Actually, patients with only evidence of eDSA (possible subclinical AMR) are treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or preformed DSA (positive virtual crossmatch) receive additionally plasmapheresis (PE) or immunoabsorption before the first IgGAM dose, and a single dose of anti-CD20 antibody (Rituximab) thereafter. Aims of this study were to present the 8-year results of the IgGAM-based therapy. Records of patients transplanted between 02/2013 and 10/2021 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA (control group). Median (IQR) follow-up was 45 (21-72) months. During the study period, among the 994 transplanted patients, 250 (25%) patients formed the IgGAM group and 721 (73%) the control group. The remaining 23 (2%) patients (14 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Fifty-Five IgGAM patients (22%) showed pre-formed eDSA and 41 (16%) patients showed possible clinical AMR. Median time to eDSA detection was 14 days after transplantation. At follow-up end, treatment was completed in 229 (92%) patients (still on treatment, n=8; in-hospital deaths, n=4; treatment interrupted earlier as intended by protocol, n=9). In these patients, IgGAM treatment cleared eDSA in 208 (91%) patients, 29 (14%) patients showing eDSA recurrence a median of 12 months after treatment end. In IgGAM vs. control patients and at 5- and 8-year follow-up, respectively, graft survival (%) was 77 vs. 76 and 68 vs. 67 (p=0.53), and freedom from CLAD was 73 vs. 72 and 65 vs. 62 (p=0.76), respectively. After lung transplantation, a treatment protocol for eDSA based on IgGAM yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 8-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]

Use of extracorporeal photopheresis (ECP) in chronic lung allograft dysfunction (CLAD) extends over 25 years. Various single centre reports suggest some benefit, but unequivocal data is lacking. Methodology and changes in CLAD definitions have hindered comparisons, and uncertainty remains about ECP efficacy in current CLAD phenotypes. This study summaries our experience of ECP in CLAD, assessing outcomes and determining treatment duration. A retrospective review of all patients receiving ECP for CLAD was performed. Data from legacy patients was reanalysed according to current definitions. Patients were treated with 2-cycles fortnightly, or occasionally 1-cycle weekly for 6 months depending on resources. Primary outcomes were nature of ECP response: stabilized, partial response or non-response and graft survival. Secondary endpoints include time to ECP response and the effect of CLAD phenotype shift during ECP, particularly regarding timing and development of restrictive spirometry. In total 369 patients commenced ECP for CLAD. Median follow-up was 27 [IQR 8.6-70.6] months. Graft stabilization was achieved in 140/369 (38%) patients. A further 85/369 (23%) of patients exhibited slowing in FEV 1 decline but failed to stabilize during the study. The remaining 144/369 (39%) demonstrated no appreciable response to ECP. Graft survival in the latter group was poorest, with 3-year survival of 18%. Among transient responders 3-year survival was surprisingly good at almost 75%, with almost all stabilized patients surviving 3 years. Patients commenced on ECP for restrictive allograft syndrome (RAS) did poorly. Bronchiolitis obliterans patients who subsequently developed restrictive features, subsequently developed ECP responses similar to RAS. A reliable prediction of lack of ECP response was evident after 106 [71 - 181] days. ECP appears to offer a survival benefit in some CLAD patients. A sizeable minority of patients stabilized and this conferred the best prognosis. Any demonstrable effect on dFEV1 within 6 months of initiation may support ECP continuation. Should no change in dFEV1 occur in this period, treatment withdrawal should be considered. Restrictive phenotypes, developing either prior to or during ECP treatment confer a very poor prognosis. [ABSTRACT FROM AUTHOR]

Solid organ transplant recipients are lacking an adequate immune response to SARS-CoV-2 vaccination. Therefore, these patients are still at risk and potentially in need of booster vaccinations. Furthermore, it is important to differentiate between the recipients of distinct organs. The efficacy of SARS-CoV-2 vaccination is usually examined via antibodies specific for the spike protein with assays containing the S1 and receptor-binding-domains (RBD) and rather rarely the S2 domain. To gain information about the humoral response in Tx recipients, it is feasible to compare the immunogenicity of these three domains. To address this, we compared the IgG antibody levels specific for the three spike protein domains in heart (HTx) vs lung (LTx) transplant recipients. Blood plasma 4-6 weeks after the second dose of SARS-CoV-2 vaccination (85% mRNA) of n=100 LTx and n=40 HTx patients was analysed for S1, S2 and RBD-specific IgG antibodies by Luminex-based multiplex assays. The threshold for positive antibody responses was set separately for each spike domain based on the median MFI + 2σ in an unexposed pre-pandemic control group. For all three spike protein domains, HTx patients showed a significantly higher rate of positive IgG responses than the LTx patients (73% vs 43%). The comparison of MFI values for S1-, S2- and RBD-specific IgG further underlines the superior antibody response by HTx patients with higher MFI values for S1 (p = 0.0001, S2 p = 0.008, RBD p < 0.0001). In the LTx cohort, MFI values for S2- (p < 0.0001) as well as for RBD-specific IgG (p < 0.0001) were higher than for S1. The same applies for S2 vs S1 (p < 0.0001) and RBD vs S1 (p = 0.0018) in the HTx cohort. Comparing the MFI of S2 vs RBD, the levels of domain-specific IgG were higher for S2 than RBD in both LTx (p < 0.0001) and HTx patients (p = 0.0914). HTx patients exhibit a moderately good IgG response to vaccination while LTx recipients show lower antibody responses. Based on the more efficient antibody production against S2 as opposed to the RBD and especially S1-domain, the S2-specific IgG response should be taken into consideration when evaluating the general immune response and the resulting protection after SARS-CoV-2 vaccination in transplant recipients. Both groups of patients might benefit from booster vaccinations. [ABSTRACT FROM AUTHOR]

Purpose α1-antitrypsin (AAT) is an acute phase protein, major inhibitor of neutrophil proteases and considered as a regulatory protein of broad immune and inflammatory responses. Inherited AAT deficiency predisposes to an early-onset pulmonary emphysema and pneumothorax, and is a common indication for lung transplantation. Both preclinical and clinical experience show that therapy with plasma purified AAT is beneficial for emphysema patients with AAT deficiency but also useful for a broad spectrum of inflammatory and immune-mediated diseases. The effects of AAT therapy during lung transplantation in vivo have only recently been addressed. Methods We used a murine MHC mismatched orthotopic single lung transplantation model (Balb/c, H2d, donors and C57/BL6, H2b, recipients). AAT was once injected at 5 mg subcutaneously to the recipients prior to transplantation. Immediately after single lung transplantations, AAT (5 mg) was injected again intraperitoneally. No immune suppressive drugs were administered. Three days after transplantation, the mice were sacrificed and samples collected for histologic assessment. Results Histological analysis according to ISHLT consensus criteria revealed that the control group showed more severe acute lung rejections (A: 2.8±0.44, n=4) as compared to the AAT treated group (A: 1.4±0.55, n=5, p<0.01). There was no significant difference in neutrophil counts between groups (control vs. AAT group: 490.8±196.7 vs. 320.3±198.9, p=0.19) and in serum CXCL1 levels (78.2±72.6 vs. 69.4±37.6, respectively, p=0.41). However, serum elastase activity in controls was higher compared to AAT treated mice (27.3±2.0% vs. 22.3±2.3%, p<0.01). As expected, serum AAT levels were remarkably higher in the AAT group than in controls, even 3 days after the administration of AAT. Conclusion Therapy with AAT suppresses acute rejection after lung transplantation. The beneficial effects might be mediated via anti-protease activity and immunomodulatory properties of the AAT protein. Further studies are warranted to assess longer term effects. [ABSTRACT FROM AUTHOR]

Purpose An important cause of early morbidity and mortality after lung transplantation is primary graft dysfunction (PGD). Natural killer (NK) cells are important components of the innate immunity and activated B cells could regulate the activity of innate cells. The involvement of B and NK cells in the immune reaction after lung transplantation remains incompletely understood. Neither the involvement of the innate immune reaction to the development of PGD after lung transplantation has not yet been thoroughly investigated. In this study, we aimed to investigate the correlation between early peripheral B and NK cell frequencies and the development of CLAD and PGD 24h. Methods We performed a retrospective study in 178 lung transplant recipients. The frequencies of circulating peripheral cell subsets were detected by flow cytometry at 3 weeks after transplantation. We analyzed B cells by CD19, CD27, IgM and IgG expressions, as well as the main NK cell subsets, CD56dimCD16+ vs. CD56bright CD16-. And correlated all measured cell types with CLAD development and PGD 24h. Results The cohort was divided into two groups based on CLAD development at 2 years after lung transplant and without CLAD development. Three weeks after lung transplantation, the B cell population in the CLAD-group was significantly more frequent (8.06±5.8% vs. 4.05±4.6; p=0.0009) compared to the non-CLAD-group. The patients in the non-CLAD group showed 3 weeks after lung transplantation higher proportions of CD56+CD16+ NK cells (73.09±20.4% vs. 63.78±22.3) compared to the CLAD group. In PGD24h, the B cell populations were similar (3.62±3.9% vs. 4.34±4.7). The patients in the PGD2/3 at 24h group showed 3 weeks after lung transplantation significantly higher proportions of CD56+CD16+ NK cells (5.33±4.6% vs. 3.19±2.4) compared to the PGD0/1 at 24h group. Conclusion At three weeks after lung transplantation, non-CLAD patients showed increased frequencies of CD56dimCD16+ NK cells and decreased frequencies of CD19+ B cells, indicating that a stable NK cell composition may contribute to protection from CLAD while upregulation of B cells could be an initiator of CLAD development. But it seems like that primary graft dysfunction is correlated with the activation of innate immunity, specifically CD56bright CD16- NK cells in the periphery. [ABSTRACT FROM AUTHOR]

Purpose Regulatory T cells (Treg) may counteract chronic lung allograft dysfunction (CLAD). In the present study, we analyzed Treg in peripheral blood at 3 weeks and at 3, 6, 12 and 24 months after lung transplantation and correlated the percentages of 3 Treg subpopulations at 3 weeks with the later incidence of CLAD and graft survival. Methods Among lung-transplanted patients between January 2009 and October 2018, only adult patients with Treg measurements after transplantation were included into the study. Tregs were detected in peripheral blood and defined as CD4+CD25highT cells and further analyzed for CD127lowand FoxP3+ using FACS analysis. CD4+CD25highIL2+ T cells were also evaluated. Associations of Treg with CLAD and graft survival, defined as patient survival and freedom from re-transplantation, were evaluated using Cox analysis. Results Among the 1,089 lung-transplanted adult patients at our institution, 830 (76%) patients had Treg measurements after transplantation. Frequencies (%) of CD127low and IL2+ but not of FoxP3+ cells were significantly higher in patients without CLAD than in patients with CLAD at each time point after transplantation (Figure 1). Similar results were found for graft survival. Treg frequencies were higher in patients treated with tacrolimus vs. cyclosporine. Follow-up was 42±29 months. Freedom (%) from CLAD was 66 at 5 years. At the Cox analysis, increasing frequencies of CD127low (HR=0.988, p<0.001) and of IL2+ Tregs (HR=0.989, p=0.016) but not of FoxP3+ (HR=0.991, p=0.11) were protective against CLAD. Graft survival (%) amounted to 68 at 5 years. Only increasing frequencies of CD127low Tregs (HR=0.992, p=0.032) were protective against mortality or retransplantation. Conclusion A higher frequency of CD127low Tregs early after lung transplantation is protective against CLAD and associated with better survival. The role of CD4+CD25highIL2+ T cells and the effect of tacrolimus on Treg deserve further investigation. [ABSTRACT FROM AUTHOR]

Purpose V-a extracorporeal membrane oxygenation (ECMO) has been successfully used for intraoperative cardiopulmonary support in patients undergoing lung transplantation. Especially patients with lung fibrosis are at risk to require intraoperative v-a ECMO. Aim of this study was to identify predisposing risk factors for intraoperative ECMO support and postoperative outcomes in this cohort of patients. Methods Patients transplanted for lung fibrosis between January 2010 and May 2018 were included into the study. Patients transplanted on v-a ECMO formed group A, the remaining, group B. Follow-up amounted to a mean of 37±27 months. Multivariate forward and backward logistic regression analysis was used to identify risk factors for ECMO. Results Among the 1042 lung-transplanted patients, 313 (30%) patients underwent bilateral transplantation for lung fibrosis. Five patients were excluded as they received conventional cardiopulmonary support due to different resaons. Among the remaining 308 patients, 109 (35%) patients formed group A, 199 (65%), group B. Presence of pulmonary hypertension (OR 3.1; 95%CI 1.8-5.3, p<0.01) and a dilated and hypertrophied right ventricle (OR 2.6 95%CI 1.4-4.9, p<0.01) were identified as risk factors for ECMO support. A PVR value exceeding 575 dynes-sec-cm−5 predicted the need of ECMO with a sensitivity of 76%. Decreased cardiac index is a risk factor for ECMO support, but did not reach significance in our study (OR 0.7; 95%CI 0.47-1.03, p=0.06). Higher recipient body surface area (BSA, OR 0.3; 95%CI 0.1-0.7, p=0.01) was a protective factor against intraoperative ECMO (H-L statistic, p=0.91). Postoperatively, more group A than B patients showed primary graft dysfunction grade 2 or 3 at 72 hours (25% vs. 14%, p=0.01), required re-thoracotomy for bleeding (7% vs. 1%, p<0.01) and temporary dialysis (16% vs. 5%, p<0.01). Survival at 5 years did not significantly differ in both groups (62% vs. 58%, p=0.63). Conclusion Smaller recipient BSA, pulmonary hypertension with high PVR values and evidence of a dilated and hypertrophic right ventricle can predict the need for intraoperative ECMO in patients transplanted for lung fibrosis. Although the postoperative course was more complicated in group A than B, long-term survival did not differ between groups. [ABSTRACT FROM AUTHOR]

Purpose A predicted total lung capacity (pTLC) ratio of 1.3 between donor and recipient has been described before as beneficial regarding survival after lung transplantation. Here, we wished to analyze data from our center regarding the effect of pTLC ratio on short- and long-term outcome following non-volume reduced lung transplantation. Methods Between 01/2005 and 08/2018 a total of 1506 lung transplantations were performed at our center. Predicted TLC-ratio was calculated retrospectively and short- as well as long-term outcome parameters were recorded. 156 transplantations with volume reduction procedures or lobar transplantations were excluded from the analysis. Results Median pTLC-ratio of all 1350 transplantations was 1.02 (IQR 0.96-1.08); (female 1.06, IQR 1.0-1.14, n=625; male 0.99, n= 725, IQR 0.91-1.05). Median follow-up time of the cohort was 41.3 months. The analysis revealed no significant correlation between pTLC ratio and mechanical ventilation time (p=0.09), postoperative ICU stay (p=0.19) or total hospital stay (p=0.26). Recipients showing PGD grade 2 or 3 (ISHLT 2005 criteria) at any time after transplantation had a median pTLC ratio of 1.02, this not being statistically different to recipients without signs of PGD at any time point (median pTLC ratio 1.02) (p=0.21). When dividing transplants into subgroups according to the respective donor/recipient pTLC-ratio (0.9-1.0; 1.0-1.1; 1.1-1.2; 1.2-1.3; 1.3-1.4) no survival difference between the different pTLC groups was detectable (p=0.24). Upon subanalysis of recipient's underlying diseases, no significant correlations between pTLC ratio and %predicted FEV1 at any time after transplantation were seen in COPD, IPF or IPAH patients. The cohort of cystic fibrosis patients showed a significant negative correlation between higher pTLC ratios and %predicted FEV1 at time of discharge from the initial hospital stay following transplantation (p=0.01), however, this was not detectable anymore in spirometry 1 year after transplantation (p=0.21). Conclusion Focusing only on those transplants performed without surgical donor lung size reductions, specific donor/recipient pTLC ratios did not impact short- and long-term outcomes in this single-center analysis. This suggests a wider range of pTLC-ratios may be safely used for allocation in lung transplantation. [ABSTRACT FROM AUTHOR]