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Cytomegalovirus infection and disease continue to be a significant cause of morbidity and mortality in lung transplant recipients (LTR) however, the optimal prophylactic strategy remains a matter of debate. At the Vienna lung transplant center all LTR receive a CMV prophylaxis combining Ganciclovir/Valganciclovir for 3 months (or 12 months for high-risk patients D+/R- since 2006) together with CMV- IVIG during the 3 weeks (Day 0,7,14,21) after LuTX (1mg/kgBW) All consecutive patients receiving a primary lung transplantation between 01/2010-12/2020 were included in this retrospective analysis (n=1100). The incidence of CMV infections (disease, viremia) was analyzed and correlated to CMV status, type of induction therapy, survival and incidence of CLAD. A total of 34 (3.1%) patients developed CMV-infection and 267 (24.3%) viremias. The rate of CMV infection was higher in seropositive LTR (32% D+R- and 29% D+R+ vs. D-/R- 6% and D-/R+ 17%). There was no correlation between CMV infection/disease and survival or incidence of CLAD. Also the type of induction treatment had no influence on the incidence or outcome of CMV infections in our cohort. The incidence of CMV viremia and disease was extrelmy low in our center compared to the published series. We hypothesize the use of CMV-IG in combination with Valganciclovir prophylaxis, the use of alemtuzumab induction therapy followed by low-dose maintenance immunosuppression and the use of TTV (Torque Teno Virus) for tailoring the immunosuppressive therapy protects LTR from CMV associated complications. [ABSTRACT FROM AUTHOR]

In recent decades, pediatric lung transplantation has developed into a well-accepted therapy for children and adolescents as ultimate ratio for terminal lung diseases. Although quality of life is an essential goal for a transplantation, only few data on this topic have been published yet. This study uses a standardized questionnaire to examine the health-related quality of life of patients who were lung transplanted at the Medical University of Vienna during childhood and adolescence. In this single-center cross-sectional study, 19 patients aged 8 to 40 were included in the study. The Euroqol-questionnaire and a self-designed questionnaire for information on school attendance, employment and housing situation were used. Pediatric patients waiting for lung transplantation served as control group. Pre- and post-transplant parameters were assessed for a potential influence on quality of life. The survey was done between November 2016 and October 2018. We demonstrated an improvement of quality of life after lung transplantation, as shown by a mean Euroqol Score of 1 (0-1) and a mean VAS score of 92 (0-100). The results were comparable to published data in healthy adults (Euroqol 0,96, VAS 87) and significantly better compared to our control group on the waiting list (Euroqol 0,43, VAS 68, both p<0,01). Employment rate also improved from 33 to 71%. Complication rates (pulmonary, nephrological, hepatological, neurological, psychiatric, diabetes mellitus) increased over time, with many of these complications correlating with a reduction in quality of life, especially the pulmonary parameters. Quality of life was found to correlate negatively with time since transplantation, however, scores after five years still exceeded those of patients on the waiting list. The results confirm a good quality of life after pediatric lung transplantation. [ABSTRACT FROM AUTHOR]

Selection of transplant recipients remains one of the major challenges in lung transplantation (LTx). Based on the most recent ISHLT consensus statement, the terms 'absolute' and 'relative' contraindications for LTx were replaced by a system of 'risk factors'. Searching the literature, there is, however, only very limited evidence supporting this concept. The aim of this study was to evaluate the benefit of LTx for patients with a risk profile according to the ISHLT definition. In this retrospective cohort study patients with fibrosis, COPD or cystic fibrosis undergoing primary bilateral lung transplantation between 2015 and 2020 were included (n=479). Comorbidities were assessed at time of listing, and scored as high (1 point) or moderate (0.5 points) risk factors according to the latest ISHLT consensus statement. The study cohort was categorized into three groups based on their scores (score 0/1-2/greater than 2). Posttransplant survival probabilities at 3, 12 and 60 months were compared between the groups with Kaplan-Meier survival analysis and log-rank tests. 479 patients (272 males) were included in the study with a median age of 56 years. 133 (27.8%) patients had no relevant comorbidities, 281 (58.7%) scored between 1-2, and 65 (13.6%) had 2 and more risk factors. In Kaplan-Meier analysis there were no significant differences in survival after 3 months (p=0.407), 12 (p=0.551) or 60 months (p=0.457) between the three groups. In uni- and multivariate analysis, only chest wall deformity was a prognostic parameter for impaired survival after the first year after LTx. LTx for well-selected recipients with substantial comorbidities is safe and associated with similar short- and long-term survival, if performed at experienced transplant centers. In the light of limited organ availability, careful recipient selection remains an ethical and medical challenge and should take an individualized risk-benefit assessment into account. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis (ECP) is routinely used by few lung transplant centers as treatment of chronic lung allograft dysfunction (CLAD). Although the reported outcomes suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of the current study is to analyze the outcomes and treatment characteristics of ECP in a multicenter large cohort. All patients who were treated with ECP for CLAD in the lung transplant centers of Vienna, Hannover and Pavia were included in the analysis. Treatment response was considered a >10% improvement in FEV1 compared to the value at the time of treatment start. Stabilization was defined as an improvement or deterioration of less than 10% compared to the value at the time of treatment start. Primary outcome was ECP response. Secondary outcomes were patient and graft survival. A total of 613 patients transplanted between 1989 and 2021 were included in this retrospective analysis. The median time to CLAD was 34 months (3-279). The median time to ECP after transplantation was 47 months (4-336). The phenotypes of CLAD at the onset of ECP were BOS in 87%, RAS in 10%, and mixed in 3% of patients. The median number of ECP cycles was 25 (1-90). Stabilization of graft deterioration was achieved in 39% of patients. No response was observed in 36% of patients. Seven percent showed a transient response within the first three months but deteriorated thereafter. The remaining 19% of patients showed a sustained response to ECP. Survival of patients who showed a sustained response and stabilization of lung function was significantly better: 96% and 81%, respectively, at 5 years. Graft survival of the two groups showed similar results: after 5 years, 95% and 77%, respectively. In contrast, patients who did not respond to ECP showed the worst results: after 5 years, patient survival was 60% and graft survival was 48%. Extracorporeal photopheresis is associated with survival benefit in a large European multicenter cohort. Lung function stabilized in the majority of patients after initiation of ECP. Further studies should focus on identifying parameters predictive of response to ECP. [ABSTRACT FROM AUTHOR]

Alemtuzumab leads to a long-lasting depletion of several immune cell subsets, thereby reducing the alloresponse against the newly implanted allograft. Until now, the mechanisms underlying immune reconstitution after alemtuzumab induction therapy are still unknown. We hypothesized that miRNAs could potentially play a fundamental role. Sixty-four recipients who received primary lung transplantation at our institution between 2018 and 2021 were included in our analysis. MicroRNA signatures were analyzed in plasma samples collected prospectively at two time points: at the time of transplantation and 12 months post-transplantation.The FirePlex miRNA Immunology-V2 Panel (Abcam) was selected for multiplex analysis of 68 miRNAs in each sample. Quantification was performed using the CytoFLEX S flow cytometer (Beckman Coulter). Eight miRNAs were differentially expressed 1 year after transplantation: hsa-miR-223-3p (fold-change 1.77, p<0.0001), hsa-miR-22-3p (fold-change: 1.54, p<0.0001), hsa-miR-320a (fold-change: 1.63, p<0. 0001), hsa-miR-320d (fold-change: 1.75, p<0.0001), hsa-miR-17-5p (fold-change 1.27, p<0.0001), hsa-miR-20a-5p (fold-change: 1. 32, p=0.001), hsa-miR-744-5p (fold-change: 2.07, p=0.0158), hsa-miR-15a-5p (fold-change 1.33, p=0.0444).Of these eight miRNAs, 5 were downregulated (miR-223-3p, miR-17-5p, miR-20a-5p, miR-744-5p, miR-15a-5p) and 3 were upregulated (miR-22-3p, miR-320a, miR-320d). Our preliminary data show that 8 miRNAs involved in immune cell subsets development are differentially expressed in a cohort of lung transplant recipients after alemtuzumab induction therapy. This pattern shows that a set of miRNAs are involved in the modeling of the circulating immune cell subsets repertoire. The inclusion of a larger cohort is necessary to confirm our results. [ABSTRACT FROM AUTHOR]

Donor-derived cell-free DNA (cfDNA) is a sensitive, however, non-specific biomarker for the detection of allograft injury including rejection or infection. A considerable number of lung transplant (LTx) recipients develop donor specific antibodies (DSA) after transplantation and their pathological value is often unclear. This study aimed to test the feasibility of cfDNA as an add-on marker in patients with persistent DSAs. A total of 27 patients, transplanted between 2020 - 2021, who had persistant donor specific antibodies and a minimum of 3 cfDNA measurements during the follow were included in this retrospective analysis. The kinetics of cfDNA in correlation to clinical events, course of DSA, infections, AMR or ACR was determined. 3 different patterns were detected: Group 1: Post-LTx increase of cfDNA > 15% with a decrease to <1% within the first 4 weeks, (n=11). None patient of this group developed AMR, CMV pneumonitis or CLAD. Group 1 seems to be the "normal" course with a peak within the first days postTX and low cfDNA values (<1%) after 1 month. Group 2: Post-LTx increase of cfDNA >15% with only a moderate decrease of cfDNA to levels between 7% to 2.5%; (n=6). One patient of this group developed CLAD, all others had a stable lung function. This group of continuously elevated cfDNA values seems to reflect constant injury to the lungs (subclinical AMR, infections, etc) Group 3: Post-LTx increase of cfDNA >15% with a decrease to less than 1% and again an increase to >3% to 18%. (n=10). 4 patients of this group developed AMR and one CMV pneumonitis. Group 3 presents a new onset of lung injury with concomitant increase of cfDNA as previously described in infections or episodes of AMR/ACR. cfDNA is a promising biomarker of lung allograft injury and could hopefully help to improve monitoring of post-LTx surveillance in cases of subclinical AMR and /or ACR (group 3) and for risk stratification for the development of CLAD in an early stage (group 2). [ABSTRACT FROM AUTHOR]

Patients with lung cancer or suspicious pulmonary nodules are traditionally rejected for lung transplantation (LTx), despite conflicting studies on the prognostic impact of early stage lung cancer in the LTx setting. In addition, there is a lack of evidence on how often suspicious nodules are found in LTx candidates and how often these nodules turn out to be lung cancer after transplantation. As suspicious nodules are not considered a contraindication for LTx by the Lung Transplant Program Vienna, we performed a retrospective analysis of all patients with suspicious lung nodules, who underwent lung transplantation between 01/2012 and 09/2022. 1169 patients received a LTx, at a mean age of 63.3±3 at the time of transplant. Prior to LTx, lung nodules were found in 81 (6.9%) patients, which were followed by chest CT-scan at a 3-month interval during the wait list period. None of the 81 patients was delisted. COPD was the most frequent indication for LTx (68/81; 83.4%) in patients with suspicious nodules. Pathology reports confirmed lung cancer in native lungs in only 14 (17.3%) of these patients. The histological subtypes were adenocarcinoma in 7 (50%), squamous cell carcinoma in 3 (21.4%), lung carcinoid tumors in 2 (14.3%), large cell lung carcinoma in 1 (7%) and large cell neuroendocrine lung carcinoma in 1 (7%) patient. Eight (57.1%) patients with carcinoma in the native lung are alive today. Death due to tumor recurrence was documented in 3 patients at 1-, 6-, and 10-months post-transplant, CMV infection in 1 (7%; at 8 months post-transplant) and MOF in 1 (7%; at 11 months post-transplant) patient. Five-year survival for LTx patients without suspicious lung nodules compared to patients with verified cancer was 73.1% vs 59.2% (Log-Rank p=0.101). Patients with suspicious lung nodules should not be excluded from LTx. Only a small proportion of these nodules are malignant and even if the explanted lung harbors an early-stage lung cancer, long-term survival is acceptable. [ABSTRACT FROM AUTHOR]

De novo donor-specific antibodies (dnDSA) against class I or II human leukocyte antigens have been reported to occur in 13-61% of recipients after lung transplantation (LTx), and dnDSA have a significant impact long-term outcomes. In recent studies, the US-lung allocation score (LAS) at the time of transplantation has been found to be an independent risk factor for the development of post-transplant DSA. However, data on which of the many different LAS variables is responsible for the increase in the risk for dnDSA is lacking. In addition, these previous findings were solely based on the US LAS system, while a potential association with the Eurotransplant (ET) LAS has not yet been investigated. We analyzed patients who received primary LTx between January 2013 and December 2020 at the Medical University of Vienna. Re-transplantations, combined organ transplantations and patients without LAS were excluded. DnDSA with MFI values <1000 were defined as positive. In case of pre-transplant DSA, dnDSA were considered positive if MFI increased by >30% or >500. Patients who developed dnDSA (Group 'dnDSA') were compared to those the remaining cohort (Group 'controls'). Values and calculation parameters of the last LAS at the time of transplantation were analyzed. In addition, demographics and outcome factors were also compared. Of the 650 patients included in this study, 217 (33.3%) developed dnDSA. 59/217 (27.2%) already had pre-transplant DSA. Median LAS values were equal in both groups (36.3 vs 36.1; p=0.629). A high LAS status (values >50) was found less frequently in patients who developed dnDSA (n=36; 16.6%) compared to those who did not (n=69; 19.0%; p=0.473). Distributions of LAS factors such as diagnosis group (p=0.121), supplemental oxygen requirement (p=0.170), assisted ventilation (p=0.500), ECLS status (p=0.067), number of exacerbations (p=0.985) and renal replacement therapy (p=0.498), as well as sPAP (p=0.191), FEV1% of predicted (p=0.259) and FVC% of predicted (p=0.999) were similar between groups. Long-term graft survival was significantly impaired in the dnDSA group compared to controls (5 years: 61.6% vs 74.8%, p=0.025). DnDSA were associated with impaired long-term survival. However, in contrast to previous studies based on the US-LAS, in our cohort of ET-LAS patients, LAS was not associated with increased incidence of dnDSA. [ABSTRACT FROM AUTHOR]

ECP is used since more than 25 years as a rescue therapy in patients with refractory acute cellular rejections (ACR), as an add on treatment in antibody mediated rejection and in patients with CLAD with significant response.Therefore a prospective randomized single centre study was initiated to evaluate the safety and efficacy of adding ECP to standard immunosuppression in preventing ACR episodes in the first 12 months after transplantation. A total of 62 consecutive adult recipients of primary LuTX at the lung transplant center Vienna, Austria (Medical University Vienna) were randomly assigned to receive either standard triple-drug immunosuppressive therapy (Tacrolimus, Mycophenolate Mofetil and prednisone, n=31) or standard triple-drug therapy plus photopheresis (n=31). Primary objective was the incidence of biopsy proven acute cellular rejection episodes in the first 12 month after transplantation. After 12 months of follow-up the mean number acute cellular rejection rates was significantly lower in the ECP group (less high grad rejection episodes ≥A2: mean±SD control group 0.48±0.67 vs ECP group 0.06±0.24, p=0.003) with less need for aggressive rejection therapy (high dose of steroids or ATG). The cumulative A scores after 12 months were 1.0±1.45 in the control group and 0.25±0.48 in the ECP group (p=0.002). The cumulative B scores after 12 months were 1.4±1.06 in the control group and 0.8±0.78 in the ECP group (p= 0.019).Furthermore the number of severe infectious complications was significantly lower in the ECP group (22 vs 5, p=0.002) due to the reduced burden of immunosuppression treatment and the immunomodulatory effects of ECP (increase of Tregs, ⋯.). No difference in survival and CLAD was observed. Addition of ECP to standard triple immunosuppression is associated with a significant lower incidence of acute cellular rejection episodes and a significant reduction of infectious complications after lung transplantation within the first post transplant year. [ABSTRACT FROM AUTHOR]

Based on published evidence, outcomes of lung retransplantation appear to be worse in patients with restrictive allograft syndrome (RAS) compared to bronchiolitis obliterans syndrome (BOS). Therefore, non-BOS phenotypes are considered as a contraindication to retransplantation by many centers. In our clinical experience we had the impression that there were no survival differences between non-BOS and BOS. We therefore aimed to analyze pre-, intra-, and early post-operative parameters and survival of CLAD patients, who received a retransplantation. This study was a retrospective single center analysis including patients undergoing lung retransplantation due to CLAD between 2000 and 2021. A total of 70 patients were included in the analysis. 73% of patients had BOS, 20% a mixed phenotype and 7% RAS. No difference was observed in terms of intraoperative use of erythrocyte concentrates (BOS 2577, 1500-3900 ml vs non-BOS 3454, 82500-6600 ml, p=0.407), fresh frozen plasma (BOS 3000, 1800-3600 ml vs non-BOS 2600, 2000-9200 ml, p=0.173), thrombocyte concentrates (BOS 0, 0-271 ml vs non-BOS 133, 0-459, p=0.300), prothrombin complex concentrates (BOS 0, 0-1500 I.E. vs non-BOS 1000, 0-2500 I.E., p=0.381) and fibrinogen (BOS 1000, 0-3000 I.E. vs non-BOS 2000, 0-2000 I.E., p=0.808). 30% of the cohort (BOS 33% vs non-BOS 26%, p=0.574) needed at least one revision after retransplantation. Length of mechanical ventilation (BOS 25, 11-45 days vs non-BOS 4, 3-25 days, p=0.267), prolonged post-operative ECMO (BOS 14% vs. non-BOS 26%, p=0.677), need for tracheostomy (BOS 26% vs. non-BOS 21%, p=0.894) and ICU time (BOS 41, 33-49 days vs. non-BOS 11, 3-34 days, p= 0.696) were comparable between the groups. Furthermore, survival between the groups did not differ with overall and graft survival rates at 90 days, 1 and 3 years of 92%, 72% and 53% for BOS and 89%, 71% and 56% for non-BOS (p=0.845). In contrast to published evidence, our retrospective analysis showed that non-BOS retransplant patients have outcomes comparable to BOS patients. This might be related to careful patient selection in non-BOS retransplant candidates, but also implicates that retransplantation should be considered in all CLAD patients irrespective of the phenotype. [ABSTRACT FROM AUTHOR]

Lung transplantation (LTx) can be considered for selected patients suffering from COVID19 ARDS or fibrosis. Besides the lung, the virus also affects the liver and cholangiopathy with progressive biliary liver failure has been described in a substantial rate of COVID19 ARDS survivors. Despite an increasing number of LTx performed worldwide for post-COVID19 ARDS, rates of cholangiopathic liver dysfunction and factors predicting this detrimental late complication are unknown. This retrospective analysis included all LTx performed for post-COVID ARDS or post-COVID fibrosis in our institution between May 2020 and October 2021. Clinical parameters available at the time of listing were compared between LTx recipients who developed irreversible cholangiopathy leading to death or consideration for liver transplantation ('cholangiopathy' group) and patients who had no or only transient liver dysfunction ('control' group). Severe elevation of LFPs was defined as greater than 5 times the upper limit of normal (ULN) of bilirubin, ASAT, ALAT, GGT and AP, respectively. A total of 23 patients were included in the analysis. While 14 (60.9%) showed no or only transient liver dysfunction post-transplant, 9 (39.1%) developed persistent cholangiopathy after LTx. In 4 of these cases, this ultimately led to death, while 2 patients had to be put on the liver transplant wait list. Median time between COVID disease onset and Tx listing (p=0.603) was similar in both study groups. Recipient BMI, previous comorbidities and SOFA score at Tx listing were comparable. Levels of AP, ASAT, ALAT and bilirubin were similar in both groups, however, GGT at the time of listing seemed to predict a later development of cholangiopathy (median 510 vs 211.5 U/L; p=0.062). Moreover, patients with a GGT > 5xULN had a 12 times higher likelihood for the development of post-transplant cholangiopathy compared to those with lower GGT values (OR 95% CI: 0.010 - 0.590). Since severe cholangiopathy is associated with a high mortality after LTx, liver function should be thoroughly assessed in all post-COVID ARDS/fibrosis LTx candidates. In this preliminary observation, we found that GGT at the time of listing was the only parameter which appeared to predict this late complication. Further large-scale studies are required to confirm our findings. [ABSTRACT FROM AUTHOR]

Alemtuzumab is a monoclonal antibody targeting CD52, one of the most predominant antigens on the surface of lymphocytes. It induces cell lysis and leads to a profound immune cell depletion. However, little is known how T- and B-cell repopulate and if there is predominance towards certain subtypes. B- and T cell subsets were analyzed from whole blood samples of 25 patients, prospectively collected at time of listing (=baseline) and 6 months post-transplant. Cell subsets were measured by FACS. Patients received alemtuzumab induction followed by low-dose tacrolimus and steroids. Median age of the cohort was 59 years (51-64) and 36% of patients were female. Underlying diagnoses were COPD (36%), fibrosis (20%), CF (12%), PPH (4%), EAA (12%) and others (16%). B- and T cell counts significantly decreased compared to baseline (p=0.009, p<0.001). Within B cell population, relative frequency of IgM+CD27−CD38high, IgM+CD27+CD38high and regulatory B cells increased 6 months after Tx (p=0.017, p=0.016, p=0.028, respectively). Within T cell population, CD4+ T cells decreased 6 months after Tx (p<0.001), while relative frequency of CD8+ T cells was significantly higher (p<0.001). A detailed analysis revealed a shift towards CD4+CD57+(p=0,002), PD1+CD4+(p<0.001), CD45RA+CD197-CD4+ (p=0.0013), CD45RA−CD197−CD4+ (p<0.001), CD27−CD28+ (p<0.001), CD27+CD28+ (p<0.001), PD1+CD8+ (p<0.001), CD45RA+CD197−CD8+ (p=0.039) and regulatory FoxP3+-T cells (p=0.005) at 6 months after Tx. After alemtuzumab induction therapy, the composition of B and T cell subsets is altered compared to baseline. Expansion of subsets such as PD1 T cells and regulatory B- and T cells suggests an immunomodulatory effect of alemtuzumab on cell repopulation. [ABSTRACT FROM AUTHOR]

Allograft adaptation after lung transplantation is a multi-factor process. We hypothesized that early adaptation can influence the risk of matrix remodeling and CLAD development by shaping the inflammatory state of the lung environment. In a longitudinal study, we followed a defined patient cohort in year 1 p.t. and detected ordered cell composition changes with repercussions in the microbiome, small molecular composition and lipidome in BAL samples. We delimited clusters of pro-inflammatory factors and identified long-chain lipid species from the lung environment that modulated inflammatory response in vitro. We used FACS to identify cell populations and 16S sequencing, metabolomics, lipidomics to characterize the lung environment. With correlations and hierarchical clustering we extracted pro- and anti-inflammatory clusters around well-characterized cell populations. For detection of inflammation drivers, we quantified feature differential abundances in samples with more or less neutrophilia. Predicted candidates were tested to modify inflammatory responses in vitro by screening IL-6 production of LPS-triggered macrophages. Early after surgery, the allograft experienced neutrophilia, a lack of resident macrophages and a gradual influx of host-derived macrophage-precursors directly resonating with changes in the pulmonary microenvironment. The computational analysis revealed features that clustered either with neutrophils or alveolar macrophages. From these, 30% showed significant abundance differences in high and low neutrophilia conditions. Consistently, certain ceramide species displayed antagonistic behavior to several phosphatidylcholines. We tested their capability of modifying macrophage response and found the ceramide to enhance, and PCs to reduce IL-6 production. Our study suggests that the lung microenvironment plays a key role in allograft adaptation and specific lipid species are capable of modulating cellular inflammatory response in a differentiated manner early after transplantation. Our results provide first fundamental concepts for developing concrete precision therapies based on reprogramming tissue homoeostasis and inflammation management. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are considered important modulators of the immune system and have been associated with several diseases. Available clinical evidence suggests improvement or stabilization of lung function in BOS patients treated by extracorporeal photopheresis (ECP). However, few studies have explored the epigenetic and molecular regulation of this therapy. In particular, no studies have addressed miRNAs expression during ECP treatment in BOS. The aim of the study was to evaluate whether a specific set of miRNAs, known to be involved in immune regulation, showed a significant dysregulation during ECP. Total RNA was isolated from serum of BOS patients prior to start ECP treatment and after 6 months. The expression profiles of different miRNAs were obtained by qPCR. Patients whose FEV 1 declined less than 10% with respect to basal value were classified as responders. Twenty-six BOS patients receiving ECP and 17 healthy subjects were included in the analysis. Among the studied miRNAs, we observed a significant down-regulation of circulating hsa-miR-155-5p (p<0.0001), hsa-miR-146a-5p (p<0.0001) and hsa-miR-31-5p (p =0.015) in BOS patients at ECP start when compared to healthy subjects. In order to investigate differential miRNAs expression associated with ECP response, miRNAs levels were compared among responders and non-responders. None of the tested miRNAs was significantly different in the two subpopulations prior to ECP initiation. In responders, paired analysis showed increased expression levels of hsa-miR-155-5p after 6-months treatment (p<0.0001). ECP also induced a significant reduction in hsa-miR-23b-3p expression levels (p<0.0001), although its levels were not significantly dysregulated at baseline compared to healthy controls. The significant down regulation of miR-155 and miR-146a in patients experiencing BOS at ECP start is in line with a low level of immunologic tolerance towards the allograft. Of note, ECP induces an increase of miR-155p among responders. Variation of miR-23b during treatment is more controversial, possibly related to a modulation of fibrogenic molecular pathways. [ABSTRACT FROM AUTHOR]

Approximately 50% of lung transplantation (LuTx) recipients develop de-novo DSA (dnDSAs) within the first year. In our institution, therapy is started only in case of clinical antibody-mediated rejection. The majority of dnDSAs disappears within 3-6 months; however, in some patients they persist. The aim of the study was to determine whether persistence of dnDSAs is associated with worse outcomes and as a consequence is worth of therapeutic intervention All patients, transplanted between 2010 and 2020. dnDSAs were defined as persistent if detectable for a time period longer than 6 months, otherwise were classified as transient. Four categories of mean fluorescence intensity were defined: I (1000-5000), II (5000-10000), III (10000-15000) and IV (>15000). 730 patients were included in the analysis, 153 patients (21%) developed dnDSAs. Eighty-one (11%) were transient while in 71 patients (10%) persisted for a period longer than six months. MFI categories were significantly different between transient and persistent dnDSAs (p<0.001): I (88% vs 17%), II (7% vs 33%), III (5% vs 19%), IV (0% vs 31%). 3 patients (4%) in the transient group and 26 (36%) in the persistent group developed clinical AMR (p<0.001) during the study period. Freedom from CLAD at 1-, 3- and 5-years was 93%, 86% and 63% in transient dnDSAs group compared to 85%, 49% and 34% in persistent dnDSAs group (p=0.001). Graft survival at 1-, 3- and 5-years was 90%, 78% and 68% in transient dnDSAs group compared to 81%, 59% and 45% in persistent dnDSAs group (p=0.008). Of not, the transient dnDSAs group showed similar 5-year survival as patients without dnDSAs (69% vs 74%, p=0.833). Contrarily, patients with persistent dnDSAs had low 5-year survival of only 48% (p=0.002). Persistent but not transient dnDSAs are associated with worse long-term outcomes. Further studies are needed to evaluate possible therapeutic strategies, aimed to prevent subclinical damage to the allograft. [ABSTRACT FROM AUTHOR]

The diagnosis and treatment of antibody-mediated rejection (AMR) after LTx has gained increasing recognition within the transplant community. Extracorporeal photopheresis (ECP) modulates various pathways of the immune system and is currently used to treat CLAD. In AMR, adding ECP to established AMR treatments could potentially prevent rebound of DSA. This study aimed to analyze the role of ECP as adjunct treatment of AMR. Patients who developed antibody-mediated rejection between 2009 and 2019 were included in this single-center retrospective analysis. The following parameters were evaluated: DSAs, C4d deposition and lung histology. A total of 39 patients developed clinical AMR during follow-up. Nineteen (48%) patients had positive DSA against HLA Class I and eighteen (46%) HLA Class II. Median time to diagnosis of AMR was 180 days (IQR: 2-2477). First line treatment was immunoadsorption (IA) in 34 (87%) patients, intravenous immunoglobulins with concomitant immunoadsorption in 3 (8%) patients and in 2 cases ATG. Twenty (51%) patients primarily treated with IA and the two patients treated with ATG received ECP. Among the patients treated with ECP, 12 had DSA against HLA Class I and 13 against HLA Class II. ECP treatment was initially performed twice a week. After stabilization of lung function and improvement of clinical situation, ECP was then performed once a month for a minimum of 6 months. Median length of treatment was 12 months. Patients who received ECP after first line treatment had 1-year survival rate of 62% compared to 27% of other AMR patients. In all patients treated with IA followed by ECP, DSA disappeared or MFI reduced below our institutional threshold of 5000. Extracorporeal photopheresis is associated with a reduction of de novo DSA after antibody-mediated rejection. Prospective studies are necessary to confirm the beneficial effect of ECP as an add-on therapy after AMR. [ABSTRACT FROM AUTHOR]

After successful lung transplantation, patients can potentially reach same strength and endurance as healthy individuals. Although high-altitude trekking has been reported after LuTX, data on the patient's physiological adaptation during prolonged exercise in a reduced oxygen environment remains scarce. In September 2019, 14 lung transplanted patients and their accompanying doctors, climbed Mount Jebel Toubkal (4167 m; 13 671 ft), the highest peak in North Africa, High Atlas, Morocco. Participants had regular cardiopulmonary exams (lung function, polysomnography, echocardiography) as well as blood sampling (capillary blood gasses, lactate, creatinine) throughout the expedition up to 3145 m (10 318 ft). Patients (♀: n=3 | ♂: n=11) had a median age of 42.1 years (24.8-65.2). Their underlying diagnoses were CF (n=10), Emphysema (n=2), IPF (n=1) and PH (n=1). Median time from LuTX to this expedition was 4.1 Years (1.7-17.6). Controls (♂: n=4) were 31.3 (29.3-46.7) years old. Over 7 days, participants hiked a distance of 81km (50.3 mi) with a cumulative elevation gain of 5496 m (18,031 ft.) vertical distance. Eleven Patients (78.6%) reached the summit whereas three patients had to abort because of altitude sickness (n=1 on day 1 at 2431m) or physical exhaustion (n=2 on day 3 at 3124m and day 6 at 3800m). Blood gas analysis and vital signs did not differ significantly between the patients and four healthy controls (pO2: 59.1 ±8.9 vs. 61.8 ±14.4 mmHg | pCO2: 29.8 ±1.5 vs. 29.8 ±0.5 mmHg | lactate 0.82 vs 0.83 mmol/l). Creatinine was significantly higher in transplanted patients (1.87 vs. 0.97 mg/dl; p=0.025). Although technically challenging, medical monitoring of lung transplanted patients is feasible during high altitude hiking. In carefully selected athletic LuTX patients, gas exchange and metabolism didn't differ compared to healthy adults. [ABSTRACT FROM AUTHOR]

Following introduction of the lung allocation score (LAS) in 2011, Eurotransplant member centers can apply for an exceptional LAS (eLAS) if the calculated LAS insufficiently reflects the perceived transplant benefit for a patient, specifically in case of primary pulmonary hypertension group 1 and 4; combined lung+non‐renal transplantation; rare diseases; or extracorporeal support. Each eLAS proposal is evaluated by a LAS Review Board, consisting of ≥3 lung transplant experts, which subsequently declines or approves the eLAS request in consensus of ≥3 votes. In case of a lower than accepted score, predefined business rules to assign LAS percentiles are used. A retrospective analysis of all eLAS requests in Eurotransplant from December 2011 until September 2019. Overall, 5183 lung transplants (deceased donors) were performed and 420 eLAS requests were made (Germany 52%, Netherlands 18%, Austria 18%, Belgium 13%), of which 116 (28%) were approved. Most eLAS requests concerned group B/Pulmonary vascular disease (44%), followed by group C/Cystic fibrosis or immunodeficiency disorder (28%), then group D/Restrictive lung disease (15%) and finally group A/Obstructive lung disease (11%); whereas 10 patients (2%) were not classified. The proportion of accepted eLAS requests significantly differed between countries (Germany 25%, Netherlands 37%, Austria 20%, Belgium 36%) (p=0.042). eLAS requests decreased in the Netherlands following its LAS introduction in 2014 (2011-2014 mean 13/yr vs. 2015-2019 mean 4.6/yr; p=0.060). However, since 2015 an overall annual increasing number of eLAS requests is seen, with doubling of the eLAS requests in 2018 vs. 2015, but no difference in acceptance rate (2015-2018: 22.4%) (Figure). Acceptance rates were 38% for Group B, 21% for Group C, 20% for Group D and 11% for Group A. The observed variations require further investigation to optimize lung allocation for specific patient populations in Eurotransplant. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) remains the only lifesaving option for certain end-stage pulmonary diseases, ARDS as indication for LTx is discussed controversially and only limited data are available. For example, in the Eurotransplant region, only 17 patients transplanted for ARDS are documented. Since we have followed a liberal approach of accepting ARDS patients for LTx, we reviewed retrospectively the outcome of this particular patient cohort in our center. From 08/98 to 03/19 a total of 10 patients transplanted for ARDS were identified in our center. Demographic and clinical data of these patients were collected and analyzed. Eight/10 patients were listed and transplanted while on extracorporeal membrane oxygenation (ECMO). The remaining 2 patients could be initially weaned from ECMO but were respirator dependent at the time of referral for LTx. The median mechanical ventilation time and median length of ECMO was 33.5 (IQR: 3.5-62.3) and 29.5 (28-38) days before LTx. Length of ICU and length of hospital stay was 38 (24.5-52) and 57 (43.5-94) days. The 30-day mortality was 10% and 1-year survival rate was calculated as 55.5% (Figure 1). One patient developed chronic lung allograft dysfunction (CLAD) and received re-transplantation 12 years after the primary procedure. The median follow up time was 82 (49.9-1065) days. Lung transplantation is feasible in carefully selected ARDS patients. Given the lack of alternative treatment options it provides acceptable long-term results. [ABSTRACT FROM AUTHOR]

Purpose Within the last years increasing attention has been given to antibody-mediated rejection (AMR) due to its poor long-term outcomes. The impact of alemtuzumab on donor-specific antibodies (DSAs) and AMR in lung transplantation is currently unclear and most evidence comes from kidney transplantation. This study aimed to analyze the impact of alemtuzumab induction on the incidence of DSAs and AMR. Methods All patients transplanted between 2007 and 2017, who received alemtuzumab as induction therapy, were included in this retrospective single-center analysis. The following parameters were evaluated: donor-specific antibodies, C4d deposition, lung histology and occurrence of antibody-mediated rejection. Results Within the study period 525 patients received alemtuzumab as induction therapy. Pre-transplant DSAs were present in 64 (12.2%) recipients (53 anti-HLA class I and 40 anti-HLA class II). De novo (dn) DSAs developed in 93 (17.7%) recipients after transplantation (78 anti-HLA class I and 113 anti-HLA class II). Median time to development of dnDSA was 104 days (42-165) and incidence rates at 1 and 5-years after transplantation were 12.1% and 21.4%, respectively. In 20 (3.8%) recipients clinical AMR was diagnosed. Among them, 7 (35%) patients had a definite diagnosis, 9 (45%) a probable one and 4 (20%) a possible one as defined by the latest ISHLT AMR grading system. Deposition of C4d was only positive in 4 (20%) clinical AMR patients. Capillaritis was observed in 4 (20%) cases and neutrophilic septal margination in 3 cases (15%). Anti-HLA class I and class II were positive in 11 (55%) and 13 (65%) recipients, respectively. Long-term survival of recipients, who developed AMR, was significantly worse than other recipients, with a 5-years rate of 45% vs 75% (p<0.001) (Fig 1). Conclusion Alemtuzumab induction therapy is associated with a low incidence of dnDSAs and AMR. Long-term outcome of these patients remains poor. [ABSTRACT FROM AUTHOR]

Purpose Anastomotic healing problems are rare but confer significant morbidity after lung transplantation. Herein, we aimed to define the incidence, classification and treatment of bronchial complications as defined by the latest ISHLT guidelines, using a single running suture as a standard technique. Methods Patients receiving lung transplantation between January 1999 and December 2017 were included in this retrospective study. All bronchial anastomoses were performed by a standardized technique using a single, polydioxanon (PDS) running suture. The rate of anastomotic complications requiring an intervention, type of complication according to the 2018 ISHLT classification and the clinical management were retrospectively analyzed. Results A total of 3028 anastomoses were performed in 1606 patients. The overall incidence of relevant bronchial complications was 1.5%, 0.6% for left-sided anastomoses and 2.4% for right-sided anastomoses. In 5 patients a surgical revision was performed, whereas endoscopic treatment alone was sufficient in 40 patients. ISHLT grade " S Lc Ec" was the most common grading. The overall incidence of bronchial complications per anastomosis decreased within the study period from 2.4% in the era 1999 to 2003 to 0.8% in the era 2014-2017. We found no significant difference in overall survival of patients with and without bronchial complications (p= 0.928; HR (95% CI) 0.98 (0.62-1.54)). Conclusion A single running suture technique is associated with a very low rate of anastomotic complications. The most common type of clinically relevant airway complications is stenosis of the intermediate bronchus, which can be treated endoscopically in the vast majority of cases. Follow-up and treatment of patients with anastomotic complications by in interdisciplinary team results in excellent long-term outcome. [ABSTRACT FROM AUTHOR]

Both, Langerhans cell histiocytosis (LCH) and Erdheim-Chester Disease (ECD) belong to the heterogeneous group of histiocytoses. Their association is exceptional and thought to be linked to the BRAF mutation. Both diseases express with different radiographic and histopathologic phenotypes. Radiological features of pulmonary LCH include cystic and fibrotic changes sparing the costophrenic angles. On histology, positive staining with CD1a and Langerin is characteristic. Lung transplantation is the only therapeutical option in end-stage LCH. Radiologic manifestations of ECD include sclerotic bone lesions, retroperitoneal fibrosis, and cardiovascular involvement with infiltration of tissues by foamy histiocytes negative for CD1a. With an end-stage pulmonary LCH, a 38 years old man received a double lung transplantation (DLuTX). The explanted lungs revealed on histology clusters of Langerhans cells histiocytes positive for CD1a. Nine years after DLuTX and continuous immunosuppression, a PET-CT presented sclerotic changes in the scapula and 3rd thoracic vertebra, soft-tissue infiltration of the right atrium and circumferentially surrounding aorta and right coronary artery ("coated" aspect) and edematous thickening of the renal capsule ("hairy kidney"). The imaging findings were thus compatible with ECD. Bone biopsy showed fibrosis of the bone marrow. Biopsy of the retroperitoneum revealed fibrosis, cells inconsistent with Langerhans cells, immune-histochemically lacking CD1a expression. The mediastinal changes slowly progressed over years, requiring biopsy, which also yielded fibrotic tissue. Additionally, the patient developed a massive jaundice and anorexia. The abdominal CT showed intra- and extrahepatic cholangiectasis with circumferential soft tissue sheathing of the common bile duct (CBD). An ERCP with biopsy of the CBD revealed cells positive for langerin and CD1a. Further cranial CT showed symmetric sclerotic bone lesions. Patient died 12 years after DLuTx due to cardiovascular complications. He had never developed any dysfunction of his lung allografts. Distinctive histopathologic results of various tissues at different time points and the extensive radiologic features in the same patient indicate the concomitant occurrence of two distinct histiocytoses, LCH and ECD after DLuTX. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We retrospectively reviewed the post-transplant outcome of ARDS patients from three high-volume European transplant centers. From August 1998 to May 2020, a total of 13 patients (mean age, 29.2 ±3.6 years) transplanted for ARDS, were identified. Demographics and clinical data of these patients were collected and analyzed. Viral infection (H1N1, cytomegalovirus, H3N1 and SARS-CoV-2) was the main reason (n=7/13, 53.8%) for ARDS. All patients were admitted to ICU, mechanical ventilated and 11/13 were supported with ECMO during listing, with a median LTx listing time of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation after LTx was 33 days (IQR 17-52.5), ICU and hospital stay were respectively 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with median duration of 2 days (IQR 2-7). The 30-day mortality was 7.7%, median survival 590 days, 1-year and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Median follow-up time was 536 (IQR 142-1524) days. Given the lack of alternative treatment options the herein presented results support the concept of offering LTx to carefully selected ARDS patients. [ABSTRACT FROM AUTHOR]

Establishing a new lung transplant (LTx) program requires besides a profound surgical and medical expertise, a distinct organizational and structural framework. A senior partner can provide invaluable support to avoid pitfalls related a new program. Herein, we summarize the concept and experience of the Hungarian Lung Transplantation Program in light of the Budapest-Vienna LTx cooperation. In 1996 the first Hungarian patient underwent LTx in Vienna, Austria. Subsequently, a mutual collaboration agreement was signed between the Vienna Lung Transplant Program and Hungarian professionals, thus contributing to a long-term cooperation between the two institutes. After several infrastructural developments and professional training of the medical personnel, the first LTx in Hungary was carried out at the National Institute of Oncology in collaboration with the Semmelweis University on December 12, 2015. In the next 5 years, the Hungarian Lung Transplant Program operated as part of the Vienna Lung Transplant Program. with a common waiting list and a shared donor pool. Both teams were in constant exchange and complex Hungarian recipients were either transplanted in Vienna or in Budapest with personnel support from Vienna. On September 8, 2020, our program became finally independent and was officially established within the framework of the Eurotransplant. During this 5-year cooperation, 92 and 10 LTxs for Hungarian recipients were performed in Budapest and Vienna, respectively. The one-year and three-year survival was 74,9% and 59,2 % of our patients. Importantly, within this period, our team received a structured training in re-transplantation, pediatric, multiorgan transplantation, LTxs for pulmonary hypertension and LTx after ECLS-bridging. Of note, the incidence of complications and mortality was similar to those reported by experienced centers. Altogether, this fruitful collaboration achieved consistently satisfactory results and could serve as a role model for establishing lung transplant centers elsewhere. [ABSTRACT FROM AUTHOR]

Prone positioning has become a standard therapy in acute respiratory distress syndrome with improved oxygenation and decreased mortality. The aim of this study was to evaluate the potential benefit of prone positioning after lung transplantation (LTx) in patients with impaired gas exchange in the early postoperative period. We retrospectively analyzed LTx recipients transplanted between 01/2014 and 12/2019 (n=553). Demographics and clinical data of these patients were collected. A subgroup analysis was performed for patients who were placed in prone position on prolonged extracorporeal membrane oxygenation (ECMO). During the study period 155 (28%) patients were placed in prone position immediately after LTx for a median of 19 (15-26) hours. Patients requiring prone positioning were mainly suffering from idiopathic pulmonary fibrosis (IPF) with a mean age of 44.3 (±1.4) years. Before prone position, median PO 2 /FiO 2 (P/F ratio) was 179 (120-280) mmHg and median dynamic lung compliance (C dyn) was 24.1 (18.3-30.6) ml/cmH 2 O. Both parameters significantly increased after proning - median P/F ratio increased to 353 (255-414; p<0.0001) mmHg and median C dyn to 28.3 (21.3-35.2; p=0.008) ml/cmH 2 O. 41 patients were placed in prone position while being supported by postoperatively prolonged femoro-femoral veno-arterial (VA) ECMO). No complications related to prone positioning (such as kinking of ECMO lines, dislocation of ECMO cannulas) were reported. Further, in this subgroup, P/F ratio (148 (81.3-219.3) mmHg to 317 (153.9-403.3) mmHg; p= 0.0002) and C dyn (16.6 (12.2-26.4) ml/cmH 2 O to 21.8 (14.6-29.8) ml/cmH 2 O; p=0.05) improved significantly by proning. Nevertheless, length of mechanical ventilation, length of intensive care unit (ICU) and hospital stay were significantly longer with a median of 2 (1.8-9.3), 12 (7-29) and 35 (21-53) days in the proning group compared to 1.4 (0.9-2.8), 7 (4-13) and 25 (18-37) days in the non-proning group (all p<0001). Prone positioning significantly improved oxygenation in LTx recipients with a complex immediate postoperative course. Placing a patient with prolonged ECMO support in prone positioning is feasible and safe. [ABSTRACT FROM AUTHOR]

The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval. A prospective evaluation of lung donors was performed in three transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary endpoint and collected data was used to build linear models predicting LMV. In total 166 donors were included in this study. Median LMV after transplantation was 32 hours (IQR:20-63). Peak inspiratory pressure (P IP) and dynamic compliance (C dyn) at the time of retrieval but not P/F ratio correlated with recipient LMV in Spearman correlations (r=0.280, p=0.002; r=-0.245, p=0.003 and r=0.064, p=0.432 respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV (table 1). The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor pCO2, aspiration, chest trauma and pathologic chest X-ray. This model performed poorly (multiple R-squared=0.063). In a second model, donor ventilation parameters were included and C dyn was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared=0.293). In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that C dyn is a strong donor-bound parameter to predict short-term graft performance, however, recipient factors are similarly relevant. [ABSTRACT FROM AUTHOR]

After lung transplantation (LTx), lung function usually increases over the first 12 months. The peak forced expiratory volume (FEV1) reached within this first year serves as the baseline value for the further clinical course and for CLAD diagnosis. However, in a number of patients FEV1 fails to increase to adequate levels and remains below 65% of the predicted value, a condition termed baseline lung allograft dysfunction (BLAD). Risk factors of BLAD and how it impacts survival and CLAD diagnosis are still poorly understood. We analyzed patients receiving primary double LTx between January 2010 and December 2018 at our center. Lobar LTx, pediatric patients and patients lost within the first 12 months were excluded. Post-transplant lung function trajectories were analyzed. Patients who failed to reach normal lung function (defined as FEV1>65% of the predicted value) formed a BLAD group. A control group consisted of patients who achieved adequate FEV1-values. Demographics and outcome factors including length of mechanical ventilation, PGD and graft survival were compared. A binary logistic regression analysis of donor parameters was performed to determine risk factors of BLAD. Of 598 patients included in the study, 77 (12.9%) did not reach an adequate lung function. Patients in group I reached their best FEV1 sooner (median 61 days; IQR: 15-282) compared to the control group (median 296 days; IQR: 113-613) (p<0.001). Intraoperative factors of both groups were comparable. Patients in the BLAD group required ECLS bridging (p=0.040) and postoperative prolonged ECMO (p<0.001) more often. Rates of PGD 3 at T72 were comparable at all time points (2.7% vs 1.8%; p=0.643). Median length of mechanical ventilation (48 hours vs 34 hours; p=0.003) and median ICU stay (8 days vs 6 days; p=0.002) were significantly longer in BLAD patients. In contrast, long-term graft survival was similar (5 years: 87.1% vs 84.4%, Log Rank: p=0.554). None of the donor parameters included in the regression model (donor age, BMI, paO2, paCO2, Oto score, smoking >20pyrs and organ ischemic time) reached statistical significance. Although BLAD may complicate the diagnosis of CLAD, it was not associated with impaired long-term outcomes. Donor quality was not associated with BLAD but affected patients had a complicated perioperative course more often than control patients. [ABSTRACT FROM AUTHOR]

In patients suffering from idiopathic pulmonary arterial hypertension (iPAH), cardiac function can be impaired in the early postoperative phase after lung transplantation as the chronically untrained left ventricle is prone to fail. Thus, restrictive fluid management is pivotal to unload the left heart. In our institution, continuous renal replacement therapy (CRRT) is implemented liberally, whenever a patient cannot be balanced negatively. It remains unclear whether such strategy impairs long-term kidney function. iPAH patients transplanted between 2000 and 2018 were included in this retrospective study. The influence of hemofiltration in the peri-operative phase on long-term outcomes was investigated. A total of 87 iPAH lung transplant recipients were included in this analysis. In 38 patients (44%) CRRT was started in the early postoperative period for a median of 16 days (3-45). In this group, urine production had significantly decreased and patients began to acquire a positive fluid balance, however, hemostatic functions of the kidney were still preserved at the time of CRRT initiation. All patients were successfully weaned from CRRT and fully recovered their kidney function at the time of hospital discharge (Figure 1). No difference in kidney function was found between CRRT and non-CRRT patients at 1, 3, and 5 years. Long-term survival was excellent with 10-year survival rates of 75%. Early implementation of CRRT for perioperative volume management does not impair long-term kidney function in iPAH recipients. Our data suggest that such a strategy leads to excellent long-term outcomes. [ABSTRACT FROM AUTHOR]

For patients, for whom the calculated LAS is not appropriately reflecting benefit of lung transplantation (LTx), a so-called exceptional LAS (eLAS) value can be requested. The aim of this study was to investigate the outcome after a first eLAS request. All patients with an eLAS request in Eurotransplant in the period between December 10, 2011 and July 31, 2019 were included (N=256). Patients were followed for at least one year until LTx or death on the waiting list (DOWL) occurred. Waiting list outflow was analyzed using competing risk method. Differences were tested using log likelihood tests. Multivariate analysis was performed to study factors determining the acceptance of an eLAS request. Of 256 patients, 97 (38%) eLAS requests were approved and 159 (62%) were declined. Within 1 year after the first request, 78 (80.4%) of the accepted patients underwent a LTx and 14 (14.4%) had died on the waiting list. In the declined group 104 (65.4%) were transplanted and 27 (17%) died on the waiting list. Patients in the approved group were significantly more likely to undergo LTX vs. the declined group (p<0.0001). No statistical difference was observed with relation to DOWL (p=0.64) (Figure) Factors significantly associated with acceptance of the eLAS request were primary diagnosis and the need for IV prostanoids (Table). No association was observed for cardiac index, ECMO, recipient age, year, and country of request. Approval of an eLAS request was associated with an increased probability of transplantation whereas decline did not result in an increased risk of death on the waiting list. [ABSTRACT FROM AUTHOR]

The pulmonary microbiome after lung transplantation has recently come into the focus of research. Especially, host-microbiome interactions are thought to be an important factor in graft-related immunological processes. In lung transplantation, temporal changes of the pulmonary microbiome have not yet been elucidated. In a total cohort of 80 patients receiving standard double lung transplantation, 50 bronchioalveolar lavage (BAL) samples from donors were collected prior to cold ischemia. After transplantation, 128 BAL samples were collected at various time points of routine follow-up bronchoscopies between 0 and 400 days post-transplant. Bacterial 16S rRNA gene sequencing was conducted to analyze the composition of the pulmonary microbiome in these samples. The lung microbiome showed significant temporal dynamics after lung transplantation. Recipient-donor similarity between matched samples decreased after the first week post transplantation. Underlying transplant indications were significantly associated with microbial profiles even after transplantation. Shannon diversity and Chao1 richness at the species level showed an increasing diversity of the microbiome over time. Our data provides new insights into the dynamics of microbial profiles after transplantation. We observed that recipient-associated factors, rather than the donor microbiome, shape the lung microbiome after transplantation. [ABSTRACT FROM AUTHOR]

Spirometric lung function is one of the central clinical parameters to assess allograft function after lung transplantation (LTX). Reduction in FEV1 can be the result of infections, rejections episodes and most importantly development of CLAD. Currently, there is no means to predict short-term changes in lung function after LTX. Bronchoalveolar samples of patients after standard double LTX were taken during follow-up bronchoscopy at multiple different time points. Lipidomic, metabolomic, flow cytometric and bacterial 16S rRNA gene sequencing (microbiome) data were analyzed. We then used a machine learning approach to predict future changes in FEV1 from these sample data to characterize patient lung function trajectories. We trained support vector machine (SVM) regressors on the collected lipidomic, metabolomic, microbiome and flow cytometry datasets. Changes in FEV1 within 30, 60 or 90 days after lavage sample collection were used as response variables. To train hyper-parameters and evaluate model accuracy, a nested leave-one-out cross validation scheme was used. Model accuracy was benchmarked against a model trained on clinical metadata. At a prediction timeframe of 30 days, lipidomic data were available from 34 samples of 20 patients. Lipidomics showed the highest predictive power for short-term changes 30 and 60 days after sample collection. Prediction accuracy (R2) of intra-alveolar lipid composition for a 30-day projection was 0.24, meaning that BAL lipid profiles could explain more than 20 percent of total variation in relative change in FEV1 for this time span. R² for clinical metadata alone was only 0.1, and metabolomics, microbiome and FACS analysis of BAL showed no predictive accuracy at this time point. Our results suggest that the intra-alveolar lipid composition is a powerful predictor of short-term changes in lung allograft function. This could potentially facilitate pre-emptive therapeutic interventions. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis (ECP) is an accepted treatment option for acute and chronic rejection after solid organ transplantation but the mode of action is not fully elucidated. In a randomized controlled trial that investigates the addition of prophylactic use of ECP to a tacrolimus-based immunosuppressive regimen after lung transplantation, a comprehensive phenotypic immune monitoring is performed to assess the immunomodulatory effects of ECP. To date, 40 (from a calculated sample size of 62) end-stage chronic obstructive pulmonary disease (COPD) patients underwent bilateral lung transplantation and were randomized into 2 treatment arms - the control group received standard triple immunosuppression consisting of tacrolimus, mycophenolate mofetil and steroids while the second group additionally received 16 ECP treatments in the first three months after surgery. For monitoring a comprehensive set of leukocyte subsets such as regulatory T cells (CD4+CD25+FoxP3+ Tregs) polychromatic flow cytometry analysis was performed on fresh whole blood samples using validated, standardized, lyophilized monoclonal antibody panels (DuraClone). Samples were acquired before and 3 months after transplantation, when the last ECP treatment was performed, as well as 6 months after transplantation. Statistical analysis was conducted by using a two-tailed paired and unpaired t-test. From 40 double lung transplanted patients, 32 patients have reached their three-month-visit and 28 patients their 6-months-visit. No significant difference in the frequency of Tregs was found between both groups at baseline (p=0.425). At 3 months, Tregs have significantly decreased in the control group (p=0.009) while in the ECP-treated group no significant decline was seen (p=0.141). Six months after transplantation the frequency of Tregs was significantly decreased in both groups when compared to baseline (p=0.043 in control; p=0.030 in ECP-treated). Preliminary data from this interim analysis of double lung transplanted patients receiving ECP as prophylactic treatment provide evidence that during ECP treatments the post-transplant decline in Treg frequency seen with standard immunosuppression is prevented. [ABSTRACT FROM AUTHOR]