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Introduction: Chronic rejection is a major complication post-transplantation. Within lung transplantation, chronic rejection was considered as airway centred. Chronic Lung Allograft Dysfunction (CLAD), defined to cover all late chronic complications, makes it more difficult to understand chronic rejection from an immunological perspective. This study investigated the true nature, timing and location of chronic rejection as a whole, within mouse lung transplantation., Methods: 40 mice underwent an orthotopic left lung transplantation, were sacrificed at day 70 and evaluated by histology and in vivo µCT. For timing and location of rejection, extra grafts were sacrificed at day 7, 35, 56 and investigated by ex vivo µCT or single cell RNA (scRNA) profiling., Results: Chronic rejection originated as innate inflammation around small arteries evolving toward adaptive organization with subsequent end-arterial fibrosis and obliterans. Subsequently, venous and pleural infiltration appeared, followed by airway related bronchiolar folding and rarely bronchiolitis obliterans was observed. Ex vivo µCT and scRNA profiling validated the time, location and sequence of events with endothelial destruction and activation as primary onset., Conclusion: Against the current belief, chronic rejection in lung transplantation may start as an arterial response, followed by responses in venules, pleura, and, only in the late stage, bronchioles, as may be seen in some but not all patients with CLAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Heigl, Kaes, Aelbrecht, Serré, Yamada, Geudens, Van Herck, Vanstapel, Sacreas, Ordies, Frick, Saez Gimenez, Van Slambrouck, Beeckmans, Acet Oztürk, Orlitova, Vaneylen, Claes, Schols, Vande Velde, Schupp, Kaminski, Boesch, Korf, van der Merwe, Dupont, Vanoirbeek, Godinas, Van Raemdonck, Janssens, Gayan-Ramirez, Ceulemans, McDonough, Verbeken, Vos and Vanaudenaerde.)

Background: Anesthesia during thrombectomy remains a matter of debate. We retrospectively investigated the influence of intraprocedural blood pressure and type of anaesthetic agent on 3-month functional outcome and mortality in stroke patients undergoing mechanical thrombectomy under general anesthesia in a single center study., Methods: All patients suffering from stroke who presented between January 2019 and July 2021 at Ziekenhuis Oost-Limburg Genk, Belgium and who received thrombectomy were included. Patient's characteristics and outcome data had been collected for benchmarking. Detailed perioperative data were exported from the electronic anesthesia records and clinically validated. Patients were stratified by peri-operative presence of hypotension (MAP < 65 mmHg at any time point) versus no-hypotension (MAP ≥ 65 mmHg)., Results: All 98 patients received mechanical thrombectomy under general anesthesia. Thirty-six percent (n = 35) was hypotensive peri-operatively at any time point. Proportion of sevoflurane use was higher in non-hypotensive patients compared to hypotensive patients (73% (n = 45) vs. 51% (n = 18), p = 0.04). Peri-operative use of vasopressors was higher in the hypotensive group compared to non-hypotensive (88% (n = 30) vs. 63% (n = 39), p = 0.008). Proportion of patients with good functional outcome at 3 months (mRS 0-2) was higher in non-hypotensive patients compared to hypotensive patients 44% (n = 27) vs. 24% (n = 8), p < 0.05. 90-day mortality was lower in non-hypotensive patients compared to hypotensive patients 21% (n = 13) vs. 43% (n = 15), (p = 0.02)., Conclusion: Patients who are hypotensive at any given time during thrombectomy under general anesthesia may have worse neurological outcome compared to non-hypotensive patients. The best anaesthetic management for mechanical thrombectomy needs to be clarified prospectively in large multicenter studies., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: Assessment and selection of donor lungs remain largely subjective and experience based. Criteria to accept or decline lungs are poorly standardized and are not compliant with the current donor pool. Using ex vivo computed tomography (CT) images, we investigated the use of a CT-based machine learning algorithm for screening donor lungs before transplantation., Methods: Clinical measures and ex situ CT scans were collected from 100 cases as part of a prospective clinical trial. Following procurement, donor lungs were inflated, placed on ice according to routine clinical practice, and imaged using a clinical CT scanner before transplantation while stored in the icebox. We trained and tested a supervised machine learning method called dictionary learning, which uses CT scans and learns specific image patterns and features pertaining to each class for a classification task. The results were evaluated with donor and recipient clinical measures., Results: Of the 100 lung pairs donated, 70 were considered acceptable for transplantation (based on standard clinical assessment) before CT screening and were consequently implanted. The remaining 30 pairs were screened but not transplanted. Our machine learning algorithm was able to detect pulmonary abnormalities on the CT scans. Among the patients who received donor lungs, our algorithm identified recipients who had extended stays in the intensive care unit and were at 19 times higher risk of developing chronic lung allograft dysfunction within 2 years posttransplant., Conclusions: We have created a strategy to ex vivo screen donor lungs using a CT-based machine learning algorithm. As the use of suboptimal donor lungs rises, it is important to have in place objective techniques that will assist physicians in accurately screening donor lungs to identify recipients most at risk of posttransplant complications., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Lung transplantation (LTx) is a challenging procedure. Following the process of ischemia-reperfusion injury, the transplanted pulmonary graft might become severely damaged, resulting in primary graft dysfunction. In addition, during the intraoperative window, the right ventricle (RV) is at risk of acute failure. The interaction of right ventricular function with lung injury is, however, poorly understood. We aimed to address this interaction in a translational porcine model of pulmonary ischemia-reperfusion injury. Advanced pulmonary and hemodynamic assessment was used, including right ventricular pressure-volume loop analysis. The acute model was based on clamping and unclamping of the left lung hilus, respecting the different hemodynamic phases of a clinical lung transplantation. We found that forcing entire right ventricular cardiac output through a lung suffering from ischemia-reperfusion injury increased afterload (pulmonary vascular resistance from baseline to end experiment P < 0.0001) and induced right ventricular failure (RVF) in 5/9 animals. Notably, we identified different compensation patterns in failing versus nonfailing ventricles (arterial elastance P = 0.0008; stroke volume P < 0.0001). Furthermore, increased vascular pressure and flow produced by the right ventricle resulted in higher pulmonary injury, as measured by ex vivo CT density (correlation: pressure r = 0.8; flow r = 0.85). Finally, RV ischemia as measured by troponin-T was negatively correlated with pulmonary injury ( r = -0.76); however, troponin-T values did not determine RVF in all animals. In conclusion, we demonstrate a delicate balance between development of pulmonary ischemia-reperfusion injury and right ventricular function during lung transplantation. Furthermore, we provide a physiological basis for potential benefit of extracorporeal life support technology. NEW & NOTEWORTHY In contrast to the abundant literature of mechanical pulmonary artery clamping to increase right ventricular afterload, we developed a model adding a biological factor of pulmonary ischemia-reperfusion injury. We did not only focus on the right ventricular behavior, but also on the interaction with the injured lung. We are the first to describe this interaction while addressing the hemodynamic intraoperative phases of clinical lung transplantation.

Introduction: Ischemic stroke is the second cause of death and leading cause of severe disability worldwide. A reduced features set of CT-DRAGON (age, NIHSS on admission and pre-stroke mRS) predicts 90-day functional outcome after stroke in a single center. The current study was designed to validate this adapted CT-DRAGON score in three major Belgian hospitals, in the framework of future case-mix adjustment., Methods: This retrospective study included stroke patients, treated by thrombolysis, thrombectomy, a combination of both or neither thrombolysis or thrombectomy (conservative treatment) in 2019. Patient characteristics and 90-day mRS were collected. Multivariable logistic regression analysis of 90-day mRS 0-2 vs. 3-6 and 0-5 vs. 6 with the reduced features set was performed. Discriminative performance was assessed by the area under the receiver operating characteristic curve (AUROC)., Results: Thirty-three percent of patients (413/1243) underwent treatment. Majority of strokes was treated conservatively (n = 830, 67%), 18% (n = 225) was treated by thrombolysis, 7% (n = 88) by thrombectomy and 8% (n = 100) by thrombolysis and thrombectomy. Age, NIHSS and pre-stroke mRS were independently associated with 90-day mRS 0-2 (all p ≤ 0.0001, AUROC 0.88). When treatment modality was added in the model, age, NIHSS, pre-stroke mRS and treatment modality were independently associated with 90-day mRS 0-2 (p < 0.0001, p < 0.0001, p < 0.0001 and p = 0.0001) AUROC 0.89). Age, NIHSS, pre-stroke mRS and treatment modality were independently associated with 90-day survival (p = 0.0001, p < 0.0001, p < 0.0001 and p = 0.008, AUROC 0.86)., Discussion: The reduced features set (age, NIHSS and pre-mRS) was independently associated with long-term functional outcome in a Belgian multicentric cohort, making it useful for case-mix adjustments in Belgian stroke centers. Treatment modality was associated with long-term outcome., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Ischemic stroke leads to substantial mortality and morbidity worldwide. Door-to-CT time, door-to-needle time (DNT), and door-to-groin time (DGT) are important quality indicators of stroke care. However, patient characteristics remain important determinants of outcome as well. In this single-center study, we investigated the interaction between these quality indicators and stroke severity regarding long-term functional outcome. All consecutive stroke patients treated at the ZOL stroke center, Genk, Belgium, between 2017 and 2020 were included in this retrospective observational study. Stroke severity was graded as "mild" if National Institutes of Health Stroke Scale (NIHSS) was equal to or lower than 8, "moderate" if NIHSS was between 9 and 15, and "severe" if NIHSS was higher than 16. Modified Rankin Scale (mRS) scores were collected before and 3 months after stroke. Ordinal regression analysis with correction for patient characteristics of functional outcome was done. A total of 1255 patients were included, of which 84% suffered an ischemic CVA (n = 1052) and 16% a TIA (n = 203). The proportion of patients treated conservatively or with thrombolysis, thrombectomy, or the combination of both differed according to stroke severity (p < 0.0001). Door-to-CT time was longer in mild and moderate stroke (p < 0.0001). Median DNT also differed between stroke categories: 46 (IQR 31-70) min for mild vs. 36 (25-56) min for moderate vs. 30 (21-45) min for severe stroke (p = 0.0002). Median DGT did not differ between stroke severity categories (p = 0.15). NIHSS on admission and pre-stroke mRS were independently associated with mRS at 90 days. Operational performance, reflected in door-to-CT time and DNT, was worse in patients with mild and moderate stroke severity. DNT was also associated with functional outcome in our center, along with pre-stroke mRS, NIHSS on admission and age., (© 2021. Belgian Neurological Society.)

Background: Primary graft dysfunction (PGD) remains a major obstacle after lung transplantation. Ischemia-reperfusion injury is a known contributor to the development of PGD following lung transplantation. We developed a novel approach to assess the impact of increased pulmonary blood flow in a large porcine single-left lung transplantation model., Materials: Twelve porcine left lung transplants were divided in two groups (n = 6, in low- (LF) and high-flow (HF) group). Donor lungs were stored for 24 h on ice, followed by left lung transplantation. In the HF group, recipient animals were observed for 6 h after reperfusion with partially clamping right pulmonary artery to achieve a higher flow (target flow 40-60% of total cardiac output) to the transplanted lung compared to the LF group, where the right pulmonary artery was not clamped., Results: Survival at 6 h was 100% in both groups. Histological, functional and biological assessment did not significantly differ between both groups during the first 6 h of reperfusion. injury was also present in the right native lung and showed signs compatible with the pathophysiological hallmarks of ischemia-reperfusion injury., Conclusions: Partial clamping native pulmonary artery in large animal lung transplantation setting to study the impact of low versus high pulmonary flow on the development of ischemia reperfusion is feasible. In our study, differential blood flow had no effect on IRI. However, our findings might impact future studies with extracorporeal devices and represent a specific intra-operative problem during bilateral sequential single-lung transplantation.

In recent years, the utility of vascular complement factor 4d (C4d) deposition as diagnostic tool for antibody mediated rejection (AMR) after lung transplantation, has become a controversial issue. We aimed to pinpoint the problematic nature of C4d as biomarker with a simple experiment. We quantified C4d in broncho-alveolar lavage (BAL) of lung transplant patients with diverse post-transplant complications in 3 different settings of clinically clear cases of: 1/ chronic lung allograft dysfunction (CLAD); 2/ acute complications acute rejection (AR), lymphocytic bronchiolitis (LB), antibody-mediated rejection (AMR) and respiratory infection (INF); 3/ patients with parallel C4d immunostaining and Anti-HLA. All groups were compared to BAL of stable patients. C4d was measured via standard ELISA. C4d was increased in CLAD, predominantly in RAS (p = 0.0026) but not in BOS (p = 0.89). C4d was increased in all acute events, AR (p = 0.0025), LB (p < 0.0001), AMR (p = 0.0034), infections (p < 0.0001). In patients with parallel C4d immunostaining and serum HLA antibodies, C4d was increased in C4d-/HLA- (p = 0.0011); C4d-/HLA+ (p = 0.013); HLA+/C4d + (p = 0.0081). A correlation of systemic C-reactive protein (CRP) with C4d was found in all patients (r = 0.49; p < 0.0001). We hypothesize that free C4d in BAL may only be representative of a general immune response in the transplanted lung., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Ex vivo lung perfusion (EVLP) is a widespread accepted platform for preservation and evaluation of donor lungs prior to lung transplantation (LTx). Standard lungs are ventilated using volume-controlled ventilation (VCV). We investigated the effects of flow-controlled ventilation (FCV) in a large animal EVLP model. Fourteen porcine lungs were mounted on EVLP after a warm ischemic interval of 2 h and randomized in two groups (n = 7/group). In VCV, 7 grafts were conventionally ventilated and in FCV, 7 grafts were ventilated by flow-controlled ventilation. EVLP physiologic parameters (compliance, pulmonary vascular resistance and oxygenation) were recorded hourly. After 6 h of EVLP, broncho-alveolar lavage (BAL) was performed and biopsies for wet-to-dry weight (W/D) ratio and histology were taken. The left lung was inflated, frozen in liquid nitrogen vapors and scanned with computed tomography (CT) to assess regional distribution of Hounsfield units (HU)., Results: All lungs endured 6 h of EVLP. Oxygenation was better in FCV compared to VCV (p = 0.01) and the decrease in lung compliance was less in FCV (p = 0.03). W/D ratio, pathology and BAL samples did not differ between both groups (p = 0.16, p = 0.55 and p = 0.62). Overall, CT densities tended to be less pronounced in FCV (p = 0.05). Distribution of CT densities revealed a higher proportion of well-aerated lung parts in FCV compared to VCV (p = 0.01)., Conclusions: FCV in pulmonary grafts mounted on EVLP is feasible and leads to improved oxygenation and alveolar recruitment. This ventilation strategy might prolong EVLP over time, with less risk for volutrauma and atelectrauma.

Objectives: Primary graft dysfunction (PGD) remains a major post-transplant complication and is associated with increased morbidity and mortality. Mechanisms evoking PGD are not completely clear, but inflammation plays a central role. We investigated the association between PGD and inflammatory proteins present in immediate postoperative bronchoalveolar lavage., Methods: All double-lung recipients transplanted at our institution from 2002 to 2018 were included in our study. We retrospectively selected 80 consecutive lung transplant recipients with different PGD grades (n = 20 for each PGD grades 0-1 to 2-3). In bronchoalveolar lavage performed within the first 24 h after donor aortic cross-clamping following lung transplantation, concentrations of 30 cytokines, chemokines and growth factors were assessed by enzyme-linked immunosorbent assay (ELISA) and correlated with donor and recipient demographics and outcomes. For analysis, 2 groups were defined: 'mild' PGD (grade 0-1) and 'severe' PGD (grades 2-3)., Results: Significant differences between mild and severe PGD were found in 8 biomarkers [interleukin (IL)-6, IL-10, IL-13, eotaxin, granulocyte colony-stimulating factor, interferon γ, macrophage inflammatory protein 1α, surfactant protein D (SP-D); P < 0.05]. Increased IL-10 and IL-13, but none of the other proteins, were associated with short-term outcome (longer time to extubation; P = 0.005 and P < 0.0001; increased intensive care unit stay; P = 0.012 and P < 0.0001; and hospital stay; P = 0.041 and P = 0.002). There were no significant differences in donor and recipient characteristics between the groups., Conclusions: Expression profiles of key inflammatory mediators in bronchoalveolar lavage fluid differed significantly between lung transplant recipients with severe versus mild PGD and correlated with clinical outcome variables. Further research should focus on the early mechanisms leading to PGD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Ex vivo lung perfusion (EVLP) is developed to increase the quantity and quality of suitable grafts for lung transplantation. Standardly, lungs are mounted supine with the risk of fluid accumulation in the dorsal regions. Therefore, we investigated the impact of experimental prone position on graft function during EVLP., Materials and Methods: Porcine lungs were mounted on a normothermic EVLP for 6 h in supine [S], (n = 7) or prone position [P], (n = 7). Physiology during EVLP was recorded. After EVLP, biopsies were assessed for wet-to-dry weight (W/D) ratios and pathology, broncho-alveolar lavage was measured, and the left lung was computed tomography (CT) scanned., Results: Physiological parameters were similar between both groups, despite a higher pulmonary vascular resistance in [P] (P = 0.0002). In [S], W/D ratios and CT density of dorsal areas were higher compared to ventral (P = 0.0017 and P = 0.053, respectively). In [P], W/D and CT density between ventral and dorsal regions were similar, meaning that pulmonary edema was distributed more homogeneously throughout the lung. Histology and cytokine levels in perfusate and broncho-alveolar lavage did not differ between both groups., Conclusions: Prone positioning during EVLP is feasible and leads to more homogenous distribution of interstitial fluid. Supine position resulted in more concentrated edema accumulation in lower dependent regions., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: Previous studies demonstrated that increased cytokine and chemokine levels, either shortly before or after lung transplantation, were associated with post-transplant outcome. However, small patient cohorts were mostly used, focusing on 1 molecule and 1 outcome. In a large single-center cohort, we investigated the predictive value of immediate post-operative broncho-alveolar lavage (BAL) expression of IL-6 and IL-8 on multiple key outcomes, including PGD, CLAD, graft survival, as well as several secondary outcomes., Material and Methods: All patients undergoing a first lung transplant in whom routine bronchoscopy with BAL was performed during the first 48 hours post-transplantation were included. IL-6 and IL-8 protein levels were measured in BAL via ELISA., Results: A total of 336 patients were included. High IL-6 levels measured within 24 hours of transplantation were associated with longer time on ICU and time to hospital discharge; and increased prevalence of PGD grade 3. Increased IL-8 levels, measured within 24 hours, were associated with PGD3, more ECMO use, higher donor paO 2 , younger donor age, but not with other short-or long-term outcome. IL-6 and IL-8 measured between 24 and 48 hours of transplantation were not associated with any outcome parameters., Conclusion: Recipient BAL IL-6 and IL-8 within 24 hours post-transplant were associated with an increased incidence of PGD3., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Donation after cardiac death (DCD) to overcome the donor organ shortage is well accepted in the clinical setting, although long-term outcome after DCD lung transplantation (LTx) remains largely unknown., Methods: In this retrospective study, DCD LTx recipients (n = 59) were compared with a cohort of donation after brain death (DBD) LTx recipients (n = 331) transplanted between February 2007 and September 2013; follow-up was until January 1, 2016. Short-term (duration of mechanical ventilation, intensive care unit stay, hospital stay, and highest primary graft dysfunction score within 72 hours) and long-term (chronic lung allograft dysfunction-free and overall survival) follow-up were compared over a median follow-up of 50.5 (±3.7) months for DCD and 66.8 (±1.5) months for DBD., Results: There were no differences between groups with regard to patient characteristics: age (P = 0.78), underlying disease (P = 0.30) and type of type of LTx (P = 0.10), except sex where more males were transplanted with a DCD donor (62.7%) vs (48.3%, P = 0.048). There was no difference in time on mechanical ventilation (P = 0.59), intensive care unit stay (P = 0.74), highest primary graft dysfunction score (P = 0.67) and hospital stay (P = 0.99). Moreover, chronic lung allograft dysfunction-free (P = 0.86) and overall survival (P = 0.15) did not differ between the DBD and DCD groups., Conclusions: In our experience, both short- and long-term outcomes in DCD lung recipients are comparable to that of DBD lung recipients. Therefore, DCD LTx can be considered a safe strategy that significantly increased our transplant activity.

Background: Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways., Methods: Lungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin-plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO 2 /FiO 2 ), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 × 30 ml) was performed., Results: Pulmonary vascular resistance, lung compliance, PaO 2 /FiO 2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-α, IL-1β and IFN-γ in the BAL, but not in IFN-α; whereas IL-4, IL-10 and IL-8 were below the detection limit., Conclusions: Although no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation.

Argon (Ar) is a noble gas with known organoprotective effects in rodents and in vitro models. In a previous study we failed to find a postconditioning effect of Ar during ex vivo lung perfusion (EVLP) on warm-ischemic injury in a porcine model. In this study, we further investigated a prolonged exposure to Ar to decrease cold ischemia-reperfusion injury after lung transplantation in a porcine model with EVLP assessment. Domestic pigs ( n = 6/group) were pre-conditioned for 6 hours with 21% O 2 and 79% N 2 (CONTR) or 79% Ar (ARG). Subsequently, lungs were cold flushed and stored inflated on ice for 18 hours inflated with the same gas mixtures. Next, lungs were perfused for 4 hours on EVLP (acellular) while ventilated with 12% O 2 and 88% N 2 (CONTR group) or 88% Ar (ARG group). The perfusate was saturated with the same gas mixture but with the addition of CO 2 to an end-tidal CO 2 of 35-45 mmHg. The saturated perfusate was drained and lungs were perfused with whole blood for an additional 2 hours on EVLP. Evaluation at the end of EVLP did not show significant effects on physiologic parameters by prolonged exposure to Ar. Also wet-to-dry weight ratio did not improve in the ARG group. Although in other organ systems protective effects of Ar have been shown, we did not detect beneficial effects of a high concentration of Ar on cold pulmonary ischemia-reperfusion injury in a porcine lung model after prolonged exposure to Ar in this porcine model with EVLP assessment., Competing Interests: Conflicts of interest None.