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BACKGROUND: Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes. METHODS: In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD). RESULTS: Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO2/FiO2 ratios and reduced incidence of PGD. CONCLUSIONS: Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes.

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Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7-8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7-307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD.

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Introduction: In recent years, the field of graft preservation has made considerable strides in improving outcomes related to solid organ restoration and regeneration. Ex vivo lung perfusion (EVLP) in line with the related devices and treatments has yielded promising results within preclinical and clinical studies, with the potential to improve graft quality. Its main benefit is to render marginal and declined donor lungs suitable for transplantation, ultimately increasing the donor pool available for transplantation. In addition, using such therapies in machine perfusion could also increase preservation time, facilitating logistical planning. Cytokine adsorption has been demonstrated as a potentially safe and effective therapy when applied to the EVLP circuit and post-transplantation. However, the mechanism by which this therapy improves the donor lung on a molecular basis is not yet fully understood. Methods: We hypothesized that there were characteristic inflammatory and immunomodulatory differences between the lungs treated with and without cytokine adsorption, reflecting proteomic changes in the gene ontology pathways and across inflammation-related proteins. In this study, we investigate the molecular mechanisms and signaling pathways of how cytokine adsorption impacts lung function when used during EVLP and post-transplantation as hemoperfusion in a porcine model. Lung tissues during EVLP and post-lung transplantation were analyzed for their proteomic profiles using mass spectrometry. Results: We found through gene set enrichment analysis that the inflammatory and immune processes and coagulation pathways were significantly affected by the cytokine treatment after EVLP and transplantation. Conclusion: In conclusion, we showed that the molecular mechanisms are using a proteomic approach behind the previously reported effects of cytokine adsorption when compared to the non-treated transplant recipients undergoing EVLP.

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Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.

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Lung transplantion (LTx) recipients have low long-term survival and a high incidence of bronchiolitis obliterans syndrome (BOS), an inflammation of the small airways in chronic rejection of a lung allograft. There is great clinical need for a minimally invasive biomarker of BOS. Here, 644 different proteins were analyzed to detect biomarkers that distinguish BOS grade 0 from grades 1-3. The plasma of 46 double lung transplant patients was analyzed for proteins using a high-component, multiplex immunoassay that enables analysis of protein biomarkers. Proximity Extension Assay (PEA) consists of antibody probe pairs which bind to targets. The resulting polymerase chain reaction (PCR) reporter sequence can be quantified by real-time PCR. Samples were collected at baseline and 1-year post transplantation. Enzyme-linked immunosorbent assay (ELISA) was used to validate the findings of the PEA analysis across both time points and microarray datasets from other lung transplantation centers demonstrated the same findings. Significant decreases in the plasma protein levels of CRH, FERC2, IL-20RA, TNFB, and IGSF3 and an increase in MMP-9 and CTSL1 were seen in patients who developed BOS compared to those who did not. In this study, CRH is presented as a novel potential biomarker in the progression of disease because of its decreased levels in patients across all BOS grades. Additionally, biomarkers involving the remodeling of the extracellular matrix (ECM), such as MMP-9 and CTSL1, were increased in BOS patients.

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Purpose: The influence of allograft ischemic time (IT) on short- and long-term mortality remains under debate in lung transplantation (LTx). Due to a scarcity in donors, better understanding of IT might improve the outcome after LTx. Methods: Between January 1990 and June 2016; 307 patients underwent LTx at Lund university hospital, Sweden. The end-point used was death/Re-LTx assessed by Cox regression and Kaplan-Meier survival. Results: Kaplan-Meier survival for mean IT (min) between subgroups ≤120, 121-240, 241-360 and 361+ showed significant difference for pairwise-comparisons with superior outcome for IT between ≤120 and 240 min. Cox regression analyses for each hour of IT in patients with a limited survival up to 1- and 5-year had a hazard ratio (HR) of 1.119 and 1.063 respectively (p < .05). Conclusions: In LTx, every 2-hour increase of IT is equivalent to an increased mortality of up to 24% within 5 years. LTx with an IT of ≤120 min had a superior survival in both 1- and 5 years in comparison to an IT of up to 360 min. Better application of IT provides a key role in improving LTx outcome.

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BACKGROUND: In 2006 and 2007 we performed double lung transplantation with marginal donor lungs assessed and reconditioned by Ex Vivo Lung Perfusion (EVLP), using a technique developed by Professor Stig Steen. Here we present a 10-year follow-up comparing the outcomes of lung transplantations performed at our clinic using EVLP lungs vs. conventional lungs. METHOD: Between 2006 and 2007, 21 patients (6 EVLP, 15 conventional) underwent double lung transplantation (LTx) with follow-up on May 2017 at Lund University Hospital, Sweden. Pulmonary function was measured at 3/6/12 months, and annually thereafter for a period of 10 years in addition to survival and freedom from chronic lung allograft dysfunction (CLAD) being analyzed. RESULTS: Regarding Forced Expiratory Volume in 1 s (FEV1) and 6MWT at 3, 6, and 12 months and annually thereafter, no difference in median FEV1 nor 6MWT was found for EVLP-LTx vs. conventional-LTx (p > 0.05). No difference was shown in post-operative survival between EVLP-LTx vs. conventional LTx for patients with an overall survival up to 10-years (p > 0.05). The same pattern was shown in sub analyses for patients with a limited survival up to 1 and 5 years (p > 0.05). CONCLUSION: No superiority was found in conventional-LTx over EVLP-LTx, neither in long-term survival nor pulmonary function. No difference in CLAD-free survival was seen between the two groups. We believe that EVLP is a safe and effective method to use in LTx, greatly increasing the donor pool by improving marginal lungs and providing an objective assessment of the viability of marginal donor lungs.

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OBJECTIVES: Our goal was to validate the Swedish Cardiac Surgery Registry by reviewing the reported cardiac operations to assess the completeness and quality of the registered data and the EuroSCORE II variables. METHODS: A total of 5837 cardiac operations were reported to the Swedish Cardiac Surgery Registry in Sweden during 2015. A randomly selected sample of 753 patient records (13%) was scrutinized by 3 surgeons at all 8 units in Sweden performing open cardiac surgery in adults. RESULTS: Coverage was excellent with 99% [95% confidence interval (CI) 98-99%] of the performed procedures found in the registry. Reported waiting times for surgery were correct in 78% (95% CI 76-79%) of the cases. The main procedural code was correctly reported in 96% (95% CI 95-97%) of the cases. The correlation between reported and monitored logistic EuroSCORE II had a coefficient of 0.79 (95% CI 0.76-0.82), and the median difference in EuroSCORE II was 0% (interquartile range -0.4% to 0.4%). The majority of EuroSCORE II variables had good agreement and coherence; however, New York Heart Association functional class, preoperative renal dysfunction, left ventricular ejection fraction, Canadian Cardiovascular Society Class IV angina and poor mobility were less robust. Postoperative complications were rare and in general had a high degree of completeness and agreement. CONCLUSIONS: The reliability of the variables in the national Swedish Cardiac Surgery Registry was excellent. Thus, the registry is a valuable source of data for quality studies and research. Some EuroSCORE II variables require improved and stricter definitions to obtain uniform reporting and high validity.

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