Post-lung Transplant Research Articles

Bronchial Complications and Survival Outcomes in Post-Lung Transplant

<h3>Purpose</h3> This study contrasts the current standard practice of continuous suturing to interrupted suturing during lung transplantation (LTx). We compared survival outcomes between groups, and further categorized the differences in the rate, type, and treatment of bronchial complications. <h3>Methods</h3> There were 889 LTx at our high-volume single center from Feb2012 to Jun2021. Continuous suturing was executed using 3/0 polypropylene suture on an SH needle. Interrupted implemented the same technique for the membranous portion of the anastomosis, and multiple interrupted 3/0 polypropylene sutures for the cartilaginous portion. Kaplan-Meier curves and log-rank tests compared survival, and Cox regression analysis examined impact on survival. Clinical parameters and demographics were compared, with p values <0.05 considered significant. <h3>Results</h3> Of 889 patients, 548 received continuous suturing while 341 received interrupted suturing. Demographics and clinical parameters between groups were: age (p = 0.029), gender (p = 0.9), race (p = 0.63), etiology (p = 0.261), lung allocation score (p = 0.25), BMI (p = 0.049), single versus double LTx (p < 0.0001). Bronchial complications occurred at similar rates (p = 0.38), as did types of complications (ischemia/necrosis, dehiscence, stenosis, malacia) except for dehiscence (4.5% continuous, 0.7% interrupted). ECMO was utilized in 54 vs 28 patients (continuous vs. interrupted; p = 0.12). Complications were treated similarly (p = 0.69) with dilation + stent being the most common treatment. Kaplan-Meier survival curve showed no significant difference in survival (p = 0.177). Cox regression analysis showed no difference between techniques, with bronchial complications, ECMO usage, and diagnosis having a statistically significant effect on survival. <h3>Conclusion</h3> Our study found similar survival outcomes, bronchial complication rates, and complication treatments between techniques, demonstrating comparable outcomes for both techniques.

Reduction of Donor Mononuclear Phagocytes During Ex Vivo Lung Perfusion Attenuates Ischemia-Reperfusion Injury in a Rat Lung Transplantation Model

<h3>Purpose</h3> Mononuclear phagocytes (MPs) play a key role in post-lung transplantation (LTx) ischemia-reperfusion injury (IRI). Clodronate-liposome is a promising drug for the depletion of MPs. We hypothesized that the administration of clodronate-liposome into the perfusate during <i>ex vivo</i> lung perfusion (EVLP) could reduce MPs and attenuate IRI in a rat LTx model. <h3>Methods</h3> Lewis rat lungs were flushed with Perfadex® solution and stored for 15 h at 4°C. In Experiment I, grafts were allocated to two groups: control and clodronate (n = 5 each). In the clodronate group, 3 mL of clodronate-liposome was administered into the perfusate before EVLP. After 4 h of EVLP, the amounts of MPs in the perfusate and digested lung tissue were measured via flow cytometry. In Experiment II, grafts were similarly allocated to two groups: control and clodronate (n = 6 each). After 4 h of EVLP, left lungs were transplanted and reperfused for 2 h. Lung function was then evaluated, and samples were collected. The Mann-Whitney U test was used for comparing the two groups. Repeated measures analysis of variance was used for comparing data obtained during EVLP. <h3>Results</h3> In Experiment I, the amounts of MPs were significantly reduced in the clodronate group (<i>P</i>=0.008, Figure 1A). In Experiment II, compliance and vascular resistance during EVLP were significantly better in the clodronate group than in the control group (<i>P</i><0.001 and <i>P</i><0.001, respectively). Two hours after reperfusion, the PaO₂/FiO₂ ratio from the pulmonary vein was significantly higher in the clodronate group (<i>P</i>=0.015, Figure 1B), whereas the wet-to-dry weight ratio was significantly lower (<i>P</i>=0.026). Regarding scoring of histological findings, less lung injury was observed in the clodronate group than in the control group (<i>P</i>=0.013). <h3>Conclusion</h3> The administration of clodronate-liposome into the perfusate during EVLP demonstrated significant attenuation of MPs in the donor lungs and IRI post-LTx.

Post-Transplantation Anemia and Risk of Death Following Lung Transplantation

<h3>Purpose</h3> Post-transplantation anemia (PTA) is frequent among solid organ transplant recipients and has been associated with increased morbidity and mortality. However, the prevalence and impact of PTA in lung transplant recipients is still not elucidated. <h3>Methods</h3> We performed a retrospective cohort study of adult Danish lung transplant recipients between January 2010 and December 2019. The prevalence and severity of PTA were determined during the first three years post-transplantation. Associations between PTA and selected risk factors were established using uni- and multivariate logistic regression models. <h3>Results</h3> A total of 278 patients were included. At one and three years post-lung transplantation the prevalence of PTA was 75% and 52%, respectively. Male sex was associated with increased odds of PTA at 6, 12, 24, and 36 months post-transplantation (aOR ranging from 2.3 (95%CI 1.1-4.6, p = 0.02) to 5.9 (95%CI 2.6-14, p < 0.001)). Cystic fibrosis was also associated with anemia at one year post-transplantation (aOR 4.3, 95%CI 1.2-17, p = 0.03). We found no strong associations between PTA and renal function or viral infections. Excess mortality in recipients with moderate or severe anemia compared to patients with mild or no anemia was borderline significant at one year post-lung transplantation (aHR 2.0, 95%CI 0.9-4.4, <i>p</i> = 0.07). <h3>Conclusion</h3> PTA is very common in Danish lung transplant recipients. Male sex and cystic fibrosis are independent risk factors for development of anemia. Our results suggest excess mortality in patients who have moderate or severe anemia one year after lung transplantation.

Donor Derived Coccidioides in a Lung Transplant Recipient

<h3>Introduction</h3> There are no universal guidelines on screening donors for coccidioides. We describe a fatal case of coccidioides empyema from a donor previously residing in an endemic region. <h3>Case Report</h3> This is a 72 year old male, status post right single lung transplantation 3 weeks prior for chronic hypersensitivity pneumonitis, who presents to clinic with a productive cough. The donor was a 31 year old male with no medical history from the southern inland region of California. A chest X-ray in clinic demonstrated a right pleural effusion. He underwent thoracentesis and bronchoscopy on post-operative day (POD) 22. Pleural fluid was lymphocytic and exudative with negative cultures, and transbronchial biopsies showed mild acute cellular rejection. He was treated with pulse dose steroids. His symptoms worsened one week later when he was seen in the emergency department. Chest CT showed a large right loculated pleural effusion. The patient was started on broad spectrum antibiotics, and a thoracostomy tube was placed, demonstrating a neutrophil predominant exudate. Repeat chest CT showed the effusion extending through the chest wall, and an additional thoracostomy tube was placed. The patient became more hypoxemic requiring mechanical ventilation and VV-ECMO. Pleural cultures taken two-days prior demonstrated mold and the patient underwent irrigation with amphotericin in the operating room, along with intravenous amphotericin. Ultimately, the patient had multi-organ failure and cardiac arrest. Following his passing, pleural fluid cultures confirmed growth of Coccidioides immitis. <h3>Summary</h3> This case describes a patient with initial negative serologies to coccidioides and a donor from the southern inland region of California, where the incidence of coccidioides is increasing. Transmission of donor-derived coccidioides has been shown to be 43% within 30 days post-transplant, with a 29% mortality. Given the high mortality and treatment availability, screening donors in endemic areas with serologies may prevent post-transplant complications.

Endothelial Protection via Heparanase Inhibition Attenuates Ischemia-Reperfusion Injury in Mice

<h3>Purpose</h3> The endothelial glycocalyx (eGC) is a protective layer covering the endothelial surface. Upon the damage to the endothelium, heparanase (HPSE) cleaves heparan sulfate in the eGC and leads to further endothelial dysfunction. We hypothesized that inhibition of HPSE may preserve endothelial glycocalyx and contribute to better organ preservation and improved post lung transplant outcomes. We tested our hypothesis by pre-treating mice with an HPSE inhibitor (heparastatin SF4) using an ischemia-reperfusion (I/R) injury model by total hilar clamping. <h3>Methods</h3> Mice left lung hilar I/R injury model was used in this study. Before ischemia, PBS (control) or SF4 (40 μM of 50 μl) was administered to the mice intraperitoneally. Left lungs were clamped for an hour followed by reperfusion for 4 hours. Oxygenation, inflammation and eGC related enzyme activities were defined to evaluate organ function. Data were compared among sham, control and SF4 groups. <h3>Results</h3> Left lung function measured by PaO2/FiO2 was significantly lower in controls (PBS) compared to SF4 after I/R injury. However, it was not different between SF4 and sham groups (Figure A). The mRNA expressions of proinflammatory cytokines, interleukin-6 and tumor necrosis factor-α, were upregulated in the lung after I/R in control compared to sham but downregulated in SF4 treated lungs (Figure B). HPSE activity in lung tissue after I/R was significantly reduced by SF4 given before ischemia. (p=0.02). In addition, the mRNA level and activity of matrix metalloproteinase (MMP)-2 were also notably decreased in lungs after I/R injury by SF4 treatment compared to control. Significant upregulation of MMP9 proactive form was observed in SF4-treated lungs. <h3>Conclusion</h3> HPSE inhibition can attenuate lung injury against I/R by preventing activation of the endothelium and eGC degradation. Protection of eGC may improve graft preservation and post-lung transplant outcomes.

Gastroparesis Following Lung Transplant: A Single Center's Experience

<h3>Purpose</h3> Gastroparesis is a known complication following lung transplantation; however, few studies have focused on the identification of risk factors for its development and literature describing the natural history of gastroparesis in lung transplant patients is lacking. Currently at our institution it is common practice for these patients to undergo various surgical and procedural interventions with the goal of ameliorating symptoms and improving gastric emptying. We aim to identify potentially modifiable risk factors for the development of gastroparesis, as well as the impact of common interventions. <h3>Methods</h3> This is a single center, retrospective observational study. From 1/1/2016 to 10/15/2020, a total of 27 patients underwent bilateral lung transplant and were subsequently diagnosed with gastroparesis as confirmed by gastric emptying study. Baseline patient characteristics, diagnostic and procedural interventions (including type of study, intervention performed and timing), and outcomes data (length of stay for transplant hospitalization, survival, and impact of intervention) were collected. <h3>Results</h3> Demographics and outcomes data are described in Table 1. Figure 1 depicts the procedural and surgical interventions within this patient population, as well as outcome data. <h3>Conclusion</h3> In conclusion, this is the largest study to date that has reviewed the natural history of gastroparesis post lung transplant and describes outcomes following procedural and surgical interventions. Larger scale, multicenter trials are needed to better define the natural history of gastroparesis as well as the utility of surgical and procedural interventions.

Extracorporeal Photopheresis in Lung Transplantation - New Frontiers in Infection Immunomodulation - A Case Series

<h3>Purpose</h3> Lung transplantation outcomes are limited by chronic lung allograft dysfunction (CLAD). Infection driven loss of graft function is a common cause of CLAD. Extracorporeal photopheresis (ECP) is a salvage therapy post lung transplantation with the indications broadening as experience and availability increases. The therapeutic role of ECP is yet to be explored in infection driven CLAD. <h3>Methods</h3> A retrospective audit of all lung transplant recipients at a single UK lung transplant centre who received ECP from 2017 to 2021 was performed using electronic records.5 patients with infection driven CLAD treated with ECP were identified. <h3>Results</h3> 40% were male with median(range) age 63(30-70) years. Median duration from lung transplant to ECP was 38(13-53)months and median duration of ECP was 14(10-15) months. All 5 patients were responders at 2 months (defined as less than 20 percent FEV1 fall). Median(range) FEV1 percentage change improved from -17% (-20 to+10%) one year pre-ECP to +1%(-1to+10%) one year post-ECP (Figure1). Mycophenolate mofetil was stopped for all patients on initiation of ECP. 4 patients had a reduction in length of stay in hospital (Figure 2). 3 patients were alive 1 year post ECP whilst 2 patients are still within their first year of follow up. <h3>Conclusion</h3> ECP can help to stabilize graft function in lung transplant recipients with recurrent infections. It allows for modification of conventional immunosuppression regimens and contributes to improved quality of life by decreasing the length of hospital stay and number of antibiotic days.

Endothelial Cell Injury and Activation in a Murine Model of Left Lung Transplantation

<h3>Purpose</h3> Endothelial cells are the first non-self-barrier encountered by the recipient's immune system after allograft transplantation and thus are involved early during alloimmune response. Our goal was to study processes of endothelial cell injury/activation in a mouse model of lung transplantation. <h3>Methods</h3> Mouse orthotopic left lung transplantation was performed in isografts (C57BL/6 to C57BL/6) and allografts (Balbc to C57BL/6), both received daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone) and were serially sacrificed at day 1, 7 and 35 post-transplant (n=6/timepoint/group). Left transplanted lungs were made into single cell suspension and absolute cell numbers were quantified by flow cytometry for CD31+ endothelial cells, CD45+ leukocytes and MHCI/II, VCAM-1 and ICAM-1 for cell activation. One additional allograft and isograft were scanned with high resolution (HR) <i>ex vivo</i> microCT (µCT) to visualize airways and blood vessels at day 70 post transplantation. <h3>Results</h3> Endothelial cell numbers decreased from day 1 until day 7 (p=0.03) in allografts and recovered slightly at day 35. While in isografts, endothelial cells seemed to increase non-significantly over time. In contrast, leukocytes significantly increased at day 7 in allografts versus day 1 (p=0.036) and isografts at day 7 (p=0.003). Leukocytes remained stable in isografts over time (p=0.3). Mean fluorescence intensity (MFI) was increased for MHC I/II and VCAM-1 (p=0.003; p<0.0001; p=0.04) on endothelial cells, the MFI of MHC I/II and ICAM-1 on leukocytes was increased in allografts versus isografts (p=0.0002; p=0.006; p=0.002). HR µCT showed normal airway morphology while lumen of arteries and veins was narrowed in allograft compared to isograft. Arterioles and venules were occluded in allograft. <h3>Conclusion</h3> Destruction of endothelial cells may represent the very first onset of alloimmune response post lung transplantation and warrant further investigations towards diagnostic and therapeutic approaches.

Clinical Predictors of Lung Transplant Outcomes in Patients with Scleroderma Compared with Pulmonary Fibrosis

Purpose Primary Graft Disfunction (PGD) is the leading cause of early morbidity and mortality after lung transplant. We sought to identify risk factors for PGD and survival in patients with scleroderma undergoing lung transplant compared to patients with pulmonary fibrosis. Methods This was a single center retrospective cohort study, of patients that underwent lung transplantation for scleroderma or pulmonary fibrosis from 2007 to 2020. Propensity scores were used to match the scleroderma group with the pulmonary fibrosis group based on lung allocation score and age at lung transplant. Univariable analyses identified factors associated with the development of PGD 72 hours posttransplant, and six-month survival. Survival rates were compared using Kaplan-Meier analysis. Results We compared 104 patients with scleroderma to 389 patients with pulmonary fibrosis who underwent lung transplant. After propensity matching, compared with pulmonary fibrosis, scleroderma patients had reduced 90-day survival (99.0% vs 90.2%, p=0.007). However, there was no statistically significant difference in 1 year (84.4% vs 79.1%, p=0.23) or 5-year survival (64.9% vs 52.9%, p=0.98). Scleroderma patients were more likely to have PGD 72 hours posttransplant (29.4% vs 11.8%, p=0.01). Scleroderma patients who developed PGD had higher volumes of intraoperative transfusion of blood products (p=0.02), plasma (p=0.04), platelets (p=0.03), but not red blood cells (p=0.28). Preoperative history of chronic kidney disease (p<0.001) and postoperative Acute Kidney Injury [AKI] (p=0.028) were also associated with the development of PGD. Donor factors for developing PGD in scleroderma patients were traumatic brain injury as cause of donor death (p=0.015) and donor history of smoking (p=0.02). Risk factors for 6-month mortality were postoperative right ventricular dysfunction (p=0.02) or dilation (p=0.003), stroke (p=0.02), atrial fibrillation (p=0.01), PGD (p<0.001), AKI (p=0.005) and decreased glomerular filtration rate 3 months posttransplant (p=0.04). Conclusion Scleroderma had higher rates of post lung transplant PGD compared to pulmonary fibrosis. Kidney function plays a prominent role in the risk of developing PGD and mortality in this population. Despite reduced 90-day posttransplant survival in scleroderma patients, 1- and 5-year survival rates were similar. Primary Graft Disfunction (PGD) is the leading cause of early morbidity and mortality after lung transplant. We sought to identify risk factors for PGD and survival in patients with scleroderma undergoing lung transplant compared to patients with pulmonary fibrosis. This was a single center retrospective cohort study, of patients that underwent lung transplantation for scleroderma or pulmonary fibrosis from 2007 to 2020. Propensity scores were used to match the scleroderma group with the pulmonary fibrosis group based on lung allocation score and age at lung transplant. Univariable analyses identified factors associated with the development of PGD 72 hours posttransplant, and six-month survival. Survival rates were compared using Kaplan-Meier analysis. We compared 104 patients with scleroderma to 389 patients with pulmonary fibrosis who underwent lung transplant. After propensity matching, compared with pulmonary fibrosis, scleroderma patients had reduced 90-day survival (99.0% vs 90.2%, p=0.007). However, there was no statistically significant difference in 1 year (84.4% vs 79.1%, p=0.23) or 5-year survival (64.9% vs 52.9%, p=0.98). Scleroderma patients were more likely to have PGD 72 hours posttransplant (29.4% vs 11.8%, p=0.01). Scleroderma patients who developed PGD had higher volumes of intraoperative transfusion of blood products (p=0.02), plasma (p=0.04), platelets (p=0.03), but not red blood cells (p=0.28). Preoperative history of chronic kidney disease (p<0.001) and postoperative Acute Kidney Injury [AKI] (p=0.028) were also associated with the development of PGD. Donor factors for developing PGD in scleroderma patients were traumatic brain injury as cause of donor death (p=0.015) and donor history of smoking (p=0.02). Risk factors for 6-month mortality were postoperative right ventricular dysfunction (p=0.02) or dilation (p=0.003), stroke (p=0.02), atrial fibrillation (p=0.01), PGD (p<0.001), AKI (p=0.005) and decreased glomerular filtration rate 3 months posttransplant (p=0.04). Scleroderma had higher rates of post lung transplant PGD compared to pulmonary fibrosis. Kidney function plays a prominent role in the risk of developing PGD and mortality in this population. Despite reduced 90-day posttransplant survival in scleroderma patients, 1- and 5-year survival rates were similar.

Malnutrition in Lung Transplant Recipients: Weighing the Outcomes

<h3>Purpose</h3> Malnutrition negatively impacts outcomes post-lung transplantation. Therefore, nutrition status is routinely considered in the selection criteria for lung transplant candidates. Malnourishment is often present in patients with end-stage lung disease, and unfortunately, it cannot always be resolved before surgery. The impact of malnutrition on lung transplant outcomes has been assessed in the literature using a variety of different methods. However, the standard of care used by nutrition experts and Registered Dietitians, the Academy of Nutrition and Dietetics/American Society of Parenteral and Enteral Nutrition (AND/ASPEN) criteria, has not been considered. Here we investigated how malnutrition identified by these criteria can affect outcomes of lung transplant recipients. <h3>Methods</h3> We retrospectively assessed twenty-two patients who met criteria for moderate or severe malnutrition at the time of transplant using the AND/ASPEN criteria between Jan 1st 2018 and June 1st 2021. We used a control group of twenty-two non-malnourished patients that had similar age and transplant type (single vs bilateral) and compared several different outcome measures using a Kruskal-Wallis test. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). <h3>Results</h3> The average age of both groups was 54.4 years, and 50% of the population was female. We found a significant increase in length of stay (LOS) for the malnourished group (p=0.045) as well as an increased need for return to the intensive care unit (ICU) within 60 days of transplant (p=0.021). Interestingly, no differences were found between the two groups regarding days on a ventilator, days in ICU, the number of rejections in the first six months, or the need for acute inpatient rehabilitation (AIR) following the transplant admission. <h3>Conclusion</h3> Malnutrition identified by AND/ASPEN criteria does seem to impact outcomes following lung transplant, specifically overall LOS and the need for return to ICU within 60 days of transplant. However, there were no significant differences with days on a ventilator, days in ICU, number of rejections in the first 6 months, or need for AIR after transplant. If possible, malnutrition should be improved before lung transplantation. Larger studies are needed to better understand the impact of malnutrition on outcomes after lung transplant.

CFTR Modulators and Lung Transplantation: Factors to Consider - A UK Transplant Centre Experience

<h3>Purpose</h3> Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are drugs that act on the defective CFTR protein in people with cystic fibrosis (pwCF), resulting in improved CFTR protein function and thus improved CF symptoms. Evidence is increasing of their positive impact on extra-pulmonary features of CF, which remains problematic in pwCF post-lung transplantation (LTx). Elexacaftor/tezacaftor/ivacaftor (ele/tez/iva) was licensed in the UK in August 2020. It has been debated since if ele/tez/iva has a role post-LTx for ongoing non-pulmonary CF symptoms. We aim to highlight the practical issues faced when considering this drug in the post-LTx CF population in a single large UK LTx unit. <h3>Methods</h3> Retrospective analysis of electronic records of pwCF post-LTx with ongoing extra-pulmonary manifestations considered for initiation of ele/tez/iva August 2020-2021, including demographics, potential benefits, contraindications and outcomes. <h3>Results</h3> 5 pwCF with LTx have been discussed with their CF physicians to consider initiating ele/tez/iva (some had more than one problem):- sinus (n = 2); bowels (n = 2); weight (n = 2); other (n = 2). All were at least 12 months post-LTx (median 42 months; range 21-191 months). Discussions were initiated by the patient in 1 case, the CF team in 2, and transplant team in 2. 3 were not initiated - 1 due to potential side effects on mental health and 2 were contraindicated with deranged liver tests and ongoing bowel symptoms. 2 were initiated on ele/tez/iva. Of these, one is on tacrolimus, needed no immunosuppression adjustment, but stopped due to drop in FEV1 (CT and biopsy negative for features of rejection) which recovered. The other is on sirolimus, needed significant reduction in immunosuppression (9mg to 4mg) and remains on ele/tez/iva. <h3>Conclusion</h3> Extra-pulmonary manifestations of CF are varied and continue post-LTx. With increasing evidence supporting using CFTR modulators to manage extra-pulmonary symptoms, it is important to establish the role these drugs can have in the post-LTx CF population, but also the potential risks. Our experience so far shows mixed results and that discussion between CF and transplant physicians, with patient involvement is vital to ensure correct decisions are taken. Randomised controlled trials are needed to ensure modulator use in pwCF post-LTx is supported by robust evidence.

The Combination of Post-Mortem Sevoflurane Ventilation and In Situ Topical Cooling Provides Improved 6h Lung Preservation in an Uncontrolled DCD Porcine Model

Purpose Recent clinical series on donation after uncontrolled cardiac death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3h post-mortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model. Methods After uDCD induction, donor pigs were allocated to one of the following groups: (1) static lung inflation only (SLI); (2) SLI + continuous intrapleural topical cooling (TC); or (3) sevoflurane preconditioning (30 min) + SLI + TC. Six hours post-asystole, lungs were retrieved and evaluated via ex vivo lung perfusion (EVLP) for 6 hours. The group with best performance on EVLP was then evaluated by transplantation in the 2nd phase of the study. Grafts were reperfused for 4h, followed by right pulmonary hilar clamping to evaluate graft oxygenation and ventilatory mechanics. Results A target intrathoracic temperature < 15°C was achieved within 1 hour of chest filling in groups 2 and 3. All lungs in group 1 failed - i.e., met EVLP termination criteria in 1h (Fig.1A). At 1h lungs from group 3 presented lower PVR, lower airway pressures, higher compliances and a higher P/F ratio compared to group 1 (Fig.1B). Despite similar early performance of groups 2 and 3, group 3 showed lower airway pressures and higher pulmonary compliances at the final hour (Fig.1C). Post-EVLP lung weight (edema) was higher in group 1 compared to groups 2 and 3 (Fig.1B). Post-transplant graft assessment in group 3 showed good oxygenation throughout the post-reperfusion observation period (Fig.1D). Conclusion Preservation of uDCD lungs with sevoflurane + static lung inflation + topical cooling maintains good pulmonary function up to 6h post-mortem with excellent early post-lung transplant function. These interventions could potentially help expand the clinical utilization of uDCD donor lungs for transplantation. Recent clinical series on donation after uncontrolled cardiac death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3h post-mortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model. After uDCD induction, donor pigs were allocated to one of the following groups: (1) static lung inflation only (SLI); (2) SLI + continuous intrapleural topical cooling (TC); or (3) sevoflurane preconditioning (30 min) + SLI + TC. Six hours post-asystole, lungs were retrieved and evaluated via ex vivo lung perfusion (EVLP) for 6 hours. The group with best performance on EVLP was then evaluated by transplantation in the 2nd phase of the study. Grafts were reperfused for 4h, followed by right pulmonary hilar clamping to evaluate graft oxygenation and ventilatory mechanics. A target intrathoracic temperature < 15°C was achieved within 1 hour of chest filling in groups 2 and 3. All lungs in group 1 failed - i.e., met EVLP termination criteria in 1h (Fig.1A). At 1h lungs from group 3 presented lower PVR, lower airway pressures, higher compliances and a higher P/F ratio compared to group 1 (Fig.1B). Despite similar early performance of groups 2 and 3, group 3 showed lower airway pressures and higher pulmonary compliances at the final hour (Fig.1C). Post-EVLP lung weight (edema) was higher in group 1 compared to groups 2 and 3 (Fig.1B). Post-transplant graft assessment in group 3 showed good oxygenation throughout the post-reperfusion observation period (Fig.1D). Preservation of uDCD lungs with sevoflurane + static lung inflation + topical cooling maintains good pulmonary function up to 6h post-mortem with excellent early post-lung transplant function. These interventions could potentially help expand the clinical utilization of uDCD donor lungs for transplantation.

Central VA-ECMO Support without Full Anticoagulation is Feasible During Lung Transplant

<h3>Purpose</h3> Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support is increasingly used instead of cardiopulmonary bypass (CPB) during lung transplant for mechanical circulatory support. In this study, we analyzed the feasibility of central VA-ECMO without full anticoagulation during lung transplantation. We also analyzed the incidence of morbidity including ischemic and thrombotic complications, stroke, and postoperative outcomes. <h3>Methods</h3> This is a retrospective review of an institutional lung transplant database. We included consecutive patients from March 2018 through January 2021. Patients were stratified into two cohorts: those undergoing central VA-ECMO during lung transplant and those undergoing traditional cardiopulmonary bypass. Patients undergoing VA-ECMO did not receive systemic anticoagulation at the time of surgery. 109 total patients were included in the study. <h3>Results</h3> 57 patients underwent central VA-ECMO during lung transplant while 52 underwent traditional cardiopulmonary bypass. The VA-ECMO patients had longer operative time and ischemic time then non VA-ECMO patients (7.9 ± 1.4 vs 6.4 ± 2.0, p<0.001, 5.3 ± 1.1 vs 4.2 ± 2.0, p<0.001). However, there was no significant difference in all of blood transfusion between two groups. Post-lung transplant complications between the VA-ECMO and non-VA-ECMO patients were similar, with the exception of AKI which was higher in VA-ECMO patients (52.2% vs 25.0%, p=0.01). Intensive care unit stay and overall hospital stay was not significantly different between the two groups. <h3>Conclusion</h3> These findings suggest that central VA-ECMO without anticoagulation is a safe alternative to traditional cardiopulmonary bypass during lung transplantation. While use of VA-ECMO increased operative time, it did not result in increased rate of blood transfusions or lengthen overall hospital stay. We believe this approach could improve outcomes associated with mechanical life support for lung transplant.

A Machine Learning Classifier to Identify Lung Transplant Recipients (LTRs) Likely to Develop Invasive Aspergillosis (IA) One Year After Transplantation

<h3>Purpose</h3> This study investigates the risk of developing invasive aspergillosis (IA) in LTRs in the first year of follow-up. We developed and validated 3 diverse machine learning (ML) models to identify patients likely to develop IA in the first year after lung transplantation. <h3>Methods</h3> A total of 791 LTRs from January 2010 to January 2017 were followed-up for 1 year after transplantation. IA diagnosis was established as per ISHLT criteria. The data consisted of 13 variables listed in Table 1. Based on transplantation dates, we divided the cohort into 553 and 238 cases for development and validation respectively. We used 3 diverse classification methods (Naïve Bayes, Decision Tree, and Simple Logistic regression) to construct ML classification models. <h3>Results</h3> The use of statins and the presence of <i>Aspergillus</i> colonization post-lung transplant present strong indicators related to IA 1 year after lung transplant (Table 1). The Naïve Bayes classifier (Table 2) achieved sensitivity of 83.3% (CI95% 52-98), specificity 66.4% (CI95% 60-73) and AUC of 86.3% (CI95% 73-100) and presented the most consistent classification performance between development and validation as shown. All 3 ML methods independently utilized the same predictor variables and achieved similar prediction performance (Table 2). <h3>Conclusion</h3> The validation of 3 independent classification models showed that the <i>Aspergillus</i> colonization was indicative of the development of IA and use of statin was associated with a fewer cases of IA. Further clinical validation to assess the utility of using these models is warranted.

Circulating Coagulation Regulator Levels After Lung Transplantation Are Associated with Acute Kidney Injury

<h3>Purpose</h3> Acute kidney injury (AKI) is a common morbidity after lung transplantation, with postoperative rates up to 65%. Since microvascular coagulation contributes to AKI in preclinical models, we hypothesized that post-reperfusion circulating levels of the coagulation regulators plasminogen activator inhibitor-1 (PAI-1), protein C, and resistin, an inhibitor of protein C, would be associated with AKI. <h3>Methods</h3> The study population included 189 recipients enrolled from 7/2017-6/2019 in the 5-center Lung Transplant Outcomes Group Acute Kidney Injury (LTOG-AKI) prospective cohort study. We used Cuzick's nonparametric test of trend to examine the associations of plasma PAI-1, resistin, and protein C levels at 6 and 24 hours post-reperfusion with AKI severity (grouping stages 2-3) over the first 7 days post-transplant. We staged AKI using Kidney Disease Improving Global Outcomes creatinine criteria. We constructed ordinal logistic regression models of the association of each biomarker with AKI stage adjusting for preoperative biomarker levels, age, gender, chronic kidney disease, and transplant diagnosis. <h3>Results</h3> AKI stage 1 occurred in 45 (24%) and stage 2-3 in 50 (26%) patients. Hospital mortality was substantially higher in stage 2-3 AKI (18% vs 2% for both no AKI and stage 1 AKI, p=0.001). Plasma PAI-1 and resistin levels at 6h were associated with AKI stage (p<0.001, p=0.001, respectively), with similar findings at 24h (p<0.001, p=0.006, respectively). Protein C levels at 6h decreased with higher AKI stage (p=0.016). Six-hour PAI-1 and protein C remained associated with AKI stage in multivariable models, while the 6h resistin-AKI stage association was attenuated, particularly by adjustment for age and preoperative resistin levels (<b>Figure 1</b>). <h3>Conclusion</h3> Plasma levels of coagulation regulators at 6h post-lung transplant are associated with AKI stage and may offer insight into pathophysiologic mechanisms contributing to high AKI rates in this population.

Tolerability of Extended Multi-Drug Fungal Prophylaxis After Lung Transplant

<h3>Purpose</h3> Lung transplant patients are at risk of fungal infections post-transplant and require anti-fungal prophylaxis (AFP). However, utilization and duration of these agents can be limited by adverse effects. The purpose of this evaluation was to assess the tolerability and duration of AFP post-lung transplant at a large academic medical center. <h3>Methods</h3> This single-center retrospective review included lung transplant patients transplanted from August 2017 to August 2018 who received at least 7 days of AFP and were followed for three years. Patients received a combination of an azole anti-fungal agent, inhaled amphotericin B lipid complex (iABLC), and nystatin suspension immediately post-transplant. Pre-transplant colonization rates, prior fungal infections, transplant indication and baseline characteristics were collected. The primary outcome was tolerability of AFP. Secondary outcomes assessed were adherence and duration of AFP. <h3>Results</h3> Forty patients were included and one patient was excluded from the azole analysis due to a history of liver hyperplasia precluding therapy (Table 1). Patients remained on an azole, iABLC, and nystatin therapy a median of 13.9, 36.6, and 32 months post-transplant, respectively. The most common reason for AFP discontinuation was provider decision to end prophylaxis coverage (Table 2). Seven (19.4%) patients in the azole group, one (4.8%) patient in the iABLC group, and one (4.3%) patient in the nystatin group discontinued therapy due to intolerable side effects and adverse reactions. Patient reported adherence rates were highest in the azole group (87.2%), followed by iABLC (67.5%) and lowest with nystatin (45%). <h3>Conclusion</h3> Despite an extended duration of broad AFP, most patients tolerated therapy without limiting adverse effects. Oral AFP of shorter duration yielded the highest patient reported adherence.

Use of a Medication Questionnaire to Identify Lung Transplant Recipients Benefiting from Pharmacist Prioritization in Clinic

<h3>Purpose</h3> Transplant pharmacist (TXP PharmD) presence in the clinic can improve patient medication knowledge retention, minimize adverse effects, decrease the need for hospital readmission, and ultimately improve outcomes. However, TXP PharmD to patient ratio in high volume clinics can range from 1 PharmD: 15-30 patients/day. Identification of patients most likely to benefit from seeing a TXP PharmD in clinic can aid in prospective interventions. <h3>Methods</h3> Beginning in 2018, questionnaires assessing medication knowledge retention were distributed to all lung transplant recipients (LTRs) during their clinic appointments. Within 1y post-transplant, all LTRs follow-up in clinic at months 1, 2, 3, 4, 5, 6, 8, 10, and 12. Questionnaires completed within 1y post-lung transplant (LT) were collated and responses graded. Variables associated with a greater total number of incorrect responses were analyzed including patient characteristics, index LT admission data, and time post-LT. <h3>Results</h3> Between 2018-2020, 404 medication questionnaires were completed within 1y post-LT. 152 LTRs completed 1 questionnaire and 113 LTRs completed ≥2. Medication retention was lowest (i.e. greatest total number of incorrect responses) at 11 months post-LT (p=0.048). Multivariable analysis of all 152 LTRs identified time post-LT, increasing age (p=0.047), and Black race (p=0.02) as associated with lower medication retention. In the 113 LTRs who completed ≥2 questionnaires, Black race (p=0.02) and location other than home pre-LT (rehab/skilled nursing facility/long-term acute care/inpatient, p=0.04) were associated with lower retention. <h3>Conclusion</h3> Pairing prospective identification of LTRs at risk for lower medication knowledge retention with assessment of patient-specific courses may allow TXP PharmDs to improve efficiency in a high volume lung clinic. Future studies should focus on the most useful types of interventions to help improve deficits in medication knowledge.

Lung cancer in recipients after lung transplant: single-centre experience and literature review

IntroductionLung cancer is a major challenge facing modern medicine. It is the leading cause of cancer-related death in the USA. Little is known of the incidence, prevalence and disease characteristics...

Association Between FEV1 Time Course and Mortality in Lung Transplant Patients Treated with Liposomal Aerosolized Cyclosporine for BOS

<h3>Purpose</h3> Pulmonary allograft function is commonly used as a surrogate marker for a survival end-point in clinical trials of lung transplantation (LTx). However, an association between progression of BOS, FEV₁ trajectory and mortality has not been defined. We sought to determine whether an association exists between longitudinal FEV₁ change (% of FEV₁ from randomization) and mortality from a prior trial of liposomal aerosol cyclosporine (L-CsA) for BOS therapy. <h3>Methods</h3> Analyses performed include all patients from a randomized controlled trial using L-CsA for BOS treatment*. A joint statistical model was utilized combining a linear mixed model for FEV₁ trajectory and Cox regression to assess a correlation between survival and FEV₁ changes. <h3>Results</h3> 21 cases were enrolled (10 single 10,11 double); Mean age 61.3 ± 13.3 years (range: 32 - 81); Maximum FEV₁ post transplant 2.5 ± 0.6 l (range: 1.4 - 3.8); Randomization FEV₁ 1.7 ± 0.6 l (range: 1.1 - 3.0 l); follow up 7.5 years (median 35 months). A significant time by treatment interaction was observed with a more pronounced decline of FEV1 using standard of care (p<0.001). In the Phase II study a borderline significant association between change in FEV₁ and survival (1% decline in FEV₁ /1.076-fold mortality increase; p=0.055) was detected indicating that a 1% decline in FEV1 is associated with a 7.6% increased death risk, 95% confidence interval:(-0.0% - 16.1%) (Figure). <h3>Conclusion</h3> A 7.5 year follow-up analysis of the clinical trial using L-CsA for BOS patients reveals an association between subject longitudinal FEV₁ deterioration and mortality. FEV₁ deterioration may be a reliable surrogate marker of survival having implications for future study designs and interpretations. *A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation. ERJ Open Res 2019; 5: 00167-2019 [https://doi.org/10.1183/23120541.00167-2019].

Survival After Lung Transplantation in Europe - Clad as Major Cause of Death

<h3>Purpose</h3> Lung transplantation (LTX) outcomes are poor in comparison to other solid organ transplantations. Our aim was to review survival, leading chronic complications, and major causes of death in Europe. A particular focus is put on Chronic Lung Allograft Dysfunction (CLAD) and its trends. <h3>Methods</h3> There is no dedicated European registry on lung transplantation, outcomes, and complications. Therefore, accessible data from ISHLT registry with focus on the European continent, European Registries and German Quality report were screened for lung transplantation survival data. Furthermore, a dedicated literature research on chronic complications following LTX and particularly CLAD was performed with focus on Europe. In a further step, clinical trial registries were screened for advanced trials addressing the leading form of CLAD - obstructive phenotype - Bronchiolitis Obliterans Syndrome (CLAD-BOS). <h3>Results</h3> Survival rate for LTX reaches 83.2% and 71% at 1 and 3 years, based on 3502 cases included between 2013 and 2016 in the ISHLT registry - European Continent, under exclusion of retransplant. Eurotransplant data from 2012 to 2016 comprising 3053 LTX from Austria, Belgium, Germany, and the Netherlands state survival rates of 83.5%, 76.8% and 62.5% at year 1, 2 and 5. Yet, pan-European data are lacking. Some large monocentric European studies report CLAD rates ranging from 38% at 3 years to 44% at longer follow-up. These findings are in line with US data. CLAD-BOS represented consistently the most prevalent phenotype, up to 80% of all CLAD cases. Although no dedicated European registry data are available, monocentric studies pinpoint CLAD as the single largest cause of death post-LTX. Within CLAD, BOS phenotype accounts for two-thirds of deaths based on reported autopsy analysis. Currently, two substances targeting CLAD-BOS are in phase 3 clinical investigation in Europe. <h3>Conclusion</h3> In Europe, 3-year post-lung transplantation survival is around 70% and 5-year survival at 63%. CLAD is consistently the most prevalent and fatal complication in lung transplant recipients. CLAD-BOS is the most frequent phenotype. New treatments to address chronic graft failure and primary cause of death in LTX, namely CLAD-BOS, are needed. Currently two therapeutic approaches are under investigation in phase 3 clinical trials aiming at CLAD-BOS in Europe.