Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

Predictors of health-related quality of life in patients undergoing extracorporeal membrane oxygenation for acute severe respiratory failure.

Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a form of life support used in severe respiratory failure. While the short-term complications of VV-ECMO are well described, impacts on health-related quality of life (HRQOL) are less well characterised. This study aims to assess the HRQOL of patients who underwent VV-ECMO for acute severe respiratory failure and explore predictors of poor HRQOL. Methods: We performed a retrospective, observational study of a large cohort of adults who underwent VV-ECMO for acute severe respiratory failure in a single tertiary centre (June 2013-March 2019). Patients surviving critical care discharge were invited to a six-month clinic, where they completed an EQ-5D-5L questionnaire assessing HRQOL. Multivariate analysis was performed to assess prognostic factors for HRQOL. Results: Among the 245 consecutive patients included in this study (median age 45 years), 187 (76.3%) survived until ECMO decannulation and 172 (70.2%) until hospital discharge. Of those, 98 (57.3%) attended a follow-up clinic at a mean (±SD) of 204 (±45) days post-discharge. Patients reported problems with pain/discomfort (56%), usual daily activities (53%), anxiety/depression (49%), mobility (46%), and personal care (21%). Multivariate analysis identified limb ischaemia (-0.266, 95% C.I. [-0.116; -0.415], p = 0.0005), renal replacement therapy (-0.149, [-0.046; -0.252], p = 0.0044), and having received more than four platelet units (-0.157, [-0.031; -0.283], p = 0.0146) as predictors of poor HRQOL. Conclusion: We report that survivors of VV-ECMO have reduced HRQOL in multiple domains at 6 months, with pain reported most frequently. Patients who had limb ischaemia, renal replacement therapy or were transfused more than four units of platelets are particularly at risk of poor HRQOL and may benefit from added support measures.

Early experience of a new national lung allocation scheme in the UK based on clinical urgency.

INTRODUCTION: A new UK Lung Allocation Scheme (UKLAS) was introduced in 2017, replacing the previous geographic allocation system. Patients are prioritised according to predefined clinical criteria into a three-tier system: the super-urgent lung allocation scheme (SULAS), the urgent lung allocation scheme (ULAS) and the non-urgent lung allocation scheme (NULAS). This study assessed the early impact of this scheme on waiting-list and post-transplant outcomes. METHODS: A cohort study of adult lung transplant registrations between March 2015 and November 2016 (era-1) and between May 2017 and January 2019 (era-2). Outcomes from registration were compared between eras and stratified by urgency tier and diagnostic group. RESULTS: During era-1, 461 patients were registered. In era-2, 471 patients were registered (19 (4.0%) SULAS, 82 (17.4%) ULAS and 370 (78.6%) NULAS). SULAS patients were younger (median age 35 vs 50 and 55 for urgent and non-urgent, respectively, p=0.0015) and predominantly suffered from cystic fibrosis (53%) or pulmonary fibrosis (37%). Between eras 1 and 2, the odds of transplantation within 6 months of registration were increased (OR=1.41, 95% CI 1.07 to 1.85, p=0.0142) despite only a 5% increase in transplant activity. Median time-to-transplantation during era-1 was 427 days compared with waiting times in era-2 of 8 days for SULAS, 15 days for ULAS and 585 days for NULAS patients. Waiting-list mortality (15% era-1 vs 13% era-2; p=0.5441) and post-transplant survival at 1 year (81.3% era-1 vs 83.3% era-2; p=0.6065) were similar between eras. CONCLUSION: The UKLAS scheme prioritises the critically ill and improves transplantation odds. The true impact on waiting-list mortality and post-transplant survival requires further follow-up.

Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome.

Background: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.

Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7 years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16 years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation.

Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6-32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.

Association of Passive Lung Insufflation Oxygen Fraction in Adult Patients on Cardiopulmonary Bypass with Postoperative Pulmonary Outcomes: A Retrospective Cohort Study.

OBJECTIVES: To determine whether FIO2 of passive lung insufflation during cardiopulmonary bypass correlates with postoperative pulmonary function. DESIGN: A retrospective, observational study SETTING: A single-center, university-affiliated, specialist cardiothoracic center in the United Kingdom. PARTICIPANTS: Adult patients presenting for nonemergency, nontransplant cardiac surgery requiring cardiopulmonary bypass without the need for deep hypothermic circulatory arrest between January 1, 2018, and December 31, 2018. INTERVENTIONS: Passive insufflation of the lungs during cardiopulmonary bypass with fresh gas flow of varying FIO2. Patients were sorted retrospectively into low FIO2 (0.21-0.44), intermediate FIO2 (0.45-0.69), and high FIO2 (0.7-1.0) groups. The primary outcome was the difference between the PaO2:FIO2 on the first postinduction blood gas and on the first blood gas recorded postoperatively in the intensive care unit (ICU) (delta PaO2:FIO2). Secondary outcomes were ICU and hospital lengths of stay, requirement for respiratory support, and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: Nine hundred patients were included in the authors' analysis (low FIO2 n = 307, intermediate FIO2 n = 459, high FIO2 n = 134). There was no significant difference in delta PaO2:FIO2 among the groups (low FIO2 = 52.5 [-38.8 to 152.4], intermediate FIO2 = 71.8 [-39.4 to 165.1], high FIO2 = 60.2 [-19.2 to 184.0], p = 0.25). There were no significant differences among groups for any secondary outcomes. CONCLUSION: Fresh gas flow with a low FIO2 delivered to the lungs without positive airway pressure during cardiopulmonary bypass was not associated with improved postoperative pulmonary function when compared to higher FIO2 levels.

Lung transplantation for acute respiratory distress syndrome: a retrospective European cohort study.

BACKGROUND: The published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres. METHODS: We conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of "ARDS/pneumonia" were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed. RESULTS: 55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015-2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977-55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Impact of surgical technique and analgesia on clinical outcomes after lung transplantation: A STROBE-compliant cohort study.

There is paucity of data on the impact of surgical incision and analgesia on relevant outcomes.A retrospective STROBE-compliant cohort study was performed between July 2007 and August 2017 of patients undergoing lung transplantation. Gender, age, indication for lung transplantation, and the 3 types of surgical access (Thoracotomy (T), Sternotomy (S), and Clamshell (C)) were used, as well as 2 analgesic techniques: epidural and intravenous opioids. Outcome variables were: pain scores; postoperative hemorrhage in the first 24 hours, duration of mechanical ventilation, and length of stay at intensive care unit (ICU).Three hundred forty-one patients were identified. Thoracotomy was associated with higher pain scores than Sternotomy (OR 1.66, 95% CI: 1.01; 2.74, P: .045) and no differences were found between Clamshell and Sternotomy incision. The median blood loss was 800 mL [interquartile range (IQR): 500; 1238], thoracotomy patients had 500 mL [325; 818] (P < .001). Median durations of mechanical ventilation in Thoracotomy, Sternotomy, and Clamshell groups were 19 [11; 37] hours, 34 [IQR 16; 57.5] hours, and 27 [IQR 15; 50.5] hours respectively. Thoracotomy group were discharged earlier from ICU (P < .001).Thoracotomy access produces less postoperative hemorrhage, duration of mechanical ventilation, and lower length of stay in ICU, but higher pain scores and need for epidural analgesia.

Combined heart-lung transplantation from a donation after circulatory death donor.

Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death.

An Incidental Finding at Transplant Assessment: Case Report.

A 43-year-old woman with chronic hypersensitivity pneumonitis was referred for lung transplant assessment. An echocardiogram as part of her work-up revealed a large left atrial myxoma, presenting a conundrum on how best to manage her combined pathology. Because of the level of pulmonary disease, early intervention to remove the myxoma was not thought be viable without postoperative support. Use of extracorporeal membrane oxygenation to bridge patients for lung transplant is feasible, yet risks increased perioperative mortality. We present the first reported case of simultaneous cardiac myxoma removal and lung transplant.

Lung donation after circulatory determined death: a single-centre experience.

OBJECTIVES: Donor organ utilization and shortage remain the major limitations to the opportunity of a lung transplantation (LTx). Donation after circulatory determined death (DCD) has been adopted as a source of additional organs worldwide. However, concerns about organ quality and ischaemia-reperfusion injury have limited its application. The aim of this study was to retrospectively analyse a single-centre experience in the DCD LTx and compare early and mid-term outcomes with those from a standard donation after brain death (DBD). METHODS: During the 6-year study period, 186 LTxs were performed: 147 bilateral LTxs (79%) and 39 single LTxs (21%). Of these, 23 recipients received organs retrieved from DCD donors (12.4%). RESULTS: No differences were found between the 2 groups of recipients except for age and cystic fibrosis as an underlying disease. No differences in terms of duration of mechanical ventilation, incidence of postoperative extracorporeal membrane oxygenation support, intensive care unit stay, hospital length of stay, airway anastomotic complications, incidence and grade of rejection and freedom from bronchiolitis obliterans syndrome were demonstrated. There was a non-statistically significant trend towards older age in the DCD group. Actuarial survival in the subgroup of bilateral LTx at 1 year and 5 years was 75% and 51% for the DCD group and 82% and 61% for the DBD group, respectively (P = 0.12). CONCLUSIONS: Short- and medium-term outcomes after the DCD LTx are comparable with those achieved after transplantation from the DBD donors, despite a tendency to use DCD lungs for older recipients. Therefore, the DCD LTx is a clinical option that can be used with favourable results to expand the lung donor pool.

Patient outcomes from time of listing for lung transplantation in the UK: are there disease-specific differences?

BACKGROUND: The demand for lung transplantation vastly exceeds the availability of donor organs. This translates into long waiting times and high waiting list mortality. We set out to examine factors influencing patient outcomes from the time of listing for lung transplantation in the UK, examining for differences by patient characteristics, lung disease category and transplant centre. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant for adult lung-only registrations between 1January 2004 and 31 March 2014. Pretransplant and post-transplant outcomes were evaluated against lung disease category, blood group and height. RESULTS: Of the 2213 patient registrations, COPD comprised 28.4%, pulmonary fibrosis (PF) 26.2%, cystic fibrosis (CF) 25.4% and other lung pathologies 20.1%. The chance of transplantation after listing differed by the combined effect of disease category and centre (p<0.001). At 3 years postregistration, 78% of patients with COPD were transplanted followed by 61% of patients with CF, 59% of other lung pathology patients and 48% of patients with PF, who also had the highest waiting list mortality (37%). The chance of transplantation also differed by height with taller patients having a greater chance of transplant (HR: 1.03, 95% CI: 1.02 to 1.04, p<0.001). Patients with blood group O had the highest waiting mortality at 3 years postregistration compared with all other blood groups (27% vs 20%, p<0.001). CONCLUSIONS: The way donor lungs were allocated in the UK resulted in discrepancies between the risk profile and probability of lung transplantation. A new donor lung allocation scheme was introduced in 2017 to try to address these shortcomings.

Prolongation of allograft survival by passenger donor regulatory T cells.

Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact on host immunity is unclear. Here, we examine whether transferred donor natural regulatory CD4 T cells (nT-regs) inhibit host alloimmunity and prolong allograft survival. Transfer of donor-strain lymphocytes was first assessed by identifying circulating donor-derived CD4 T cells in 21 consecutive human lung transplant recipients, with 3 patterns of chimerism apparent: transient, intermediate, and persistent (detectable for up to 6 weeks, 6 months, and beyond 1 year, respectively). The potential for transfer of donor nT-regs was then confirmed by analysis of leukocyte filters recovered from ex vivo normothermic perfusion circuits of human kidneys retrieved for transplantation. Finally, in a murine model of cardiac allograft vasculopathy, depletion of donor CD4 nT-regs before organ recovery resulted in markedly accelerated heart allograft rejection and augmented host effector antibody responses. Conversely, adoptive transfer or purified donor-strain nT-regs inhibited host humoral immunity and prolonged allograft survival, and more effectively so than following administration of recipient nT-regs. In summary, following transplantation, passenger donor-strain nT-regs can inhibit host adaptive immune responses and prolong allograft survival. Isolated donor-derived nT-regs may hold potential as a cellular therapy to improve transplant outcomes.

Native lung pneumonectomy for post-transplantation lymphoproliferative disorder refractory to rituximab following contralateral lung transplantation.

Post-transplantation lymphoproliferative disorder (PTLD) is a life-threatening complication following lung transplantation. We report a PTLD case of high-grade, B-cell lymphoma following contralateral single-lung transplantation. The disease involved the liver, right kidney and right native lung. While the PTLD affecting the abdominal organs regressed with rituximab chemotherapy, the native lung disease progressed and was treated surgically (right pneumonectomy). Some aspects are unique in this case: (i) different response to medical treatment between lung and abdominal organs; (ii) absolute absence of involvement of the native lung and (iii) surgical treatment with a pneumonectomy, still very rarely described in the literature. We hypothesized that a different morphotype of the disease involved the abdominal organs or the penetrance of rituximab, and chemotherapy could have been impaired by the presence of pulmonary fibrosis.

Comparison between cellular and acellular perfusates for ex vivo lung perfusion in a porcine model.

BACKGROUND: Ex vivo lung perfusion with acellular solutions is an established technique for assessing marginal donor lungs. We evaluated the utility of a blood-based lung preservation fluid as an alternative perfusate. METHODS: Donor lungs from 50-kg donation after cardiac death pigs (n = 24) were randomized into 3 groups: acellular, commercial blood-based, and Papworth-Blood. Physiologic function was evaluated using conventional markers of pulmonary vascular resistance, pulmonary compliance, lactate excretion, partial pressure of oxygen/fraction of inspired oxygen, and wet-to-dry ratios. The immunologic profile was assessed by fluorescence-activated cell sorting analysis of bronchoalveolar lavage and cells entrapped in the leucocyte filter. Cytokines were quantified using a commercial platform. RESULTS: No significant difference was noted in pulmonary vascular resistance (p = 0.26), compliance (p = 0.12), partial pressure of oxygen/fraction of inspired oxygen (p = 0.06) and wet-to-dry ratios (p = 0.26) between groups. There was no difference between the percentages of lymphocytes (p = 0.51), macrophages (p = 0.87), monocytes (p = 0.68), and dendritic cells (p = 0.65) in the leukocyte filters. Interleukin (IL)-1ß (p = 0.36), IL-6 (p = 0.08), IL-8 (p = 0.64), and IL-18 (p = 0.14) were elevated in all groups. In bronchoalveolar lavage, IL-8 was significantly higher in the acellular group (p = 0.04). Electron microscopy cell characteristics were similar among the groups. CONCLUSIONS: This study demonstrated no significant difference in the physiologic, immunologic, or ultrastructural parameters between lungs perfused with cellular or acellular solutions. The Papworth-Blood solution is a potential alternative perfusate for ex vivo lung perfusion.