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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., Competing Interests: Competing interests: AJF has received honoraria for speaking at educational meetings organised by Mallinckrodt Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Fungal infections are common and frequently associated with clinical failure in patients receiving extracorporeal membrane oxygenation (ECMO). Antifungal drugs have physicochemical characteristics associated with a higher likelihood of sequestration onto ECMO circuitry potentially leading to a subtherapeutic drug concentration. The percentage of sequestration of the antifungal drugs-caspofungin, posaconazole, and voriconazole-was determined using an ex vivo ECMO model. The circuits were primed with whole human blood, sodium chloride 0.9%, and human albumin solution. Serial 2 ml samples were taken at baseline, 0.5, 1, 2, 6, 12, and 24 hours after drug addition, paired with non-ECMO controls stored in a water bath at 37°C. Mean loss from the blood-primed ECMO circuits and controls at 24 hours relative to baseline were 80% and 61% for caspofungin ( p = ns), 64% and 11% for posaconazole ( p < 0.005), and 27% and 19% for voriconazole ( p < 0.05). Calculated AUC 0-24 showed a 44% for caspofungin ( p = ns), 30.6% posaconazole ( p < 0.005), and 9% loss for voriconazole ( p = 0.003) compared with the controls, suggesting therapeutic concentrations of these antifungal agents cannot be guaranteed with standard dosing in patients on ECMO. Posaconazole exhibited the greatest loss to the ECMO circuit correlating with both high lipophilicity and protein binding of the drug., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Background: Idiopathic pulmonary artery hypertension (iPAH) is a relatively minor indication for lung transplantation (LTx) with comparatively poorer outcomes. Extracorporeal life support (ECLS) in various forms is increasingly being used in the management of this entity. However, the data and experience with this therapy remains limited. We evaluated the role of ECLS in the management of severe iPAH patients as a bridge to LTx as well as post LTx support., Methods: A retrospective analysis of iPAH patients that received LTx between January 2007 and May 2014 was performed. Early- and mid-term outcomes were analyzed for this patient cohort. Also, early and mid-term outcomes after LTx were compared to the control group of patients with other diagnoses using unadjusted analysis and 1:3 propensity score matching., Results: Of 321 LTx performed during the study period in our centre 15 patients had iPAH as a cause of end-stage lung disease. Four iPAH (27%) patients were bridged to LTx utilizing ECLS in the form of veno-arterial ECMO and extra-corporeal CO 2 removal device, whereas 9 patients (60%) required ECLS support for primary graft dysfunction (PGD) after surgery. Patients with iPAH required more frequently on-pump LTx, both pre and post LTx ECLS, and had significantly lower pO 2 /FiO 2 ratio at 24, 48 and 72 hours after LTx. Also iPAH patients had significantly longer ICU and hospital stay. Whereas the incidence of postoperative bronchiolitis obliterans syndrome (BOS) and rejection was comparable to the control group, overall cumulative survival with up to 6 years follow-up was significantly poorer in the iPAH group. After propensity score matching, the results in terms of postoperative outcomes remained as in the unadjusted analysis., Conclusions: ECLS is an essential tool in the armamentarium of any lung transplant program treating iPAH with a potential of bridge patients to transplantation and to overcome graft dysfunction after LTx. Despite utilization of ECLS in the management of iPAH, the outcomes in terms of primary graft failure and survival remain poor compared to patients with other diagnoses., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Closure of the chest after lung transplant in cases of oversized grafts is often difficult. Lung volume reduction and delayed closure of the chest with Bogota bag are the only options available in such situations. Here, we propose to keep the sternum and intercostal spaces open and approximate skin over it. Once lung function improves and reperfusion-related edema recovers, the chest can be closed.

Objectives: Cannabis is the most commonly abused illicit drug and the smokers are at the risk of lung infections, bullous emphysema and lung cancer. However, no evidence about the outcomes of lung transplantation (LTx) utilizing the lungs from such donors is available in the literature., Methods: We retrospectively analysed lung 'organ offers' and LTx at our centre between January 2007 and November 2013. The outcomes of LTx utilizing lungs from donors with a history of cannabis smoking were compared with the outcomes of those with no such history using unadjusted model as well as propensity score matching., Results: A total of 302 LTxs were performed during this period and were grouped depending on the history of cannabis smoking in donors-'cannabis' (n = 19) and control group (n = 283). All the donors in 'cannabis' group were tobacco smokers compared with 43% in the control group. Preoperative characteristics in recipients in both groups were comparable. Intraoperative and post-LTx variables including 1- and 3-year survivals were comparable in both groups., Conclusions: The history of donor cannabis smoking does not appear to affect early and mid-term outcomes after LTx and potentially improve the donor pool. As it does not seem to negatively affect the outcomes after LTx, it should not be per se considered a contraindication for lung donation., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis., Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants., Methods: We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies., Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape., Conclusions: These observations identify programmed, necrosis-dependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.

Background: Because of improved surgical expertise and intraoperative management, pleural disease (PD+) represents a relatively minor contraindication to lung transplantation (LTx). The presence of pleural abnormalities from previous procedures or pleural involvement from fungal or bacterial disease is not considered a limiting factor for LTx. However there are no studies available to assess the impact of pleural diseases on short- and midterm outcomes after LTx., Methods: We retrospectively reviewed 163 consecutive patients who underwent LTx between 2010 and 2013. Patients were divided according to the presence of pleural abnormalities before the operation (PD+ versus PD-). The primary end point of the study was primary graft dysfunction (PGD; grade 3) and overall survival. To avoid possible selection bias and to heck the robustness of the results, a propensity score-matching analysis (1:3) was performed., Results: A total of 26 patients (16%) had pleural abnormalities before transplantation. Intra- and postoperative variables were comparable. PD+ was associated with a significantly higher incidence of PGD at 0 and 48 hours postoperatively (p = 0.037 and p = 0.032, respectively). Moreover, PD+ was associated with significantly worse survival at 3 months (p = 0.021). Although there was a trend toward worse early overall survival in the Kaplan-Meier estimate (Breslow p = 0.050), midterm survival was comparable (log-rank p = 0.240)., Conclusions: LTx in patients with preoperative pleural abnormalities is feasible. Identifying higher-risk recipients with pleural abnormalities might have important clinical relevance because of a higher incidence of PGD and worse early survival, even though midterm survival is comparable., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Minimally invasive lung transplantation (MILT) via bilateral anterior thoracotomies has emerged as a novel surgical strategy with potential patient benefits when compared with transverse thoracosternotomy (clamshell incision, CS). The aim of this study is to compare MILT with CS by focusing on operative characteristics, postoperative organ function and support and mid-term clinical outcomes at Harefield Hospital., Methods: It was a retrospective observational study evaluating all bilateral sequential lung transplants between April 2010 and November 2013., Results: CS was performed in 124 patients and MILT in 70 patients. Skin-to-skin surgical time was less in the MILT group [285 (265, 339) min] compared with CS [380 (306, 565) min] and MILT-cardiopulmonary bypass [426 (360, 478) min]. Ischaemic time was significantly longer (502 ± 116 vs 395 ± 145 min) in the MILT group compared with CS (P < 0.01). Early postoperative physiological variables were similar between groups. Patients in the MILT group required less blood [2 (0, 4) vs 3 (1, 5) units, P = 0.16] and platelet transfusion [0 (0, 1) vs 1 (0, 2) units, P < 0.01]. The median duration of mechanical ventilation was shorter (26 vs 44 h, P < 0.01) and intensive therapy unit stay was 2 days shorter (5 vs 7) in the MILT group. While overall survival was similar, fraction of expired volume in 1 s (FEV1) and forced vital capacity (FVC) were consistently higher in the MILT group compared with CS during mid-term follow-up after transplantation. Specifically, FEV1 and FVC were, respectively, 86 ± 21 and 88 ± 18% predicted in the MILT group compared with 74 ± 21 and 74 ± 19% predicted in the CS group (P < 0.01) at the 6-month follow-up., Conclusions: MILT was successfully introduced at our centre as a novel operative strategy. Despite longer ischaemic times and a more complex operation and management, MILT appears to offer early postoperative and mid-term clinical benefits compared with our traditional approach of clamshell operations. These observations warrant larger definite studies to further evaluate the impact of MILT on physiological, clinical and patient-reported outcomes., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Limited data are available about lung transplantation (LTx) from donors suffering cardiac arrest (CA) prior to actual donation., Methods: A retrospective analysis of LTx performed between January 2007 and September 2012 was done with the focus on CA in donors. The recipients were grouped depending on the history of donor CA and CA duration (downtime) as: No cardiac arrest ("NoCA"), CA downtime less than 20 min ("CA < 20"), and CA downtime equal to or more than 20 min ("CA > 20"). Early and mid-term outcomes after LTx were compared among the three groups., Results: A total of 237 LTx were performed during the study period. One hundred eighty-eight patients received organs from "NoCA" donors, 25 from "CA < 20" donors, and 24 patients from "CA > 20" donors. There was a trend toward better overall cumulative survival in both CA groups (log rank p = 0.076) whereas the survival in the "CA > 20" group was significantly better than in the "NoCA" group in the subgroup analysis (log rank p = 0.045). Freedom from bronchiolitis obliterans syndrome (BOS) also increased with increase in CA duration, although it did not reach statistical significance., Conclusions: Transplantation of lungs from donors with a history of CA is safe and feasible. Longer duration of cardiac arrest may improve the outcomes after the LTx in terms of survival and freedom from BOS., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The risk-benefit for utilizing cardio-pulmonary bypass (CPB) in lung transplantation (LTx) remains debatable. This study compares outcomes after LTx utilizing different CPB strategies - elective CPB vs. off-pump vs. off-pump with unplanned conversion to CPB., Methods: A total of 302 LTx performed over seven yr were divided into three groups: "off-pump" group (n = 86), "elective on-pump" group (n = 162), and "conversion" group (n = 54). The preoperative donor and recipient demographics and baseline characteristics and the postoperative outcomes were analyzed; 1:1 propensity score matching was used to identify patients operated upon using elective CPB who had risk profiles similar to those operated upon off-pump (propensity-matching 1) as well as those emergently converted from off-pump to CPB (propensity-matching 2)., Results: Preoperative group demographic characteristics were comparable; however, the "off-pump" patient group was significantly older. The "conversion" group had a significantly greater number of patients with primary pulmonary hypertension, pulmonary fibrosis, preoperative mechanical ventilation, and preoperative extracorporeal life support (ECLS). Postoperatively, patients from the "conversion" group had significantly poorer PaO2 /FiO2 ratios upon arrival in intensive care unit (ICU) and at 24, 48, and 72 h postoperatively, and they required more prolonged ventilation, longer ICU admission, and they experienced an increased need for ECLS than the other groups. Overall, cumulative survival at one, two, and three yr was significantly worse in patients from the "conversion" group compared to the "off-pump" and "elective on-pump" groups - 61.9% vs. 94.4% vs. 86.9%, 54.4% vs. 90.6% vs. 79.5% and 39.8% vs. 78.1% vs. 74.3%, respectively (p < 0.001). The "off-pump" group had significantly better PaO2 /FiO2 ratios, and a significantly shorter duration of ventilation, ICU stay, and hospital length of stay when compared to the propensity-matched "elective on-pump" group. There were no statistically significant differences in postoperative outcomes and overall survival between the "converted" group and the propensity-matched "elective on-pump" group., Conclusions: Despite segregation of unplanned CPB conversion cases from elective on-pump cases, patients with comparable preoperative demographic/risk profiles demonstrated better early postoperative outcomes and, possibly, an improved early survival with an off-pump strategy. A considerable proportion of high-risk patients require intraoperative conversion from off-pump to CPB, and this seems associated with suboptimal outcomes; however, there is no significant benefit to employing an elective on-pump strategy over emergent conversion in the high-risk group., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Kidney failure after lung transplantation is a risk factor for chronic kidney disease. Calcineurin inhibitors are immunosuppressants which play a major role in terms of postoperative kidney failure after lung transplantation. We report our preliminary experience with the anti-interleukin-2 monoclonal antibody Basiliximab utilized as a "calcineurin inhibitor-free window" in the setting of early postoperative kidney failure after lung transplantation. Between 2012 and 2015 nine lung transplant patients who developed kidney failure for more than 14 days were included. Basiliximab was administrated in three doses (Day 0, 4, and 20) whilst Tacrolimus was discontinued or reduced to maintain a serum level between 2 and 4 ng/mL. Baseline glomerular filtration rate pre transplant was normal for all patients. Seven patients completely recovered from kidney failure (67%, mean eGFR pre and post Basiliximab: 42.3 mL/min/1.73 m(2) and 69 mL/min/1.73 m(2)) and were switched back on Tacrolimus. Only one of these patients still needs ongoing renal replacement therapy. Two patients showed no recovery from kidney failure and did not survive. Basiliximab might be a safe and feasible therapeutical option in patients which are affected by calcineurin inhibitor-related kidney failure in the early post lung transplant period. Further studies are necessary to confirm our preliminary results., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: As Gastroesophageal reflux disease (GORD) affects long-term survival in lung transplant recipients, the aim of this observational prospective study was to analyze the efficacy of The Reflux Symptom Index Questionnaire (RSI) compared to the esophageal impedance test., Methods: Both esophageal impedance studies and RSI questionnaire were routinely performed in all patients who had completed rehabilitation following lung transplantation from June 2013 till March 2014. RSI generates a score of between zero and forty-five, taking into account any symptoms within four wk of the questionnaire. Our analysis considered RSI score cut-offs of 10 and 13 indicating significance of reflux., Results: Out of 84 patients, 50 (59.5%) had evidence of GORD detected by impedance studies, whereas only 33 (39.2%) and 22 (26.2%) had RSI >10 and 13, respectively. An elevated RSI was not found to be associated with positive impedance studies using a score of either 10 or 13 (p = 0.127 and p = 0.142, respectively); 32.1% (n = 27) and 40.5% (n = 34) were found to have negative RSI and positive impedance test using 10 or 13 as cut-off, respectively., Conclusion: RSI Score is an unreliable predictor of GORD among lung transplant recipients. The authors therefore recommend the routine use of impedance testing in post-transplant patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Invasive fungal infections cause significant morbidity and mortality after lung transplantation. Fungal prophylaxis following lung transplantation is not standardised, with transplant centres utilising a variety of regimens. Posaconazole is a broad-spectrum antifungal triazole that requires further investigation within the setting of lung transplantation. This prospective, single-centre, observational study explored the pharmacokinetics of posaconazole oral suspension (POS) in the early perioperative period following lung transplantation in 26 patients. Organ recipients were scheduled to receive 400mg POS twice daily for 6 weeks as primary antifungal prophylaxis. Therapeutic drug monitoring (TDM) of serum posaconazole levels was performed in accordance with local clinical protocols. Bronchoalveolar lavage fluid (BALF) was sampled during routine bronchoscopies. Posaconazole levels were measured both in serum and BALF using mass spectrometry. Posaconazole levels were highly variable within lung transplant recipients during the perioperative period and did not achieve 'steady-state'. Serum posaconazole concentrations positively correlated with levels within the BALF (r=0.5527; P=0.0105). Of the 26 patients, 10 failed to complete the study for multiple reasons and so the trial was terminated early. Unlike study findings in stable recipients, serum posaconazole levels rarely achieved steady-state in the perioperative period; however, they do reflect the concentrations within the airways of newly transplanted lungs. The role of POS as primary prophylaxis in the perioperative period is uncertain, but if used TDM may be helpful for determining attainment of therapeutic levels., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Background: Traditionally, patients on extracorporeal membrane oxygenation (ECMO) are sedated and mechanically ventilated, which increases risk of complications related to immobility and mechanical ventilation. The purpose of this study was to assess the feasibility and highlight the benefits of a bridge to lung transplant (LTx) using "awake ECMO" support., Methods: The peripheral venovenous or venoarterial ECMO was implanted at a bedside. A retrospective study of patients undergoing LTx between January 2007 and March 2013 was performed. Outcomes in patients supported on ECMO as a bridge to LTx and kept "awake" (Group 1) were compared with the rest of the LTx patients (Group 2)., Results: In this period, 249 LTx were performed and in them 7 patients were bridged to LTx using "awake ECMO" strategy. Two patients were awake at ECMO implantation and throughout the therapy, and two patients were on ventilator support at the time of ECMO implantation who were extubated later and maintained awake until LTx. The remaining three patients were awake for some time during the ECMO. There was no statistically significant difference in most donor characteristics and recipient baseline characteristics as well as post-LTx parameters between the two groups. One-year survival estimate was not different between the groups: Group 1, 85.7% vs. Group 2, 86.3% (log rank p = 0.99)., Conclusion: In end-stage lung disease, the ECMO can be commenced in "awake" patients and patients can be awakened on ECMO. The "awake ECMO" strategy may avoid complications related to mechanical ventilation, sedation, and immobilization and provide comparable outcomes in the high-risk LTx patients., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Suicidal hanging may cause compression of the neck blood vessels and the airway leading, to hypoxic brain damage caused by cerebral ischemia and respiratory distress. Hanging engenders global tissue hypoxia, particularly affecting the lungs as the result of pulmonary edema and barotrauma. There is scant evidence about outcomes of transplantation with the use of lungs from "hanging donors." This study evaluates the outcomes of lung transplantations (LTx) that use organs from this group., Methods: We retrospectively analyzed lung "organ offers" and LTx at our center between January 2007 and November 2013. The outcomes of LTx with lungs from donors with hanging as the cause of death ("hanging group") were compared with those with donors having other causes of death (control group), with the use of an unadjusted model as well as propensity score matching., Results: LTx (n = 302) were performed during this period and were grouped on the basis of the cause of death in donors: the hanging group (n = 8) and the control group (n = 294). No statistically significant difference was found in the donor characteristics except for the incidence of cardiac arrest, which was significantly higher in hanging donors. Preoperative characteristics in recipients in both groups were comparable. Intra-operative and post-LTx variables including PaO2/FiO2 ratios, duration of mechanical ventilation, and intensive care unit and hospital stays were comparable. One-year and 3-year survival rates were also comparable in both groups. Two recipients in the hanging group required extracorporeal life support after LTx and could not survive., Conclusions: Suicidal hanging is a relatively rare cause of death for potential organ donors. Because it does not appear to negatively affect outcomes after LTx, it should not be considered per se a contraindication for lung donation. A word of caution is necessary until we gather larger experience with lungs from hanging donors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Bronchiolitis obliterans syndrome (BOS) is the major cause of late graft failure after lung transplantation. The objective was to determine whether de novo donor human leukocyte antigen (HLA)-specific antibodies (DSA) are associated with the development of BOS or patient survival. Data were analyzed from 188 lung transplant recipients with a follow-up period up to 8 years., Methods: HLA antibody monitoring was performed at 3-month intervals post-transplant at routine outpatient clinic attendances and during the investigation of any acute deterioration. HLA antibody data were available for 148 patients; 66 (45%) had produced HLA antibodies after transplant, of which 38 (26%) were DSA and 28 (19%) non-donor-specific HLA antibodies., Results: De novo DSA was associated with development of BOS Stage 1 (BOS1; hazard ratio [HR] = 2.302, p = 0.0015), BOS2 (HR = 3.627, p < 0.0001) and BOS3 (HR = 5.736, p < 0.0001). De novo persistent DSA correlated strongly with shorter time to onset of BOS3 (HR = 6.506, p = 0.0001). There was a significant reduction in patient survival associated with de novo DSA (HR = 1.886, p = 0.047). In multivariable analyses, de novo DSA was an independent predictor for development of all stages of BOS as well as an independent predictor of poor patient survival., Conclusions: De novo DSA is a major risk factor for progression to BOS and shorter patient survival. Treatments to remove antibodies or limit antibody-mediated damage could be considered when DSA are first detected. However, a randomized, controlled trial of treatment options would enable a clearer understanding of the benefits, if any, of antibody-removal therapies., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Lung transplantation (LTx) is a complex surgical procedure conventionally performed with clamps on the recipient pulmonary artery (PA) and left atrial (LA) cuff, with or without cardiopulmonary bypass (CPB). The clamps may be awkward to apply and maintain on these structures, potentially causing injury and possibly compromising the quality of anastomosis. We describe a no-clamp technique for performing these types of anastomoses., Methods: A total of 184 LTx procedures performed under CPB were grouped depending on clamping of recipient PA and LA during anastomosis using either the "no-clamp" technique (Group 1, n = 41) or the conventional technique (Group 2, n = 143). Pre-operative donor and recipient demographics and baseline characteristics as well as post-operative outcomes were compared., Results: The demographics and pre-operative baseline characteristics of donors and recipients in both the groups were similar. Patients in Group 1 had a significantly shorter total ischemic time (p < 0.001), CPB time (p < 0.001), decreased incidence of post-LTx atrial fibrillation (p = 0.048), less need for blood and blood products transfusion, and fewer post-LTx pulmonary infections (p = 0.038). No patient in any group had post-LTx stroke. Although the incidence of post-operative bronchiolitis obliterans syndrome (BOS) did not differ between the two groups (p = 0.638), patients in Group 1 had significantly better mid- and long-term survival (p = 0.013): 89.7% vs 80%, 89.7% vs 66.5% and 89.7% vs 62.2% at 1, 3 and 6 years after LTx, respectively., Conclusions: The no-clamp technique for anastomosis of PA and LA in LTx is feasible and safe. It may reduce warm ischemia time as well as CPB time, with improvement in post-LTx outcomes. It may also reduce the incidence of post-LTx atrial arrhythmias., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Lung transplantation (LTx) from "extended donor criteria" donors may reduce significantly organ shortage. However, its influence on results remains unclear. In this study, we evaluate retrospectively the results of LTx from donors outside standard criteria: PaO2/FiO2 ratio < 300 mmHg, age over 55 years, and history of smoking > 20 pack-years. Two hundred and forty-eight patients underwent first time LTx in our institution between January 2007 and January 2013. Seventy-nine patients (Group I) received organs from "extended donor criteria" and 169 patients (Group II) from "standard donor criteria." Recipients' and donors' demographics, perioperative variables, and outcome were compared. Donors from Group I were significantly older [median (interquartile range)]: 52.5 (44;58) vs. 42 (28.5;48.5) years (P < 0.001) with lower PaO2/FiO2 ratio: 366 ± 116.1 455 ± 80.5 mmHg (P < 0.001), higher incidence of smoking history: 57.7% vs. 41.8% (P = 0.013), and more extensive smoking history: 24(15;30) vs. 10(3.75;14) pack-years (P < 0.001). Other parameters were comparable. Recipients' gender, diagnosis, percentage of patients operated on pump and receiving double LTx were also comparable. Recipients from Group I were significantly older: 50 (42;57) vs. 44 (29.5;53.5) years (P = 001). There were no differences observed in recipients' prevalence of primary graft dysfunction (PGD) grade 3 over first three postoperative days, duration of mechanical ventilation, intensive care and hospital length of stay, prevalence of rejection, and bronchiolitis obliterans syndrome (BOS). 90-day, 1-year, and 5-year survival (Group I vs. II) were also similar: 88.6% vs. 91.7%, 83.2% vs. 84.6%, and 59% vs. 68.2% (log rank P = 0.367). Carefully selected donor lungs from outside the standard acceptability criteria may expand existing donor pool with no detrimental effect on LTx outcome., (© 2014 Steunstichting ESOT.)

Background: The impact of Luminex-detected HLA antibodies on outcomes after lung transplantation is unclear. Herein we have undertaken a retrospective study of pre-transplant sera from 425 lung transplants performed between 1991 and 2003., Methods: Pre-transplant sera, originally screened by complement-dependent cytotoxicity (CDC) assays, were retrospectively tested for the presence of HLA-specific antibodies using HLA-coated Luminex beads and C4d deposition on Luminex beads. The results were correlated with graft survival at 1 year., Results: Twenty-seven patients were retrospectively identified as having been transplanted against donor-specific HLA antibodies (DSA) and 36 patients against non-donor-specific HLA antibodies (NDSA). DSA-positive patients had 1-year survival of 51.9% compared with 77.8% for NDSA and 71.8% for antibody-negative patients (p = 0.029). One-year survival of patients with complement-fixing DSA was 12.5% compared with 62.5% for non-complement-fixing DSA, 75.8% for non-complement-fixing NDSA and 71.8% for antibody-negative patients (p < 0.0001). DSA-positive patients with mean fluorescence intensity (MFI) >5,000 had 1-year survival of 33.3% compared with 71.4% for MFI 2,000 to 5000 and 62.5% for MFI <2,000 (p = 0.0046). Multivariable analysis revealed DSA to be an independent predictor of poor patient survival within 1 year (p = 0.0010, hazard ratio [HR] = 3.569) as well as complement-fixing DSA (p < 0.0001, HR = 11.083) and DSA with MFI >5,000 (p = 0.0001, HR = 5.512)., Conclusions: Pre-formed DSA, particularly complement-fixing DSA, and high MFI are associated with poor survival within the first year after lung transplantation. Risk stratification according to complement fixation or MFI levels may allow for increased transplantation in sensitized patients., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

We describe the case of a 29-year-old woman with end-stage chronic obstructive pulmonary disease secondary to vascular Ehlers-Danlos syndrome. Because of critical deterioration, respiratory arrest, and complete lung failure, she required urgent implantation of a venovenous extracorporeal membrane oxygenator as a bridge to lung transplantation. After 6 days of extracorporeal life support, a successful bilateral sequential lung transplantation was performed. This is the first case of lung transplantation in a patient with a diagnosis of chronic obstructive pulmonary disease secondary to Ehlers-Danlos syndrome., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to determine the safety of anti-reflux surgery for lung transplant recipients and assess its effect on lung function., Methods: We retrospectively collected and analyzed data from all lung transplant recipients who underwent anti-reflux surgery at St Mary's Hospital London from July 2005 to May 2012. The indications for surgery were histologic evidence of gastroesophageal reflux aspiration on bronchoscopy biopsy specimens or a positive impedance study with symptomatic reflux or a consistent decline/fluctuating forced expiratory volume in 1 second (FEV(1)). We studied the difference in mean FEV(1) and rate of change of FEV(1), before and after fundoplication. The safety of anti-reflux surgery was determined by post-operative morbidity and mortality and compared with predicted figures, using a risk prediction model based on the P-POSSUM (Portsmouth Modification of the Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity) assessment., Results: Forty patients underwent laparoscopic Nissen fundoplication. Overall, mean FEV(1) declined from 2119 ± 890 to 1967 ± 1027 ml (p = 0.027), and mean rate of change in FEV(1) improved from -2.42 ± 4.40 to -0.41 ± 1.77 ml/day (p = 0.007). Patients referred for fundoplication based on histologic evidence of reflux (n = 9) showed an improvement in rate of change of FEV(1) from -3.39 ± 6.00 to -0.17 ± 1.50 ml/day (p = 0.057), and those with positive impedance study and consistent decline in FEV(1) (n = 13) showed a significant improvement from -3.62 ± 3.35 to -0.74 ± 2.33 ml (p = 0.021). Actual and predicted morbidity was 2.5% and 31%, respectively. Actual and predicted 30-day mortality was 0% and 1.9%, respectively., Conclusions: Anti-reflux surgery is safe for lung transplant recipients and results in an improvement in the rate of change in FEV(1) despite a decline in mean FEV(1) post-operatively., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5-12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-α (TNFα), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNFα, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.

Objectives: Donor organ shortage remains to be the major limitation in lung transplantation, and donation after circulatory death (DCD) might represent one way to alleviate this problem. DCD was introduced to our institution in 2007 and has been a part of our clinical routine since then. Here, we present the mid-term results of lung transplantation from DCD in a single institution and compare the outcomes with the lung recipient cohort receiving lungs from donation after brain death (DBD)., Methods: Since initiation of the DCD programme in March 2007, of the 157 lung transplantations performed, 26 (16.5%) were retrieved from DCD donors, with 25 double- and 1 single-lung transplants being performed. Results were compared with standard DBD transplantations. Analyses included, amongst others, donor characteristics, survival, prevalence of primary graft dysfunction, acute rejection, lung function tests during follow-up, onset of bronchiolitis obliterans syndrome (BOS) as well as duration of mechanical ventilation, hospital and intensive care unit length of stay., Results: While there was no significant difference between lung function, BOS and survival between the two groups, lungs from DCD donors had a higher PaO(2) (median; interquartile range) 498.3 (451.5; 525) vs. DBD 442.5 (371.25; 502) kPa before retrieval (P = 0.009). There was also a longer total ischaemic time in the DCD vs. DBD group: 320 min (298.75; 393.25) vs. 285.5 min (240; 373) (P = 0.025). All other parameters were comparable., Conclusions: Medium-term results after lung transplantation with organs procured after circulatory death are comparable with those obtained after standard lung transplantation. Therefore, DCD could be used to significantly increase the donor pool.

Objectives: Lung transplantation is an established treatment for patients with advanced emphysema. Double-lung transplantation is favoured to avoid complications following single-lung transplantation, including native lung hyperinflation. Nonetheless, single-lung transplantation continues due to limited donor organ availability. The aim of this study was to evaluate the pre-operative assessment, surgical techniques and outcomes in patients undergoing lung volume reduction surgery for native lung hyperinflation., Methods: Eight patients underwent lung volume reduction surgery for native lung hyperinflation between October 2008 and April 2011. Symptoms, pre-operative evaluation, peri-operative morbidity, length of stay, pulmonary function and survival were examined. The mean follow-up was 17 months., Results: Participants underwent high resolution CT and bronchoscopy with transbronchial biopsy and bronchial washings to exclude alternative causes for deterioration in pulmonary function tests. V/Q scan was performed to assess the contribution of each lung to overall function. Measurement of inspiratory airflow resistance in each lung was performed in one case. Seven patients underwent multiple wedge resections and one underwent bilobectomy. All patients survived to hospital discharge, and mean length of stay was 13.9 days. Functional improvement was demonstrated in all cases at follow-up, with a mean percentage increase of 29.3% in forced expiratory volume in one second and 21.6% in forced vital capacity. Symptomatic improvement was also reported by all patients post-operatively., Conclusions: Lung volume reduction surgery for native lung hyperinflation is an effective treatment strategy with an acceptable level of surgical risk. Patient selection, however, remains vital. The non-anatomical multiple wedge excision technique used here was as effective as anatomical lung volume reduction surgery used in other series. With regard to pre-operative assessment, the measurement of single-lung inspiratory airflow resistance is of particular interest. We feel that this may provide an additional method of differentiating between native lung hyperinflation and obliterative bronchiolitis prior to surgery, thus improving patient selection.

Background: Ex vivo lung perfusion (EVLP) is a novel approach for extended evaluation and/or reconditioning of donor lungs not meeting standard International Society for Heart and Lung Transplantation criteria for transplantation., Methods: We retrospectively evaluated 13 consecutive EVLP runs between January 2009 and December 2010. Lungs rejected for routine transplantation were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Göteborg, Sweden) up to a target flow rate of 40% of the donor's calculated flow at a cardiac index of 3.0 liters/min/m(2); target left atrial pressure < 5 mm Hg; and pulmonary artery pressure < 15 mm Hg. Mechanical ventilation was introduced after rewarming to 32°C: tidal volume, 6 to 8 ml/kg; respiratory rate, 7 to 8 breaths/min; duration of inspiration/expiration (I/E) ratio, 1:2; and positive end-expiratory pressure, 5 to 10 cm H(2)O. Hemodynamic and respiratory data monitoring with hourly clinical assessment were performed. Donor data, conversion rate to transplantation, and recipient outcome were analyzed., Results: Donor data (n = 13) were: age, 44.23 ± 8.33 years; female/male, 8:5; cause of death: intracranial hemorrhage, 11 (85%), stroke, 1 (7.5%), hypoxic brain injury, 1 (7.5%); smoking history, 9 (69%), 17.44 ± 8.92 pack-years; mechanical ventilation, 102.6 ± 91.92 hours; chest x-ray imaging: abnormal, 12 (92.5%); normal, 1 (7.5%). EVLP: mean 141 ± 28.83 minutes. Arterial partial pressure of oxygen/fraction of inspired oxygen 100% before termination of the circuit vs pre-retrieval value: 57.32 ± 9.1 vs 42.36 ± 14.13 kPa (p < 0.05). Six (46%) pairs of donor lungs were transplanted. Median follow-up was 297.5 days (range, 100-390 days), with 100% survival at 3 months., Conclusions: EVLP may facilitate assessment and/or reconditioning of borderline lungs, with a conversion rate of 46 % and good short-term survival., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

We report a case of the interdisciplinary management of recurring bronchial stenosis after bilateral sequential single-lung transplantation (BSSLT) in a 35-year-old female with cystic fibrosis. Initial bronchoscopic therapy including balloon dilatation, stenting, and cryotherapy for granulation tissue overgrowth was unsuccessful in maintaining airway patency. In view of the persistent left lower lobe (LLL) atelectasis and fibrosis predisposing to recurrent infections, she was submitted for left lower lobectomy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Lack of suitable donor lungs is still a major limitation of lung transplantation. Extended donor acceptance criteria combined with innovative assessment tools can be used to expand the number of suitable organs. We describe a successful transplantation of lungs retrieved from a donor who had undergone aortic root replacement 9 days before donation after cardiac death. The lungs were assessed using ex-vivo lung perfusion., (Copyright © 2011 Elsevier Inc. All rights reserved.)