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Since the early days of clinical lung transplantation the preservation of donor organs has become a fairly standardized procedure and most centers do follow similar processes. This includes the use of low-potassium high dextran flush solutions and static cold storage (SCS) in a cooler filled with ice. Depending on the length of SCS, organs usually arrive at the recipient hospital at a temperature of 0°C–4°C. The question of the optimal storage temperature for donor lung preservation has been revisited as data from large animal experiments demonstrated that organs stored at 10°C experience less mitochondrial damage. Thus, prolonged cold ischemic times can be better tolerated at 10°C—even in pre-damaged organs. The clinical applicability of these findings was demonstrated in an international multi-center observational study including three high-volume lung transplant centers. Total clinical preservation times of up to 24 hrs have been successfully achieved in organs stored at 10°C without hampering primary organ function and short-term outcomes. Currently, a randomized-controlled trial (RCT) is recruiting patients with the aim to compare standard SCS on ice with prolonged SCS protocol at 10°C. If, as anticipated, this RCT confirms data from previous studies, lung transplantation could indeed become a semi-elective procedure.

The effect of graft ischemic time on early graft function and long-term survival of patients who underwent lung transplantation remains controversial. Consequently, graft ischemic time has not been incorporated in the decision-making process at the time of graft acceptance. To investigate the relationship between graft ischemic time and (1) early graft function and (2) long-term survival after lung transplantation. The data from 752 patients who underwent single lung transplantation (n = 258), bilateral lung transplantation (n = 247), and heart-lung transplantation (n = 247) in seven French transplantation centers during a 12-year period were reviewed. Independent data quality control was done to ensure the quality of the collected variables. Mean graft ischemic time was 245.8 +/- 96.4 minutes (range 50-660). After adjustment on 11 potential confounders, graft ischemic time was associated with the recipient Pa(O2)/FI(O2) ratio recorded within the first 6 hours and with long-term survival in patients undergoing single or double lung transplantation but not in patients undergoing heart-lung transplantation. The relationship between graft ischemic time and survival appears to be of cubic form with a cutoff value of 330 minutes. These results were unaffected by the preservation fluid employed. The results of this large cohort of patients suggest a close relationship between graft ischemic time and both early gas exchange and long-term survival after single and double lung transplantation. Such relationship was not found in patients undergoing heart-lung transplantation. The expected graft ischemic time should be incorporated in the decision-making process at the time of graft acceptance.

Background Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. Main body All patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD. Conclusions Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.

Purpose The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant. Methods Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed. Results For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CF patients had a slower absorption rate (K a ), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates. Conclusions The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V 2 /F and V 3 /F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.

Harald Ott and his colleagues build on their earlier work, based on reconstruction of a decellularized heart, to develop a new way to bioengineer a functioning lung. Through a process of decellularization, seeding with endothelial and epithelial cells, and maturation in an innovative bioreactor system, followed by transplantation into rats of the regenerated lungs in orthotopic position, the group was able to demonstrate adequate ventilation, blood flow and gas exchange in vivo for short periods of time. About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.

Aim The aim of this pharmacokinetic (PK) study was to evaluate tacrolimus (TAC) exposure in stable cystic fibrosis (CF) lung transplant (LT) recipients, converted from TAC twice daily to TAC once daily in an open-label, prospective, single-centre study. Methods Eligible patients were post-transplant CF patients (18–65 years) with stable lung function, on stable doses of TAC twice daily and who were candidates to switch to TAC once daily. Twelve consecutive patients were included in the study. Patients had their first PK analysis on day 1, still under the stable TAC twice-daily regimen, and were converted to TAC once daily from day 2 onwards. The doses were adjusted according to clinical judgement to achieve target levels, and a second 24-h PK period profile was obtained once the patient was on a stable dosage on the therapeutic range. Results The mean total (SD) daily dose of TAC twice daily at baseline upon enrolment was 0.17 (0.10) mg/kg/day. The mean (SD) daily dose of TAC once daily after adjustments was 0.22 (0.12) mg/kg/day. In order to achieve target C min levels with a similar AUC 0–24 , 82 % of subjects who were converted to TAC once daily required an increase of dose, in a range of 0–66.7 %, with a mean dose increase of 28 %. Conclusions Our study results indicate that the switch for conversion from TAC twice daily to TAC once daily in patients with CF may need dose adjustment in order to reach levels within the therapeutic target.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering. In a new strategy for increasing the availability of lungs for transplantation, human lungs declined for transplantation because of their poor quality can be recuperated by connecting them to the circulation of a pig.

Background: Recent reports have shown evidence of host derived parenchymal engraftment in several human allografts including the lung, leading to speculation that stem cell therapy may be useful for lung repair in diseases such as cystic fibrosis (CF). To date, previous studies have looked at single surgical or autopsy specimens and no longitudinal studies have been reported. The aim of this study was to assess whether transbronchial biopsies could be used to study the time course of chimerism following lung transplantation. Methods: Specimens of archived transbronchial lung biopsies from five time points taken for clinical purposes from two boys who had received a sex mismatched heart-lung transplant for end stage CF were examined. Sections were dual stained for cytokeratin (epithelium) and a mixture of leucocyte common antigen and CD68 for inflammatory cells. Co-localisation of cells containing a Y chromosome was confirmed by fluorescent in situ hybridisation. Results: Evidence of chimerism was found in up to 6.6% of epithelial cells in bronchial (median 1.4% (range 0–6.6)) and alveolar (median 3.6% (range 2.3–5.5) tissue without apparent evidence of fusion. This engraftment was seen as early as 3 weeks and remained relatively constant up to 37 months. Conclusions: This study has demonstrated proof of principle for long term chimerism in lung epithelium. Transbronchial biopsies may provide a new method for studying the kinetics of stem cell engraftment in the lung.

First performed in 1963, lung transplantation is approaching the half-century mark. With more than 32,000 procedures having been performed worldwide, lung transplantation has become the standard of care for select patients with advanced lung diseases of various nonmalignant etiologies. Indications for transplantation have broadened over the years, and selection criteria have become less restrictive. A relatively scarce donor pool limits wider application of this therapy, but this is being addressed in part through relaxation of donor selection criteria, donor management protocols that preserve and optimize lung function, and development of ex vivo perfusion techniques to \"recondition\" suboptimal organs. Bilateral lung transplantation has become the procedure of choice for most indications, although its preferential use in patients with idiopathic pulmonary fibrosis remains controversial. Post-transplantation survival has steadily improved, but significant constraints on long-term survival persist as evidenced by a median survival rate that currently stands at 5.7 years. This has brought into focus the question of whether and for whom transplantation actually confers a survival advantage, a question that in the absence of randomized trials can only be answered with statistical modeling. Primary graft dysfunction, infection, and bronchiolitis obliterans syndrome are common complications encountered by the lung transplant recipient and are major impediments to long-term survival. This review provides an overview of the current status of lung transplantation, highlighting both the many advances that have taken place and the challenges that remain.

The use of extracorporeal membrane oxygenation (ECMO) in patients who are awake and spontaneously breathing may represent a novel bridging strategy toward lung transplantation (LuTx). To evaluate the outcomes of patients treated with the \"awake ECMO\" concept as bridge to transplantation. We performed a retrospective, single-center, intention-to-treat analysis of consecutive LuTx candidates with terminal respiratory or cardiopulmonary failure receiving awake ECMO support. The outcomes were compared with a historical control group of patients treated with conventional mechanical ventilation (MV group) as bridge to transplant. Twenty-six patients (58% female; median age, 44 yr; range, 23-62) were included in the awake ECMO group and 34 patients (59% female; median age, 36 yr; range, 18-59) in the MV group. The duration of ECMO support or MV, respectively, was comparable in both groups (awake ECMO: median, 9 d; range, 1-45. MV: median, 15 d; range, 1-71; P = 0.25). Six (23%) of 26 patients in the awake ECMO group and 10 (29%) of 34 patients in the MV group died before a donor organ was available (P = 0.20). Survival at 6 months after LuTx was 80% in the awake ECMO group versus 50% in the MV group (P = 0.02). Patients in the awake ECMO group required shorter postoperative MV (P = 0.04) and showed a trend toward a shorter postoperative hospital stay (P = 0.06). ECMO support in patients who are awake and nonintubated represents a promising bridging strategy, which should be further evaluated to determine its role in patients with end-stage lung disease awaiting LuTx.