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BackgroundProgression of chronic lung disease often leads to the requirement for a lung transplant (LTX). Despite improvements in short-term survival after LTX, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the relationship between the metabolome of bronchoalveolar lavage fluid (BALF) from subjects post-LTX with underlying lung disease and CLAD severity.MethodsUntargeted LC-MS/MS metabolomics was performed on 960 BALF samples collected over 10 years from LTX recipients with alpha-1-antitrypsin disease (AATD, n=22), cystic fibrosis (CF, n=46), chronic obstructive pulmonary disease (COPD, n = 79) or pulmonary fibrosis (PF, n=47). Datasets were analyzed using machine learning and multivariate statistics for associations with underlying disease and final CLAD severity.ResultsBALF metabolomes varied by underlying disease state, with AATD LT recipients being particularly distinctive (PERMANOVA,p=0.001). We also found a significant association with the final CLAD severity score (PERMANOVA,p=0.001), especially those with underlying CF. Association with CLAD severity was driven by changes in phosphoethanolamine (PE) and phosphocholine lipids that increased and decreased, respectively, and metabolites from the bacterial pathogenPseudomonas aeruginosa. P. aeruginosasiderophores, quorum-sensing quinolones, and phenazines were detected in BALF, and 4-hydroxy-2-heptylquinoline (HHQ) was predictive of the final CLAD stage in samples from CF patients (R=0.34;p≤0.01). Relationships between CLAD stage andP. aeruginosametabolites were especially strong in those with CF, where 61% of subjects had at least one of these metabolites in their first BALF sample after transplant.ConclusionsBALF metabolomes after LTX are distinctive based on the underlying disease and reflect final CLAD stage. In those with more severe outcomes, there is a lipid transition from PC to predominantly PE phospholipids. The association ofP. aeruginosametabolites with CLAD stages in LTX recipients with CF indicates this bacterium and its metabolites may be drivers of allograft dysfunction.Key messagesDespite the high prevalence of CLAD among LTX recipients, its pathology is not well understood, and no single molecular indicator is known to predict disease onset. Our machine learning metabolomic-based approach allowed us to identify patterns associated with a shift in the lipid metabolism and bacterial metabolites predicting CLAD onset in CF. This study provides a better understanding about the progression of allograft dysfunction through the molecular transitions within the transplanted lung from the host and bacterial pathogens.

Background This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. Study Design and Methods Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. Results Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non‐random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP‐treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non‐survivors (−212 ± 177 ml/month) when compared to the survivors (−95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. Conclusions These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

BACKGROUND Induction immunosuppression regimens for kidney transplants in lung transplant recipients vary widely. We studied the impact of induction types for kidney after lung transplant recipients. METHODS Using the Scientific Registry of Transplant Recipients database between 1994 and 2015, we studied outcomes of patients and kidney grafts for 330 kidney after lung transplant recipients for whom induction before kidney transplant included depletional (n = 115), non-depletional (n = 170), or no induction (steroids only; n = 45). We studied risk factors for recipient and graft survival using Cox proportional hazards model adjusted for kidney and lung induction, kidney donor type, dialysis status, recipient and donor ages, time from lung to kidney transplant, cause of lung disease, bilateral vs single lung transplant, diabetes, and human leukocyte antigen mismatches before kidney transplant, with transplant center as a random effect. RESULTS There was no difference between groups in patient survival or death-censored kidney allograft survival. The 1-year kidney acute rejection rates were 15.5%, 7.14%, and 0% in depletional, non-depletional, and no induction groups, respectively. In the Cox model for patient survival, living kidney donor recipients and bilateral lung transplant recipients were favorable predictors. For death-censored graft survival, kidney induction type did not predict graft survival. Results did not change when models only included recipients on tacrolimus and mycophenolate based maintenance. CONCLUSIONS The type of kidney induction did not influence patient or kidney graft survival following kidney transplants for those with previous lung transplants. No induction may be the preferred choice for kidney after lung transplant because of the lack of benefits from biologic induction in this large cohort.

BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD).METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model.RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.

Summary Background Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. Methods In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. Findings Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). Interpretation Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. Funding TransMedics Inc.

Background: Alpha-1-antitrypsin (A1AT) deficiency (A1ATD) is characterized by accelerated degradation of lung function. We examined our experience with lung transplantation for chronic obstructive pulmonary disease (COPD) with and without A1ATD to compare survival and rates of postoperative surgical complications. Methods: Patients with A1ATD and non-A1ATD COPD undergoing lung transplantation from 1988−2015 at our institution were analyzed. Complications were categorized into non-gastroenteritis gastrointestinal (GI), wound, airway, and reoperation for bleeding. Overall and complication-free survival were evaluated using Kaplan-Meier curves and Cox proportional hazards models. Results: Three hundred and eighty-five patients underwent lung transplant for COPD (98 A1ATD). For A1ATD, 56.1% underwent single lung transplantation (80.6% for COPD). Early overall and complication-free survival was worse for A1ATD, but this trend reversed at longer follow up. Unadjusted estimated survival showed advantage for COPD at 90 days and 1 year, which attenuated by 5 years and reversed at 10 years (P

Prior coronary artery bypass grafting (CABG) has been considered a relative contraindication to lung transplantation due to the atherosclerotic disease burden and technical challenges. We hypothesized that lung transplant recipients with prior CABG have increased mortality compared to recipients without prior CABG. Further, the causes of death are different for lung transplant recipients with prior CABG vs without CABG. The Scientific Registry of Transplant Recipients database was queried to define the survival and causes of death of lung transplant recipients with or without CABG during the Lung Allocation Score era from May 5, 2005 to December 31, 2015. The primary end-points were all-cause mortality at 1 year and 5 years, as well as mortality due to major causes of death. This retrospective study cohort included a total of 13,064 lung transplant recipients, of whom 319 patients had previously undergone CABG, representing 2.4% of all transplants. Patients without prior CABG were more likely to have undergone bilateral lung transplantation compared to those with prior CABG (61.2 % vs 15.7%, P0.001). Among patients with prior CABG, single right lung transplant was most common. Overall patient survival at 1 year was 76.8% for lung transplant recipients with prior CABG and 85.4% for patients without prior CABG. Freedom from death due to graft failure at 1 and 5 years in patients with a prior CABG was 93.1% and 76.2% respectively, cardiac and/or cerebrovascular disease 96.2% and 88.5% respectively, and hemorrhage 97.9% and 97.5% respectively. In a multivariate Cox regression model utilizing time-dependent coefficients for recipient age, prior CABG, among several other risk factors, was associated with increased mortality within 1 year. Prior CABG is associated with short- and long-term mortality in lung transplant recipients with history of CABG despite the majority of these patients undergoing single lung transplantation vs bilateral lung transplantation. Graft failure and/or pulmonary causes are the most common cause of death regardless of whether or not the lung transplant recipient had prior CABG, but patients with prior CABG are at increased risk of death due to graft failure, cardiac or cerebrovascular disease, and hemorrhage.

Objective The purpose of this study was to determine the relationship between blood product transfusion, with or without recombinant human activated factor VIIa, and survival after lung transplantation. Design Retrospective analysis of a single center with follow-up out to 6 years post-transplantation. Setting Single-center academic lung transplantation program. Participants The study comprised 265 adult patients who underwent single or bilateral sequential lung transplantation from March 2011 to June 2017. Interventions Overall survival using Kaplan-Meier curves was compared among the following 3 cohorts: those not transfused with blood products, those transfused with blood products, and those given blood products and recombinant human activated factor VIIa. Cox proportional hazards regression was used to estimate hazard ratios (HRs), confidence intervals (CIs), and p values. Measurements and Main Results Seventy-eight patients received no packed red blood cell transfusions, 149 received packed red blood cell transfusions, and 38 received both packed red blood cell transfusions and recombinant human activated factor VII. Packed red blood cell transfusion was associated with an increased risk of mortality that did not reach statistical significance (HR 2.168, CI 0.978-4.805; p = 0.057). Additional packed red blood cells beyond 15 U were associated with worsened survival (HR 1.363, CI 1.137-1.633; p = 0.001), but recombinant human activated factor VIIa did not increase the risk of mortality. Conclusion Blood product transfusion during and after lung transplantation is associated with decreased survival, especially with large-volume transfusions. Survival is not worse with recombinant human activated factor VIIa administration, but additional studies are needed to determine whether recombinant human activated factor VIIa administration reduces the need for blood product transfusions.

BACKGROUND Tracheostomy is an important adjunct for lung transplant patients requiring prolonged ventilation. We explored the effects of post-transplant tracheostomy on survival and bronchiolitis obliterans syndrome after lung transplant. METHODS A retrospective, single center analysis was performed on all lung transplant recipients during the Lung Allocation Score (LAS) era. Risk factors for post-transplant tracheostomy or death within 30 days were assessed. Kaplan-Meier estimates and Cox proportional hazards models were used to examine the association between tracheostomy within 30 days after transplant and survival at 1 and 3 years. A total of 403 patients underwent single or bilateral lung transplant between May 2005 and February 2016 with complete data for 352 cases, and 35 patients (9.9%) underwent tracheostomy or died (N = 10, 2.8%) within 30 days. RESULTS In adjusted analyses, primary graft dysfunction grade 3 (PGD3) was associated with a composite end point of tracheostomy or death within 30 days (HR 3.11 (1.69, 5.71), P-value

Purpose To compare 5-year survival of lung transplant (LTx) recipients in donation after circulatory death (DCD) versus donation after brain-death (DBD) donors. Methods We examined the ISHLT Thoracic Transplant Registry data for LTx patients transplanted between 2003 and 06/2017 at 23 centers in North America, Europe and Australia participating in the DCD Registry. Distribution of continuous variables was summarized as median and interquartile (IQR) values. Mann-Whitney test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx during 2003-06/2016 were compared between DCD-III [Maastricht category III withdrawal of life sustaining therapy (WLST)] only and DBD using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. Results The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD transplants. DCD-III category comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx increased from 0.6% in 2003 to 15.2% in 2017. DCD donor management included extubation in 91%, intravenous heparin in 51% and pre-transplant normothermic ex-situ pulmonary allograft perfusion in 15%. Median time interval from WLST to cardiac arrest was 15 min [IQR: 11-22 min] and to cold flush 32 min [IQR: 26-41 min]. Compared to DBD, donor age was higher (47 [IQR: 34-55] vs 40 [IQR: 24-52] years), bilateral LTx was performed more often (88.3% vs 76.6%), more recipients had COPD/emphysema as transplant indication, and recipient hospital stay was longer (25 [IQR: 17-39] versus 18 [IQR: 12-29] days) in DCD-III (all p Conclusion This ISHLT DCD Registry report with 5-year follow-up demonstrated similar excellent long-term survival in DCD-III and DBD lung donor recipients in 23 experienced centers. These data support measures to implement and increase DCD LTx more widely.

US pediatric transplant candidates have limited access to lung transplant due to the small number of donors within current geographic boundaries, leading to assertions that the current lung allocation system does not adequately serve pediatric patients. We hypothesized that broader geographic sharing of pediatric (adolescent, 12-17 years; child

A 53-year-old woman who underwent bilateral lung transplantation 14 months before presented with 2 to 3 weeks of severe exertional dyspnea. Workup revealed a complete embolic occlusion of her left main pulmonary artery related to a femoral deep venous thrombosis. The occlusion did not respond to systemic anticoagulation, and a trial of catheter-directed thrombolysis was pursued. Flow to the left lower lobe was restored after 2 days of thromobolytic therapy. The patient is alive and well at more than 1 year of follow-up.

The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH).Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease.The utility of PAH-specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases.

Summary Background Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage. Methods In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434. Findings Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate −9·1%; 95% CI −∞ to −1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0–98·4) in the OCS group and 165 patients (100%; 97·8–100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1–93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8–92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate −0·045%; 95% CI −∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1). Interpretation The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation. Funding TransMedics Inc.

BACKGROUND: The objective of this study was to review the international experience in lung transplantation using lung donation after circulatory death (DCD).METHODS: In this retrospective study, data from the International Society for Heart and Lung Transplantation (ISHLT) DCD Registry were analyzed. The study cohort included DCD lung transplants performed between January 2003 and June 2013, and reported to the ISHLT DCD Registry as of April 2014. The participating institutions included 10 centers in North America, Europe and Australia. The control group was a cohort of lung recipients transplanted using brain-dead donors (DBDs) during the same study period. The primary end-point was survival after lung transplantation.RESULTS: There were 306 transplants performed using DCD donors and 3,992 transplants using DBD donors during the study period. Of the DCD transplants, 94.8% were Maastricht Category whereas 4% were Category IV and 1.2% Category V (euthanasia). Heparin was given in 54% of the cases, donor extubation occurred in 90% of the cases, and normothermic ex vivo lung perfusion (EVLP) was used in 12%. The median time from withdrawal of life support therapy (WLST) to cardiac arrest was 15 minutes (5th to 95th percentiles of 5 to 55 minutes), and from WLST to cold flush was 33 minutes (5th to 95th percentiles of 19.5 to 79.5 minutes). Recipient age and medical diagnosis were similar in DCD and DBD groups (p = not significant ENS]). Median hospital length of stay was 18 days in DCD lung transplants and 16 days in DBD transplants (p = 0.016). Thirty-day survival was 96% in the DCD group and 97% in the DBD group. One-year survival was 89% in the DCD group and 88% in the DBD group (p = NS). Five-year survival was 61% in both groups (p = NS). The mechanism of donor death within the DCD group seemed to influence recipient early survival. The survival rates through 30 days were significantly different by donor mechanism of death (p = 0.0152). There was no significant correlation between the interval of WLST to pulmonary flush with survival (p = 0.11).CONCLUSION: This large study of international, multi-center experience demonstrates excellent survival after lung transplantation using DCD donors. It should be further evaluated whether the mechanism of donor death influences survival after DCD transplant. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

Increased industrialization and urbanization have led to marked increases in air pollutants in China over the last decade. Pollutant levels in the north and eastern regions are often four times higher than current daily levels in the United States. Recent reports indicate a higher incidence of lung cancer and mortality in men and urban dwellers, but the contribution of air pollution to these findings remains unknown. Future studies that define individual exposures, combined with biomarkers linked to disease, will be essential to the understanding of risk posed by air pollution in China.

Lungs are allocated to adult and adolescent transplant candidates (aged ⩾ 12 years) on the basis of age, geography, blood type compatibility, and the lung allocation score (LAS), which reflects risk of waitlist mortality and probability of posttransplant survival. In 2013, the most adult candidates, 2394, of any year were added to the list. Overall median waiting time for candidates listed in 2013 was 4.0 months. The preferred procedure remained bilateral lung transplant, representing approximately 70% of lung transplants in 2013. Measures of short-term and longterm survival have plateaued since the implementation of the LAS in 2005. The number of new child candidates (aged 0-11 years) added to the lung transplant waiting list increased to 39 in 2013. A total of 28 lung transplants were performed in child recipients, 3 for ages younger than 1 year, 9 for ages 1 to 5 years, and 16 for ages 6 to 11 years. The diagnosis of pulmonary hypertension was associated with higher survival rates than cystic fibrosis or other diagnosis (pulmonary fibrosis, bronchiolitis obliterans, bronchopulmonary dysplasia). For child candidates, infection was the leading cause of death in year 1 posttransplant and graft failure in years 2 to 5.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Lung transplantation is the only therapy associated with prolonged survival. The ideal transplant procedure for IPF is unclear. Outcomes after single transplantation (SLTx) versus bilateral lung transplantation (BLTx) in IPF patients after introduction of the Lung Allocation Score were examined. Methods Records of patients undergoing lung transplantation for IPF at our institution between May 2005 and March 2017 were reviewed to examine the effect of transplant laterality. Primary outcomes were overall, rejection-free, and bronchiolitis obliterans (BOS)-free survival at 1 and 5 years post-transplant. Results Lung transplantation was performed in 151 IPF patients post-Lung Allocation Score. Most recipients were male with average age 59 ± 8 years. SLTx was performed in 94 patients (62%). In the overall cohort, comparative survival between SLTx and BLTx was similar at 1 and 5 years before and after adjusting for age and pulmonary hypertension (PH). SLTx was associated with shorter ventilator time and intensive care unit stay and trended toward improved survival over BLTx in patients without PH. Conclusions The use of SLTx versus BLTx in IPF did not correspond to significantly different survival adjusting for age and PH. BLTx was associated with prolonged postoperative ventilation and length of stay compared with SLTx. Patients without PH, all older patients, and patients with PH and advanced disease should be considered for SLTx for IPF.

Background With the relative paucity of acceptable donors for lung transplantation, criteria for extended donor consideration are being explored. We sought to evaluate the suitability of donors whose cause of death was asphyxiation or drowning (A/D) as a potential option to enlarge the donor pool. Methods We queried the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research registry for lung transplantation from 1987 to 2010 to assess associations between cause of death and recipient survival using the Kaplan-Meier method. To adjust for potential confounders, we used a Cox proportional hazards model and a logistic regression model to evaluate incidence of rejection within the first year. Results There were 18,250 adult primary lung transplantations performed, with 309 A/D donors. There was no difference in survival between groups (log-rank, p = 0.52). There were no differences in demographics, length of stay, airway dehiscence, lung allocation score (LAS), or ischemic time in univariate analysis (all p > 0.05). The A/D lung recipients had fewer deaths from pulmonary causes (5.8% versus 9.5%; p = 0.02). Proportional hazards analysis was significant for double lung transplantation (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.8–0.9), height difference (HR, 1.002; 95% CI, 1.00–1.003), donor age greater than 50 years (HR, 0.89; 95% CI, 0.83–0.96), and recipient age greater than 55 years (HR, 0.8; 95% CI, 0.76–0.84). A/D cause of death did not impact survival in multivariate analysis. Conclusions A/D as a donor cause of death was not associated with poor long-term survival or incidence of rejection in the first year after transplantation. Donor cause of death by A/D, when carefully evaluated and selected, should not automatically exclude the organ from transplant consideration. These results provide important justification for potentially broadening the donor pool safely.

On June 5, 2013, a US Federal Court ordered a temporary restraining order to allow two children within the court's jurisdiction to be registered on the adolescent lung transplant waiting list. On June 10, 2013, the Organ Procurement and Transplantation Network's Executive Committee altered lung allocation policy to offer candidates aged younger than 12 years greater access to adult lungs at the discretion of the national Lung Review Board. The Scientific Registry of Transplant Recipients reviewed trends over time in deceased donor lung transplant waitlist mortality and transplant rates, comparing children and adults. Mortality rates of candidates active on the waiting list have been higher for children aged 0-5 years, but have not differed for children aged 6-11 years compared with adolescents aged 12-17 years or adults aged 18 years or older. Transplant rates among active waitlist candidates have been comparable across all age groups. Thus, there is little evidence that the allocation system led to differences in waitlist mortality or transplant rates for children compared with adults. However, these comparisons are difficult to interpret given that current policies likely led to unaccounted differences in the severity of illness at the time of listing.

Purpose Donation after circulatory death (DCD) donors and ex-vivo lung perfusion (EVLP) both share the potential to attenuate lung shortage. We report the experience of the OCS Lung EXPAND trial on lung transplantation following EVLP for DCD pulmonary grafts. Methods OCS Lung EXPAND is an international multi-center clinical trial aiming to evaluate the safety and effectiveness of the OCS™ Lung to recruit, preserve and assess donor lungs that may not meet current standard donor lung acceptance criteria for transplantation. We performed a post-hoc analysis of the DCD donors. Data are reported as mean±standard deviation. Results Out of 93 OCS perfused donor lungs, 32 (34%) were DCD grafts of which 26 (81% utilization rate) were transplanted. Recipient age was 55±11 years; 18 male/ 8 female; indications were emphysema (n=11), fibrosis (n=5), cystic fibrosis (n=4), other (n=6); donor age was 40±14 years; 17 male/ 9 female. EVLP time was 389±127 min, final PO2/FiO2 was 403±84 mmHg. Pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and peak airway pressure (PAWP) remained stable during EVLP (Figure 1). Intensive care unit and hospital stay was 12±8 and 31±25 days, respectively. Time until first extubation was 5±8 days. Ratio of primary graft dysfunction grade 3 at 24, 48 and 72 hours was 15%, 8% and 8%, respectively. With a follow-up of 1 year, no acute rejections occurred and 1 patient developed chronic lung allograft dysfunction. Two patients died at 73 and 139 days post-transplant due to hyperkalemia and esophageal perforation; 24 patients were alive, resulting in a 1-year patient survival of 92%. Conclusion Portable EVLP is a safe and effective modality to assess functional performance of DCD lungs prior to transplantation, resulting in a high utilization rate and good clinical outcome.

Background Clostridium difficile infection (CDI) and associated mortality in solid organ transplant recipients is rising, but data are scarce in lung transplant recipients. We aimed to characterize CDI and its effect on mortality in a large cohort of lung transplant recipients. Methods Lung transplant recipients were identified from our transplant database from 2000 to 2011. Cox proportional hazard models were used to calculate hazard ratios for CDI and death after adjusting for potential confounders identified from bivariate analysis. Results We identified 388 patients (196 female, 192 male), with a median age of 56 years (range, 8–75 years), during the study period. CDI developed after transplant in 89 (22.9%), with 27 (7.0%) developing CDI during the initial hospitalization at a mean diagnosis of 12.7 ± 11.4 days. Incidence varied widely each year (median, 24%; range, 5%–32%), with the highest rates in 2007 to 2008. Post-operative length of stay was identified as a significant predictor of CDI (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01–1.03). Early CDI was an independent significant predictor of death (HR, 1.96; 95% CI, 1.14–3.36) as well as CDI anytime after transplant (HR, 1.61; 95% CI, 1.02–2.52). Conclusions CDI rates varied widely from 2000 through 2011, with the highest rates in 2007 to 2008. Lung transplant recipients who developed CDI had a higher risk of death, especially when CDI occurred in the first 6 months after transplant.

Background Tacrolimus (FK506) has a superior immunosuppressive effect compared with cyclosporine (CSA) without a significant increase in generalized infectious complications. Differences in specific infections such as Clostridium difficile (CDI) have not been reported. We investigated the relationship between calcineurin inhibitors and CDI, hypothesizing that choice of calcineurin inhibitor (CSA or FK506) after lung transplantation would have no effect on the incidence of CDI. Methods We performed a retrospective chart review of lung transplant recipients between June 1, 2000, and December 31, 2005, at a single institution. Positive CDI assays through December 11, 2011, were also recorded. We used Student's t- and chi-squared tests (α = 0.05) to compare CSA and FK506 groups. We calculated adjusted hazard ratios for CDI using Cox proportional hazard models. Results We identified 217 lung transplant recipients: 106 patients in the CSA group and 111 patients in the FK506 group. A total of 31 patients (27.9%) in the FK506 group developed CDI postoperatively compared with 20 patients (18.9%) in the CSA group (P = 0.16). The adjusted hazard ratio for CDI in the FK506 group was not significantly higher (1.53; 95% confidence interval, 0.78-2.98). There was no significant difference in the intensive care unit or total length of stay, in-hospital incidence rate, time to first CDI episode, or recurrence rate between groups. Conclusions The CDI rates were not significantly higher in the FK506 group than the CSA group in our study. These data are consistent with previous studies on FK506 that show no increase in infectious complications over CSA, and demonstrate its continued safety in lung transplantation.

In this paper, we study the multi-class differential gene expression detection for microarray data. We propose a likelihood based approach to estimating an empirical null distribution to incorporate gene interactions and provide more accurate false positive control than the commonly used permutation or theoretical null distribution based approach. We propose to rank important genes by p-values or local false discovery rate based on the estimated empirical null distribution. Through simulations and application to a lung transplant microarray data, we illustrate the competitive performance of the proposed method.

Purpose Clostridium difficile infection (CDI) rates have been rising in recent years. We aimed to characterize CDI in lung transplant recipients in the modern era and hypothesized that CDI would increase the mortality risk. Methods We performed a retrospective chart review of patients undergoing transplantation at our center from 1/2006 to 7/2011. Attributes of CDI+ and CDI− groups were compared using Student's t- and chi-square tests (α = 0.05). Multivariate Cox proportional hazard models were used to control for confounding factors. Results Overall CDI incidence was 22.5%. Seven of 151 patients (4.6%) developed CDI during the initial hospitalization after transplantation (mean time 10.6 ± 6 d) while 27 patients (19.7%) developed CDI after discharge (mean time 467 ± 471 d). Incidence rate was 224.6 cases/100 000 patient-days compared to 110 cases/100 000 patient-days (rate for entire hospital). CDI was not predictive of mortality (HR 2.06, 95% CI 0.94–4.52). Conclusion CDI rates in lung transplant recipients are high in the modern era. No risk factors for CDI were identified. Although not statistically significant, CDI+ patients had a higher risk of death. The economic burden of CDI and trend toward worse outcomes for CDI patients have important implications for post-operative surveillance of CDI-related complications and need for CDI prophylaxis.

Lungs are allocated in part based on the Lung Allocation Score (LAS), which considers risk of death without transplant and posttransplant. Wait-list additions have been increasing steadily after an initial decline following LAS implementation. In 2011, the largest number of adult candidates were added to the waiting list in a single year since 1998; donation and transplant rates have been unable to keep pace with wait-list additions. Candidates aged 65 years or older have been added faster than candidates in other age groups. After an initial decline following LAS implementation, wait-list mortality increased to 15.7 per 100 wait-list years in 2011. Short- and long-term graft survival improved in 2011; 10-year graft failure fell to an all-time low. Since 1998, the number of new pediatric (aged 0-11 years) candidates added yearly to the waiting list has declined. In 2011, 19 pediatric lung transplants were performed, a transplant rate of 34.7 per 100 wait-list years. The percentage of patients hospitalized before transplant has not changed. Both graft and patient survival have continued to improve over the past decade. Posttransplant complications for pediatric lung transplant recipients, similar to complications for adult recipients, include hypertension, renal dysfunction, diabetes, bronchiolitis obliterans syndrome, and malignancy.

The purpose of this study was to clarify the significance of recipient gender status on lung transplant outcomes in a large single-institution experience spanning three decades, we analyzed data from all lung transplants performed in our institution since 1986. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate the effect of recipient characteristics on survival and BOS score ≥1-free survival. Logistic regression analysis was used to explore the association of gender with short-term graft function. About 876 lung transplants were performed between 1986 and 2016. Kaplan-Meier survival estimates at 5 years post-transplant for females vs males in the LAS era were 71% vs 58%. In the LAS era, females showed greater unadjusted BOS≥1-free survival than males (35% vs 25%, P=.02) over 5 years. Female gender was the only factor in the LAS era significantly associated with improved adjusted 5-year survival [HR 0.56 (95% CI 0.33, 0.95) P=.03]. Conversely, in the pre-LAS era female gender was not associated with improved survival. Female recipients showed significantly improved survival over 5 years compared to males in the LAS era. A prospective analysis of biologic and immunologic differences is warranted.

Background We sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. Methods From 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score ≥1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. Results In the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori–defined donor age groups: age P = .8). Unadjusted 5-year freedom from BOS ≥1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. Conclusions Long-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed.

On behalf of the Registry Executive Committee, I am pleased to present the 2012 Annual Reports of the Scientific Registry (the Registry) of the International Society for Heart and Lung Transplantation (ISHLT). The Registry has now collected, analyzed, and reported data regarding more than 150,000 heart, heart-lung, and lung transplants. We are delighted to report a new relationship with the Registro Espanol de Trasplante Cardiaco, which will allow us, for the first time, to add data to the Registry regarding more than 4,000 heart transplants performed in Spain between May 1984 and March 2012. The addition of the Spanish data, in combination with continued participation of more than 200 other centers worldwide (Appendix), has resulted in the past year being our most active to date, with 6,915 reported transplants (Table 1).

The Registry of the International Society for Heart and Lung Transplantation (ISHLT) has documented trends in clinical lung and heart-lung transplantation since the inception of these procedures. Detailed heart-lung transplantation data have been included in the Registry annual reports since 1984 and lung transplantation data since 1989. Through June 30, 2010, the Registry contains data on 4,248 heart-lung and 38,119 lung transplants from centers around the world. This 28th Lung and Heart-Lung Registry Report summarizes the current status of lung and heart-lung transplantation by reporting data on this international group of patients, focusing on adults. More detailed information is presented in the full set of more than 200 slides that can be found on the ISHLT Web site at www.ishlt.org/registries/.

We enthusiastically present the 2011 Annual Reports of the Scientific Registry (the Registry) of the International Society for Heart and Lung Transplantation (ISHLT). The Registry has now collected, analyzed, and reported data for more than 142,000 heart, heart-lung, and lung transplants. We are delighted to announce a new reporting relationship with L’agence de la Biomedicine, which allows us, for the first time, to add to the Registry data related to more than 13,000 heart, heart-lung, and lung transplants performed in France between April 1968 and December 2009. The addition of the French data, in combination with continued participation of more than 200 other centers worldwide (Appendix), has resulted in the past year being our most active to date (Table 1). We also note a transition in Registry report authorship: Dr Christian Benden is the first author of this year’s Pediatric Lung and Heart-Lung Transplant report, and will assume the position of Associate Medical Director from Dr Paul Aurora, who has served extremely ably in that capacity since 2007. There are many ways to access the Transplant Registry data. As in past years, all of the data figures and tables included in the Registry reports are also available on the ISHLT Web site (www.ishlt.org/registries) in the Microsoft PowerPoint (Microsoft Corp, Redmond, WA) format. The Web site also contains many additional data slides that are not included in the published reports. Those who wish to

This Twenty-eighth Report of the International Society for Heart and Lung Transplantation (ISHLT) Transplant Registry is based on data submitted by participating transplant centers worldwide. A total of 388 heart transplant centers have contributed information to the Registry. This year we have also achieved another important milestone: the 100,000 heart transplant recipient was registered in the database. This report reviews important statistics for the entire cohort of patients registered in the database. However, similar to prior reports, many of the more detailed analyses will focus on recent transplant recipients, exploring information relevant to contemporary heart transplantation practice. The first part of the report reviews important donor, recipient, and medical center demographics. The second part provides an overview of immunosuppressive therapies used after transplantation. The third part examines survival, mortality risk factors, and causes of death after adult heart transplantation. The last section focuses on quality of life after transplant.

Whitson BA, Shelstad RC, Hertz MI, Kelly RF, D’Cunha J, Shumway SJ. Lung transplantation after hematopoietic stem cell transplantation. Clin Transplant 2011 DOI: 10.1111/j.1399-0012.2011.01482.x. © 2011 John Wiley & Sons A/S. Abstract: Introduction: Pulmonary insufficiency following bone marrow transplant (BMT) is common and has significant associated mortality. Lung transplantation (LTX) is the only viable treatment for patients with end-stage pulmonary disease, but LTX after BMT is an uncommon event given the medical candidacy of the potential recipients. We sought to evaluate the short- and long-term outcomes of LTX in BMT recipients. Methods: We performed a retrospective evaluation of our institution’s longitudinal LTX and BMT databases. Demographic and outcomes variables were collected. Results: We identified 639 LTX from January 1, 1988, through December 31, 2009, and 5525 BMT from program inception, March 21, 1974, through December 31, 2009. From the cross-referenced cohort, we identified four patients who had BMT followed by LTX. Our series was composed of two men and two women, with a mean age of 32.3 yr (range, 20–59 yr). Single LTX were performed in two recipients (50%). All patients had significant and expected morbidities related to their transplant immunosuppression. Three patients (75%) required cardiopulmonary bypass at the time of LTX. The two recipients who underwent bilateral LTX required open chest management and subsequent tracheostomy. All patients are still alive at follow-up (range, 19–119 months, median 39.5). Conclusion: Our study demonstrates that LTX in the setting of BMT is a high-risk operation with the potential for a tumultuous perioperative course. Despite this, good outcomes and survival are obtainable in carefully selected patients. Selection factors include clinically stable patients without active sepsis and preoperative optimization of nutrition in anticipation of a prolonged recovery. An experienced multidisciplinary team approach and a protocol-driven management plan are paramount for successful outcomes in this challenging population.

This tenth official pediatric report of the International Society for Heart and Lung Transplantation (ISHLT) covers the international pediatric lung and heart-lung transplantation experience from 1982 to 2006. As of last year's report, pediatric lung and heart-lung transplant data are now reported separately from pediatric heart transplant data and adult lung transplant data. For the first time this year, Registry data are analyzed by geographic region in addition to the usual aggregate analyses. All figures and tables included in this report and additional supplementary slides are available from the ISHLT website (www.ishlt.org/registries).