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

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

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

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

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

BackgroundChronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. ResultsA total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. ConclusionBased on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions

Comparison of culture and qPCR for the detection of Pseudomonas aeruginosa in not chronically infected cystic fibrosis patients

Pseudomonas aeruginosa is the major respiratory pathogen causing severe lung infections among CF patients, leading to high morbidity and mortality. Once infection is established, early antibiotic treatment is able to postpone the transition to chronic lung infection. In order to optimize the early detection, we compared the sensitivity of microbiological culture and quantitative PCR (qPCR) for the detection of P. aeruginosa in respiratory samples of not chronically infected CF patients.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Lung transplantation after allogeneic stem cell transplantation : a pan-European experience

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT. SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed. Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.Peer reviewe

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current LAS era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N=3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤ 45 years, p<0.0001), were less often smokers (35% vs. 46%, p<0.0001), had more often clear chest X-rays (82% vs. 72%, p<0.0001), had better donor oxygenation ratio's (20% vs. 26% with PaO /FiO ≤ 300 mmHg, p<0.0001) and had better lung donor score values (LDS) (28% vs. 17% with LDS=6, p<0.0001) compared to donors used for LTx in countries with low donation rate. Survival rates for the groups LDS =6 and ≥7 at 5 years were 69.7% and 60.9% (p=0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant – a historical prospective study

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2/FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized

Lung allocation score: The Eurotransplant model versus the revised US model - a cross-sectional study

Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET

Un long roman pour une bibliothécaire

SCOPUS: ar.jinfo:eu-repo/semantics/publishe