Search

Background: The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France., Methods: A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age author groups: young (≤30 years), middle-aged (30-60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results., Results: Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-year post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD., Conclusion: Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes., Competing Interests: Disclosure statement P. Pradère, J. Le Pavec, S. Morisset, V. Gerovasili, R. Kessler, A. Adlakha, V. Bunel, K. Santhanakrishnan, X. Demant, A. Roux, L. Falque, V. Cottin, J. Parmar, M. Reynaud-Gaubert, T. Villeneuve, A. Tissot have nothing to declare related to the content of the manuscript. O. Mercier reports grants from Edwards Lifescience outside the scope of the submitted work. A.J. Fisher reports institutional grant funding from NIHR Blood and Transplant Research Unit, consultancy and non-financial support from Mallinckrodt Pharmaceuticals, consultancy from Altavant and Sanofi, and grants from Pfizer and Chiesi, all outside the scope of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented., Methods: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France., Results: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35-55]. About 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (<90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p = 0.046), FVC (p = 0.021), FEV1 (p = 0.009) and high emergency lung transplantation (p = 0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p = 0.07)., Conclusion: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes., Gov Identifier: NCT05044390., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development., Methods: Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after., Results: MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0-253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%., Conclusion: Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD., (© 2024. The Author(s).)

Objectives: A lung transplant is the final treatment option for end-stage lung disease. We evaluated the individual risk of 1-year mortality at each stage of the lung transplant process., Methods: This study was a retrospective analysis of patients undergoing bilateral lung transplants between January 2014 and December 2019 in 3 French academic centres. Patients were randomly divided into development and validation cohorts. Three multivariable logistic regression models of 1-year mortality were applied (i) at recipient registration, (ii) the graft allocation and (iii) after the operation. The 1-year mortality was predicted for individual patients assigned to 3 risk groups at time points A to C., Results: The study population consisted of 478 patients with a mean (standard deviation) age of 49.0 (14.3) years. The 1-year mortality rate was 23.0%. There were no significant differences in patient characteristics between the development (n = 319) and validation (n = 159) cohorts. The models analysed recipient, donor and intraoperative variables. The discriminatory power (area under the receiver operating characteristic curve) was 0.67 (0.62-0.73), 0.70 (0.63-0.77) and 0.82 (0.77-0.88), respectively, in the development cohort and 0.74 (0.64-0.85), 0.76 (0.66-0.86) and 0.87 (0.79 - 0.95), respectively, in the validation cohort. Survival rates were significantly different among the low- (< 15%), intermediate- (15%-45%) and high-risk (> 45%) groups in both cohorts., Conclusions: Risk prediction models allow estimation of the 1-year mortality risk of individual patients during the lung transplant process. These models may help caregivers identify high-risk patients at times A to C and reduce the risk at subsequent time points., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Survival after lung transplantation (LTx) still remains limited by chronic lung allograft dysfunction (CLAD), thought to represent a form of chronic rejection. We investigated whether the immune checkpoint HLA-G/ILT2 expressed by peripheral T-cell subpopulations could predict CLAD., Methods: We used data for 150 LTx recipients from COLT (Cohort-For-Lung-Transplantation) cohort with ≥1 available blood sample at 1-, 6-, or 12-months post-Tx. Analysis of T cells by flow cytometry focused on the ILT2 receptor of HLA-G and other markers (CD57, CD25, CD127). T-cell subset analyses compared stable patients and those with CLAD at 3 years post-LTx., Results: With data for 78 stable and 72 CLAD patients, among 21 T-cell subsets expressing ILT2, only CD4+CD57+ILT2+ T cells were associated with outcome. At 1-month post-Tx, low proportion of CD4+CD57+ILT2+ T cells was associated with reduced 3-year incidence of CLAD (CD4+CD57+ILT2+ T cells ≤ first IQR [25%] vs > first IQR, log-rank test, p = 0.028). Furthermore, the incidence of CLAD was higher with >2.6- vs ≤2.6-fold increased proportion of CD4+CD57+ILT2+ T cells over the first year post-LTx (3-year freedom frequencies: 27% [95%CI: 8-50] vs 64% [95%CI: 48-77] (log-rank test, p = 0.014). On multivariable analysis, increased proportion of CD4+CD57+ILT2+ T cells over the first year predicted CLAD (hazard ratio 1.25; 95%CI: 1.09-1.44; p = 0.001). Focusing on CD4+CD57+ILT2+ T cells, we demonstrated ex vivo that they are cytotoxic CD4+ T cells, selectively inhibited by HLA-G., Conclusions: Our data suggest that an early increase of CD4+CD57+ILT2+ T cells after LTx may be associated with CLAD onset., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients., Methods: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed., Results: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 (40.6-62.9) years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6%) required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days (41.0-56.5). Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio, 16.0; 95% confidence interval, 1.5-170.6; P = 0.02)., Conclusions: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Long-term survival after lung transplantation (LT) is hampered by the occurrence of chronic lung allograft dysfunction (CLAD). CLAD may manifest as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS), and is triggered by several factors, e.g. post-transplant infections. As immunoglobulin (Ig) A is crucial to ensure mucosal immunity and limit airway microbial load, we explored whether IgA and its epithelial receptor, the polymeric Ig receptor (pIgR) are impaired in BOS. Bronchoalveolar lavages (BAL, n=120) and sera (n=179) from LT recipients included in the Cohort for Lung Transplantation were collected at defined timepoints after LT, prior to the diagnosis of functional stability (BOS-free, n=30) or BOS (pre-BOS, n=30). BAL were assessed for secretory (S)-IgA. Sera were assessed for IgA, S-IgA and secretory component (SC, released by pIgR apical cleavage after transcytosis). pIgR epithelial expression was quantified in transbronchial biopsies from BOS-free (n=20), pre-BOS (n=19) and BOS LT recipients (n=12), as well as in end-stage BOS explants (n=15). BAL S-IgA was reduced in pre-BOS LT recipients (Fig. 1A, 16.1 vs 33.4 µg/ml, p<0.01). Serum IgA was reduced after LT, with no difference across the groups. In contrast, serum SC and S-IgA were increased in pre-BOS LT recipients (Fig. 1B-C, S-IgA: 40.6 vs 21.2µg/ml, p<0.05; SC: 156.0 vs 97.2ng/ml, p<0.001). pIgR bronchiolar expression was reduced in transbronchial biopsies from BOS (Fig. 1D-E, p<0.05 vs BOS-free and pre-BOS), with further decrease in end-stage BOS explants (p<0.0001 vs BOS-free and pre-BOS). BAL S-IgA and pIgR decreased levels suggest that the pIgR/IgA system is impaired in BOS. This alteration is present prior to the functional diagnosis of CLAD. Serum SC and S-IgA increased levels in pre-BOS may reflect a spill-over from bronchoalveolar fluids, witnessing an permeability of the respiratory barrier. These features could play a pathogenic role by increasing susceptibility to local infections. [ABSTRACT FROM AUTHOR]

Survival after lung transplantation (LTx) still remains limited by chronic lung allograft dysfunction (CLAD). Prior studies showed an association between graft cellular expression of the checkpoint HLA-G and acceptance, whereas conversely, soluble HLA-G (sHLA-G) in plasma/BAL was associated with acute rejection. We investigated whether plasma levels of extra-vesicular (EVs)-bound HLA-G could predict CLAD. We used data for 79 LTx recipients from COLT (Cohort For Lung Transplantation) cohortwith ≥1 available blood samples at 6-, or 12-months post-Tx, all with a stable function within the 1st year. Among them, 41 developed subsequent CLAD (Group CLAD=33 BOS and 8 RAS) and 38 remained STABLE at 3 years. 20 heathy individuals (HI) were negative controls. EVs from plasma were isolated by size exclusion chromatography and characterized by nanoparticule tracking analysis. Plasma levels of EVs-bound HLA-G (sHLA-G EV) and of total soluble-HLA-G (sHLA-G TOT =sHLA-G EV + free sHLA-G) were measured by ELISA. Uni- and multivariate were performed to assess association of EVs levels and CLAD/survival. In stable patients, mean plasma levels of sHLA-G EV at M6 and M12, were significantly increased as compared to those of HI (M6: 30.2 vs 15,1 ng/mL, p=0.008, and M12: 37.8 vs 15.1 ng/mL, p=0.0009, respectively). In BOS patients, a decreased plasma levels of sHLA-G EV were observed at M6 and M12 as compared to stable patients, with a significant difference at M12 (mean sHLA-G EV of 23.7 ng/mL vs 38.7 p=0.02). In those BOS patients, sHLA-G EV levels remained increased as compared to HI at M6 (p=0.01). In RAS patients, sHLA- GEV levels was similar to stable patients at M6 and M12, and increased as compared to HI (M12: 40,5 vs 15,6 ng/mL, p=0.004). Among the whole cohort, a higher freedom from CLAD was observed in patients with sHLA-G EV level > first IQR (=21.3 g/ml) at M12 post-LTx (p=0.01, Figure 1). Our data suggest that an early decrease of sHLA-G EV levels after LTx may be predictive of subsequent CLAD onset. [ABSTRACT FROM AUTHOR]

Limited published data exist on outcomes related to lung transplantation (LTx) in human immunodeficiency virus (HIV)-infected individuals. We conducted a multicenter retrospective study of LTx in HIV- infected patients and describe key transplant- and HIV-related outcomes. We identified 22 HIV-infected LTx recipients across 25 transplant centers from 2007 through 2021. At transplantation, mean age was 53 [46 - 59] years, 55% were male. Two (9%) patients had an history of previous opportunistic infection and AIDS status. Pretransplant CD4 T cell count was 514 [351 - 670] cell/mm3 and RNA viral load was negative in all patients and their values did not change significantly post operatively. Due to calcineurin inhibitor interactions, 3 (15%) patients required an antiretroviral regimen change before LTx. Main indications for LTx were pulmonary arterial hypertension in 7 (32%), fibrosis in 5 (23%) and cystic fibrosis in 3 (14%). LTx procedure was predominantly bilateral-lung transplantation (91%). Immunosupression was giving according to local protocols including induction in 7 (32%) patients. During first post-LTx year, acute cellular rejection, antibody-mediated rejection, and infections requiring hospitalization occurred in 7 (37%), 2 (11%) and 8 (40%), respectively. During the median [range] follow-up of 25 [0.1-172] months, 26% and 14% of patients developed chronic lung allograft dysfunction and malignancy, respectively. Posttransplant survival rates after 1, 3, and 5 years were 79%, 79%, and 79%, respectively. At last news evaluation, 59% of the patients were fully active and independent. Apart from early infection rates, survival rates and post-operative outcome were similar to their HIV-uninfected LTx recipients. At last follow-up, more than half of the patients had near-normal functional status. [ABSTRACT FROM AUTHOR]

Lung transplantation (LT) has become the standard of care in selected children with end-stage parenchymal and vascular pulmonary diseases. In patients with pulmonary hypertension (PH) and cystic fibrosis (CF), new highly effective medical therapies have extended the period before lung transplantation is needed. These innovations will change pediatric LT indications and candidate outcomes. This study aimed to examine waitlist outcomes and posttransplant survival in pediatric lung transplant candidates listed during the 2010-2020 period in France. All candidates registered on the national waiting list before 18 years old between January 2010 and December 2020 were included in this cohort study using the national registry Cristal. Candidate demographics, primary diagnosis, clinical status and laboratory values were analyzed. Cumulative incidence of transplantation and waitlist mortality were estimated with the competing risk analysis with transplantation and death or delisting for worsening medical condition as the competing events. Posttransplant survival curve was estimated using the Kaplan-Meier method. Univariate analyses were performed to identify variables associated with outcomes. The 139 listings in 131 candidates resulted in 121 LT. At listing, 122 candidates were ≥11 years of age, 76 were females, 84 had CF, 35 pulmonary fibrosis (PF) and 16 PH, 80 were CMV-negative, 63 had HLA alloantibodies, 73 were hospitalized, 15 were on ECMO support, 4 had mechanical ventilation without ECMO, 61 were with high-urgency status. Cumulative incidence of transplantation and death or delisting for medical condition at 12-month was 80% [72-86] and 7% [4-13], respectively. ECMO support was associated with waitlist mortality. At transplant, 110 candidates were ≥11 years of age, 76 had CF, 28 PF and 14 PH, 54 had HLA alloantibodies, 73 were hospitalized, 21 were on ECMO support, 4 had mechanical ventilation without ECMO. One-year posttransplant survival was 82%. Pretransplant ECMO and mechanical ventilation, and donor-recipient height ratio >1.2 were associated with posttransplant mortality. Our findings will be useful for evaluation of the impact of new medical therapies on future indications and results of pediatric LT. [ABSTRACT FROM AUTHOR]

Lung transplantation (TxP) is now a validated treatment of end-stage pulmonary diseases, but long-term survival are still hampered by the development of chronic allograft dysfunction (CLAD) affecting> 50% of patients. Bronchiolitis obliterans syndrome/obliterative bronchiolitis (BOS/OB) is the most common manifestation of CLAD. Survival after onset of BOS is poor (<50% at 3 years). OB is thought to arise from repeated injury to graft epithelial cells, leading to fibrous scarring and obliteration of the small airway lumen. The crucial role of a dysregulated fibrotic repair demonstrated in BOS strongly suggests the potential role of tyrosine kinase inhibitors (TKI) that target these growth factors involved in OB. The TKI Nintedanib, demonstrated as effective in the treatment of idiopathic pulmonary fibrosis (IPF) appears as a candidate molecule. Hence, we started a Nintedanib trial in LTx recipients with BOS because of : (i) High unmet medical need in BOS; (ii) fibrotic pathway involved in BOS; (iii) efficacy of nintedanib in IPF. A phase III clinical randomized trial to assess the efficacy of Nintedanib in LTx recipients with BOS. Inclusion criteria: n=80 LTx recipients with BOS 0p-1-2, with a decline of FEV1> 200ml within the previous year. Primary Objective : to assess Nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 sec) at a dose of 150 mg twice daily (bid) compared to placebo over 6 months. Secondary Objectives : to assess Nintedanib efficacy and tolerance in the treatment of BOS 0p-1-2, based on the change over 6 months of : 6WT, QOL, BOS grade/graft failure, O2 saturation, KL-6, SPD, VEGF, PDGF parameters, and tolerance. The trial was started in December 2019 among 8 french LTx centers (Hôpital Foch, Bichat, HEGP/Cochin, Marie-Lannelongue, Marseille, Bordeaux, Strasbourg, and Grenoble), for a total duration of inclusion anticipated at 36 months. On October 15th 2020, 14 patients were already included. Infinitix-BOS is the first therapeutic randomized trial testing the efficacy of nintedanib in LTx recipients with BOS. In case of demonstrated effectiveness of Nintedanib, the benefit for LTx patients with BOS seems high in terms of stabilization of lung function and enhancement of survival. [ABSTRACT FROM AUTHOR]