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Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented. 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. 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). 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. NCT05044390. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [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 (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]

Patients with short telomeres and interstitial lung disease (ILD) appear to have increased mortality and bronchiolitis obliterans syndrome after lung transplant. Given the dysfunctional response of short telomere patients to cell damage and stress due to cell senescence, they may be more susceptible to impaired large airway healing. We hypothesized that post-transplant airway complications, including dehiscence and bronchial stenosis, would be more common in the short telomere ILD transplant population. We studied 63 recipients transplanted at two centers between 2009 and 2019 with ILD and short telomeres, defined either by telomere length below the 1st percentile for age in any lineage or below the 10th percentile in the lymphocyte lineage by flow-FISH telomere length analysis of peripheral blood lymphocytes, with or without the presence of a known telomere-related mutation. The primary outcomes were the presence of dehiscence or of significant stenosis (i.e. requiring dilation or stenting) after transplant. The control population was 4,359 adult recipients with ILD transplanted over similar years, taken from the Scientific Registry of Transplant Recipients (SRTR). Among the short telomere cohort, 6 patients (9.5%) had dehiscence and 9 (14.3%) had stenosis compared to 1.4% and 3.4%, respectively, in the SRTR cohort. When adjusted for age, sex, and bilaterality, the presence of short telomeres was associated with a significantly higher odds of dehiscence (odds ratio (OR)=7.34, 95% confidence interval (CI)=3.01-17.92, p<0.001) and higher odds of stenosis (OR=4.72, 95% CI 2.26-9.85, p<0.001). We identified an association between the presence of short telomeres and post-transplant large airway complications, including dehiscence and significant stenosis. Airway complications may be a contributor to worse outcomes in patients with telomere-related ILD. [ABSTRACT FROM AUTHOR]

The MDS classification (i.e. Macroscopic aspect, Diameter, Suture) allows an endoscopic grading of bronchial complications after lung transplantation. We aimed to determine the long-term prognosis value of the MDS airway evaluation after lung transplant and to propose a new organization in prognostic stage of the MDS classification. We performed a retrospective monocentric cohort study of the consecutive patients who underwent a single or double lung transplant between the January 2015 and December 2021. We analyzed the prospectively evaluated MDS status at day 7, 28 and 90 after transplantation and the long term follow-up. Analyzed outomes were overall survival (OS), chronic lung allograft dysfunction (CLAD) and airways complications (AC) defined by reoperation or rigid bronchoscopy requirement. During the study period 221 lung transplants were performed. 437 bronchial anastomoses were analyzed at day 7, 378 at day 28 and 336 at day 90. At day 7, patients with extremely severe and extensive necrosis of the bronchial mucosa (M3d) presented worse OS (p<0.01); While extensive ischemic or necrosis bronchial mucosa (M3c) was associated with AC (p<0.01). At day 28, patients with bronchial mucosa necrosis distal to the anastomosis (M3b, 3c and 3d) presented a worse OS (all p≤0.01) and AC (all p<0,01). At day 90, patients who still presented M3c presented worsened OS (p<0.01) and increased risk of AC (p<0.01). Separate analysis of patients with M3b, c and d (at day 28 and 90) showed similar relationship with OS, CLAD and AC (all p<0.01); as far as patients with M0 and M1 had the same prognosis in terms of OS (all p=NS), CLAD and AC (all p=NS), it was the same for M2 and M3a (all p=NS). Therefore, we have reorganized the MDS classification in 3 stages: G1 for M0/M1 a, b, c, d; G2 for M2 a, d, c, d/M3 a; G3 for M3b, c, d. We have compared the 3 groups of patients with G1 as reference. Stage G3 at day 7 was associated with AC (p<0.05) while at days 28 and 90 it was associated with OS, AC and CLAD (all p<0.05) The endoscopic MDS grading system can be simplified into 3 groups providing prognostic risk stratification of OS, AC and CLAD development after lung transplantation. [ABSTRACT FROM AUTHOR]

Many scientific societies recommend SARS‐CoV‐2 vaccination for solid-organ transplant recipients. The immunogenicity of two or three vaccine doses in lung transplant (LTx) recipients is unclear. The aim of this study was to evaluate the humoral response to the vaccine in LTx and heart-lung transplant (HLTx) recipients. We conducted a prospective study of LTx and HLTx recipients at seven centers in France. Anti-spike-protein antibody titers after two or three SARS‐CoV‐2 vaccine injections were measured. We studied 2186 patients (1091 [51%] males) with a median age of 49 [45-55] years. Double LTx was performed in 1792 (82%) patients. The main reasons for LTx were chronic obstructive pulmonary disease (n=656, 30%), fibrosis (n=459, 21%), and cystic fibrosis (n=350, 16 %). Median time from LTx to vaccination was 59 [29-108] months and mean time from the last vaccine dose to serological testing was 3 months [1.5-3.8]. We used WHO definitions to classify antibody titers as negative (&lt. 30 BAU/mL), suboptimal (30-260 BAU/mL), or protective (&gt 260 BAU/mL). Of the first 1081 patients, 270 (25%) were partially vaccinated and 649 (60%) fully vaccinated (three doses or history of COVID-19 then two doses); Among these patients,133 (12%) were infected by covid. Of the 649 fully vaccinated patients, 461 (71%), 84 (13%), and 97 (15%) had negative, suboptimal, and protective antibody titers, respectively. The proportion of patients with protective titers was 8% vs. 18% in patients vaccinated within 5 years vs. 5 or more years after LTx, respectively. Among covid-infected patients, 48% developed a protective rate, whether fully or partially vaccinated. LTx recipients usually fail to develop protective antibody titers in response to SARS-CoV-2 vaccination. Once further data are collected, we will seek to identify risk factors for a poor antibody response. [ABSTRACT FROM AUTHOR]

In the context of sarcoidosis, lung transplantation is often performed in patients with irreversible advanced lung disease unresponsive to medical therapy. The clinical phenotypes and posttransplant survival remain unclear, due primarily to the recurring nature of the disease and extrapulmonary involvement. The objective of this study in a large multicenter European cohort was to describe the clinical characteristics and outcomes of patients with pulmonary sarcoidosis treated by lung transplantation. We retrospectively reviewed the data of 147 patients with pulmonary sarcoidosis who underwent lung or heart-lung transplantation between 1990 and 2019 at 15 European centers. Inclusion criteria were sarcoidosis meeting international diagnostic criteria and availability of data from pretransplantation right heart catheterization, lung function testing, and chest computed tomography (CT) staged using a standardized system. At transplantation, mean age was 50±8 years, 62% were male, and 20% had extrapulmonary manifestations. Mean values before transplantation were as follows: FVC (%pred), 46±17%; FEV1 (%pred), 38±19; FVC/FEV1 (%), 55±32; DLCO (%pred), 31±13; mPAP (mmHg), 36±13; PCWP (mmHg), 10±5; cardiac index (L/min/m²), 3.0±0.8; and pulmonary vascular resistance (dyn·s·cm−5), 480±340; furthermore, 60% of patients had severe pulmonary hypertension. Posttransplant survival rates after 1, 3, and 5 years were 85%, 69%, and 63%, respectively. During the median [range] follow-up of 43 [17-79] months, 38% of patients developed chronic lung allograft dysfunction. Factors significantly associated with outcomes were high emergency transplantation, era of transplantation, preoperative extrapulmonary sarcoidosis, and extent of fibrosis by CT. Posttransplant survival rates and freedom from chronic lung allograft dysfunction in patients with pulmonary sarcoidosis were similar to those in patients with other reasons for lung transplantation. Factors associated with worse outcomes were high emergency transplantation, earlier transplantation era, preoperative extrapulmonary sarcoidosis, and greater burden of fibrosis by CT. [ABSTRACT FROM AUTHOR]