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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]

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]

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]

Pulmonary arterial hypertension (PAH) is rare but remains fatal in infants and children despite the advance of targeted therapies. Lung transplantation (LTx), first performed in pediatric patients in the 1980s, is, with the Potts shunt, the only potentially life-extending option in patients with end-stage PAH but is possible only in tightly selected patients. Size-matching challenges severely restrict the donor organ pool, resulting-together with peculiarities of PAH in infants-in high waitlist mortality. We aimed to investigate survival when using a high-priority allocation program (HPAP) in children with PAH listed for double-LTx or heart-LTx. We conducted a single-center, retrospective, before-after study of consecutive children with severe Group 1 PAH listed for double-LTx or heart-LTx between 1988 and 2019. The HPAP was implemented in France in 2006 and 2007 for heart-LTx and double-LTx, respectively. Fifty-five children with PAH were listed for transplantation. Mean age at transplantation was 15.8±2.8 years and 72% had heart-lung transplantation. PAH was usually idiopathic (65%) or due to congenital heart disease (25%). HPAP implementation resulted in the following significant benefits: decreased cumulative incidence of waitlist death within 1 and 2 years (P <0.0001); increased cumulative incidence of transplantation within 6 months, from 44% to 67% (P <0.01); and improved survival after listing (at 1, 3, and 5 years: 61%, 50%, and 44% vs. 92%, 84%, and 72% before and after HPAP implementation, respectively; P =0.02). HPAP implementation was associated with significant improvements in access to transplantation and in survival after listing in children with end-stage PAH. [ABSTRACT FROM AUTHOR]

Purpose Restrictive allograft syndrome (RAS) has been identified as a chronic lung allograft dysfunction (CLAD) with the worst prognosis after lung transplantation (LTx). Diagnostic criteria of RAS have been proposed in double-LTx (DLTx), but how to apply these criteria in single (S)-LTx remain debatable. Hence, there is a need to validate and refine these criteria in SLTx. Our aim was to investigate functional, allosensitization, and CT-scan abnormalities patterns in SLTx recipients with RAS, as compared to single LTx with BOS or in stable condition. Methods We retrospectively reviewed data from all SLTx recipients during the 2009-2015 period at Bichat hospital. Among them, RAS phenotype in SLTx was identified using criteria defined in BLTx, including both PFTs (FVC ≤ 80% of baseline or FEV1 ≤ 80% of baseline with FEV1/FVC > 0.7) and CT-scan with persistent opacities suggestive of RAS. These SLTx with RAS were compared with SLTx with BOS and stable patients. We compared outcome of PFTs (FVC, FEV1, FEV1/FVC), repeated CT-scan (both CT-volumetry and CT parenchymal score), and DSA between the 3 groups at the following 4 time points with available CT-scan: (1) at the date of best post-Tx functional status, (2) at the date of CLAD onset, defined at first irreversible decline of PFTs or graft CT-volume, or first onset of pleuroparenchymal abnormalities reflected by RAS parenchymal score; (3) at last available CT-scan; (4) at an average time between 2 and 3. Results 17 SLTx were identified with RAS diagnosis, and compared to 17 SLTx with BOS and 17 stable SLTx. In RAS patients, outcome of FVC, FEV1, CT-volume, and CT-score showed all a significant decrease from time-point of CT baseline to last CT-scan (p< 0.001, p<0.001, p<0.001, p<0.001, respectively for the 4 parameters). Interestingly, CT-scan score showed the earlier significant increased value to identify RAS diagnosis at the date of CT-onset (p<0.05 for CT-score ≥ 3), as compared no significant decline for FVC, FEV1, CT volumetry (p=ns). Criteria of RAS based only on spirometry lacked of specificity, since 35 % of BOS SLTx patients also had FVC < 80% of baseline during follow-up. Conclusion RAS diagnosis remains challenging in SLTx. We observed that the increase of a CT score ≥3 may lead to earlier identification of RAS patients in this population, as compared to standard criteria of RAS initially defined in DLTx. [ABSTRACT FROM AUTHOR]