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International audience; Almost 25% of patients with pulmonary fibrosis referred for lung transplantation have a germline rare variant of a telomere-related gene. Acquired TERT promoter mutations may counterbalanced the germline defect and reduce the risk of hematological complications in this population. In a series of 34 patients with a germline telomere-related gene mutation who underwent lung transplantation, 12 (35%) patients had at least 1 acquired TERT promoter mutation. Six patients presented myelodysplasia before lung transplantation, with no difference between patients with and without an acquired TERT promoter mutation. After lung transplantation, myelodysplasia developed in only 1 of 8 patients with an acquired TERT promoter mutation versus 7 of 18 patients without a mutation. Survival did not differ between patients with and without an acquired mutation. The presence of an acquired TERT promoter mutation could be associated with reduced hematological complications after transplantation and with better outcome in telomere-related gene mutation carriers but requires further study. (C) 2022 International Society for Heart and Lung Transplantation.

International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

BACKGROUND Restrictive allograft syndrome (RAS) after lung transplantation (LTx) is associated with the poorer graft survival in patients with chronic lung allograft dysfunction (CLAD). Nevertheless, its diagnostic criteria have not been clearly defined after single-LTx (SLTx). Hence, we studied an SLTx cohort with CLAD to investigate the utility of both computed tomography (CT)-score/volume measures and functional spirometric criteria for the early identification of RAS in this population. METHODS We included 51 patients with SLTx (17 RAS, 17 bronchiolitis obliterans syndrome [BOS], and 17 stable condition). The criteria for RAS diagnosis in SLTx included forced vital capacity (FVC) 0.7 and persistent CT-scan-lung opacities. We defined 4 time points (T): T-baseline, T-onset (first CT-scan-opacities), T-follow-up, and T-last. RESULTS In patients with RAS, the spirometric criteria for RAS at T-onset were reached in only 47% (FVC decline 0.7 [41%]), whereas at the same T-onset date, the graft CT-score increased to 5 (4-6) vs 1 (0-2) at baseline (p < 0.001) (CT - score ≥2 at T-onset in 100% and ΔCT - score ≥2 in 74% of patients with RAS), and the median CT-scan graft volume decreased to 1,722 ml (vs 1,796 ml at T-baseline, p = 0.003) (decreased CT-graft - volume

Hemoptysis isn't rare in lung transplant recipients (LTR). Yet, trans-arterial embolization (TAE) in LTR has been rarely reported in the literature. The aim of the study was to present the feasibility and outcomes of TAE for hemoptysis in LTR.Retrospective study of all LTR who underwent TAE for hemoptysis in our single institution between 2005 and 2020.A total of 787 patients underwent lung transplantation between 2005 and 2020. Fifteen LTR underwent 21 TAE for hemoptysis in a median delay of 42 days after LT. TAE was performed within a year after LT in 13 patients (86.7%) with 12 of those patients having concomitant severe ischemic airway injury with necrosis and anastomotic dehiscence. Bronchoscopy confirmed bronchial anastomoses has being the source of the bleeding in 11 LTR (84.6%). Restoration of bronchial vascularization was highlighted in 13 patients (87%). Despite TAE, bronchial anastomosis healing was observed in all surviving patients with anastomotic dehiscence in a median delay of 43 days.In our experience, hemoptysis requiring TAE in LTR was rare, frequently occurring in the first weeks after LT, and seemed associated with anastomotic ischemia and dehiscence. Bleeding mainly originated from ischemic bronchial anastomosis through the restoration of the bronchial artery circulation. Our results suggest that bronchial arteriography should be routinely proposed in such patients in the event of hemoptysis.

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.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.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%] vsfirst IQR, log-rank test, p = 0.028). Furthermore, the incidence of CLAD was higher with2.6- 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.Our data suggest that an early increase of CD4+CD57+ILT2+ T cells after LTx may be associated with CLAD onset.

International audience; BackgroundLow income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF.MethodsPatients were selected from the French national prospective cohort COFI. Patients’ income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as “low income” vs. “higher income” depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis.Results200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI95%: 1.24–2.62, p = 0.001) and overall survival (HR: 1.49; CI95%: 1.0006–2.23, p = 0.049).ConclusionsLow income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures.

IntroductionInterstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.MethodsThe consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.ResultsFor the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.DiscussionThis study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

BackgroundPre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised.MethodsFor all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan–Meier analysis and Cox multivariate analysis.ResultsWe compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (pversus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02–9.17 versus no pre-formed DSAs; p=0.048).ConclusionThe desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

Study questionIn patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation.Patients and methodsWe retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart–lung transplantation between 2006 and 2019 at 16 European centres.ResultsPatient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46–59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16–89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications.Answer to the study questionPost-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.

Interstitial lung diseases (ILDs) can be caused by mutations in theThe consequences of the 11For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic

International audience; We have studied experimentally particle suspension when injecting a gas at the bottom of an immersed granular layer confined in a Hele-Shaw cell. This work focuses on the dynamics of particles slightly denser than the surrounding fluid. The gas, injected at constant flow-rate, rises through the granular bed then forms bubbles which entrain particles in the above liquid layer. The particles settle down on the edges of the cell, avalanche on the crater formed at the granular bed free surface, and are further entrained by the continuous bubbling at the center. We report the existence of a stationary state, resulting from the competition between particle entrainment and sedimentation. The average solid fraction in the suspension is derived from a simple measurement of the granular bed apparent area. A phenomenological model based on the balance between particle lift by bubbles at the center of the cell and their settling on its sides demonstrates that most of the particles entrained by bubbles come from a global recirculation of the suspension.

Purpose 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 ( Methods 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. Results The trial was started in December 2019 among 8 french LTx centers (Hopital 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. Conclusion 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.

Purpose Pre-formed donor-specific antibodies (pf-DSA) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch (CXM)-based strategy for perioperative desensitization protocol has been used for immunized LTx candidates since 2012 at Foch hospital. We compared the outcome of desensitized LTx candidates with high pf-DSA mean fluorescence intensity (MFI) and those with low or no pf-DSA, not desensitized. Methods For all consecutive LTx recipients (January 2012-March 2018), freedom from CLAD and graft survival were assessed by Kaplan-Meier analysis and Cox proportional-hazards multivariate analysis. Results We compared outcomes for desensitized patients with high pf-DSA (n=39) and those with no (n=216) or low pf-DSAs (n=66). The desensitization protocol decreased the level of immunodominant pf-DSA (class I/II) at 1, 3, and 6 month post-LTx (p Conclusion The desensitization protocol in LTx recipients with high pf-DSAs was associated with satisfactory outcome, with cleared high pf-DSAs after desensitization identified as an independent predictor of graft survival.

Introduction La survie apres transplantation pulmonaire (TxP) reste limitee par la survenue d’une dysfunction chronique pulmonaire (CLAD), qui touche > 50 % des greffes. La forme obstructive de CLAD, bronchiolite obliterante (BO)/syndrome de BO (SBO), est le phenotype le plus frequent de CLAD (80% des cas). Les lesions de BO semblent dues a des agressions repetees de l’epithelium bronchique avec developpement d’une cicatrice fibreuse. Il n’existe actuellement pas de traitement demontre pour stabiliser le SBO. Le role crucial de la dysfonction de reparation fibrotique est demontre dans la BO via le remodellage bronchique, l’augmentation de matrice extra-cellulaire, la transition epithelio-mesenchymateuse, l’augmentation des facteurs de croissance PDGF, VEGF, FGF, IGF- Le TKI Nintedanib, demontre efficace dans la fibrose pulmonaire idiopathique, et qui cible ces facteurs de croissance, est une molecule candidate. Un essai therapeutique testant le nintedanib dans la BOS post-TxP a debute en France fin 2019. Methodes Essai multicentrique, randomise double aveugle contre placebo, evaluant l’efficacite du Nintedanib dans le traitement du syndrome de bronchiolite obliterante grade 0-p et grade 1-2 chez les patients greffes pulmonaires. Criteres d’inclusion: BOS 0-p, 1, 2 et forme mixte de CLAD (criteres ISHLT). Objectif principal: evaluer l’efficacite du nintedanib sur la reduction du taux de declin du VEMS dans le SBO post-TxP (150 mg × 2/j versus placebo pendant 6 mois (± 100 mg × 2/j si effets secondaires). Objectifs secondaires: evaluer l’efficacite du nintedanib sur l’evolution de: 6WT, QOL (SGRQ); mesures repetees VEMS; grade BOS; Saturation O2; ainsi que frequence des effets secondaires, et evolution de parametres sanguins KL-6, SPD, VEGF, PDGF. Resultats L’essai a ete ouvert entre dec 2019 et mars 2020 parmi 8 centres de greffe en France (Hopital Foch, Bichat, HEGP/Cochin, Marie-Lannelongue, Marseille, Bordeaux, Strasbourg et Grenoble), pour une duree d’inclusion prevue de 36 mois. Au 31/08/2020, 7 patients greffes ont ete inclus dans 3 centres. Afin d’augmenter le nombre de patients eligibles, une modification du protocole du 2/07/2020, permet d’inclure desormais les patients avec BOS grade 0-p et les regreffes. Conclusion InfinitixBOS est le 1er essai therapeutique randomise controle evaluant l’efficacite du Nintedanib dans les formes obstructives/mixtes de CLAD. En cas de demonstration d’une efficacite sur la fonction pulmonaire, le benefice au patient est eleve au vu de la frequence du SBO.

Introduction Les formes rapidement progressives de PID (RP-PID) sont frequentes au cours des dermatomyosites (DM), en particulier associees a un anticorps (AC) anti-MDA5 (PID-MDA5). Les facteurs predictifs de survenue d’une RP-PID sont mal connus. L’objectif principal etait de determiner les elements facteurs predictifs de survenue des formes RP au cours de PID-MDA5. Methodes Il s’agit d’une etude retrospective multicentrique nationale de patients adultes ayant une PID-MDA5. La RP-PID, a ete definie par une deterioration respiratoire ou Resultats 92 patients ont ete inclus (29 (31 %) hommes, âge median 50,1 ans (38,7–58,6), 57,6 % afro-caribeens, 79,3 % non fumeurs) ( Fig. 1 ). CVF mediane: 68 % (52,2–86,8), DLCO mediane: 47 % (40,5–60,5). Des lesions ulcerations etaient notees chez 42.4 % des patients et 69.6 % etaient amyopathiques. L’extension de la PID etait > 20 % chez 34,8 % des patients. Le pattern initial etait le suivant: PINS (33,7 %), PINS-PO (29,3 %), PID indeterminee (19,6 %) et PIA (7,6 %). Le delai de suivi median etait de 36 mois (7.7-63). Douze patients ont presente un pneumomediastin au cours du suivi. Quarante et un patients (44,5 %) avaient une PID-RP. Les donnees demographiques, le tabac, les signes cutanes et musculaires etaient comparables mais les PID-RP avaient une fievre plus frequente (65.9 vs 29.4 % p = 0,001), et plus de condensations (75.6 vs 49 % p = 0,008). Vingt-neuf patients sont decedes dont 25 dans le groupe PID-RP et 3 ont ete greffes, tous dans le groupe PID-RP. L’extension de la PID, la fievre et la ferritinemie au diagnostic etaient associees a la survenue d’une PID-RP en analyse de regression logistique. La survenue d’une PID-RP etait associee a un pronostic defavorable avec 28 % de survie estimee a 5 ans (p Fig. 1 ). Les patients ayant une forme « limitee » avaient une meilleure survie que ceux ayant une forme « etendue » (p = 0,012). Enfin, en analyse multivariee, l’âge, l’extension de la PID, la ferritinemie etaient des facteurs pronostiques associes a la mortalite. Conclusion Dans cette serie francaise de PID-MDA5, la fievre, la ferritinemie et l’extension de la PID au diagnostic sont associes a la survenue d’une PID-RP.

Introduction La gestion de la neutropenie, principal effet indesirable du Valganciclovir (vGCV), peut impacter les resultats de la greffe. L’objectif principal de cette etude est d’evaluer la tolerance du vGCV chez les patients D+/R-. Les objectifs secondaires sont d’evaluer l’impact de la neutropenie et des modifications de posologie de Mycophenolate Mofetil (MMF) sur les resultats de la greffe. Methodes Nous avons conduit une etude retrospective monocentrique du 01/01/2010 au 31/12/2018 chez 531 transplantes pulmonaire. Resultats 59 des 108 D+/R- (55%) ont presente au moins un episode de neutropenie lors de la premiere annee conduisant pour 31 d’entre eux (29%) a son arret premature ( Tableau 1 ). Les prevalences de neutropenie et de reduction du dosage de MMF sont significativement plus importantes chez les patients D+/R− pour lesquels le vGCV est arrete precocement en comparaison a ceux ayant eu un traitement complet (87% vs 42%, p Conclusion Les effets indesirables associes a un an de prophylaxie primaire par Valganciclovir ont un impact negatif sur les resultats de la greffe et incitent a proposer une alternative.

Introduction La maladie a nouveau coronavirus 2019 (COVID-19) a actuellement un taux de progression rapide mondial. Le nombre de cas severes rapportes chez les greffes d’organes solides reste limite, mais leur statut d’immunodeprime fait supposer un risque eleve de complications liees au SARS-Cov-2. L’insuffisance respiratoire aigue liee au syndrome de detresse respiratoire aigue (SDRA), qui se developpe chez environ 5 % des patients, reste la cause principale de deces. Il est maintenant etabli qu’un sous-groupe de patients porteurs d’infection severe COVID-19 developpe un syndrome de tempete cytokinique associe au risque de deces, chez qui des traitements immunomodulateurs pourraient etre benefiques. Les options therapeutiques, entre autres, incluent les corticoides a doses elevees, mais il etait anticipe une balance risque–benefice defavorable a leur utilisation au tout debut de l’epidemie. Une autre question dans la population des transplantes pulmonaires (TxP) est l’eventuel role prophylactique de l’azithromycine au long cours sur l’acquisition du SARS-Cov-2, frequemment administre dans cette population specifique en cas de la dysfonction chronique du greffon. Resultats Nous rapportons 2 cas severes de SDRA-COVID-19 hyper-inflammatoires ayant menace leur pronostic vital, survenus au sein de notre cohorte monocentrique de greffes pulmonaires malgre un traitement d’azithromycine faible-dose au long cours. Un traitement par methylprednisone a doses elevees (2 mg/kg/j), debute precocement apres le debut du SDRA sous ventilation mecanique, a permis une recuperation pulmonaire rapide et ad integrum chez les 2 patients. Conclusion Ces 2 cas de SDRA-COVID-19 suggerent : – que des formes graves peuvent survenir malgre un traitement au long-court d’azithromycine faible-dose apres TxP ; – le benefice de l’utilisation precoce des corticoides a dose elevee en cas de survenue de SDRA-COVID-19 hyper-inflammatoire apres TxP, comme observe recemment dans un essai therapeutique testant l’efficacite de la dexamethasone au sein d’une population generale de patients.

International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Lung transplantation. Lung transplantation is one therapeutic option for selected patients with end stage respiratory insufficiency secondary mainly to emphysema, pulmonary fibrosis and cystic fibro sis. Because of increased number of graft proposals, priority access to transplantation for the more severe patients (High Emergency program) and the ex vivo reperfusion, the annual number of lung transplantations rose in France up to 371 in 2016. Global survival greatly improved at first because of perioperative and early mortality reduction. Then the main challenges for the long term survival are the prevention and treatment of graft rejection including its cellular/humoral and acute/chronic component and the improvement of the preventive immunosuppressive treatment taking into account its increased risk of infectious, proliferative and metabolic complications. At least, with appropriate evaluation of risk/ benefit balance, lung transplantation is associated not only with an increased survival but also with a clear improvement of the quality of life.Transplantation pulmonaire. La transplantation pulmonaire est une option de traitement de certaines insuffisances respiratoires chroniques principalement secondaires à l’emphysème, la fibrose pulmonaire et la mucoviscidose. L’augmentation du nombre de propositions de greffon, la priorisation d’allocation par « super-urgence » puis la procédure ex vivo ont permis d’augmenter le nombre de greffes, pour atteindre 371 transplantations en France en 2016. La survie des patients s’est considérablement améliorée grâce surtout aux progrès réalisés dans la prise en charge de la période périopératoire et des premiers mois transformant de fait la survie à long terme. À moyen et long terme, l’enjeu est la prévention et le traitement du rejet dans ses composantes cellulaire et humorale, aigu et chronique par un traitement immunosuppresseur adapté en prenant en compte préventivement les risques de complications infectieuses, prolifératives et métaboliques. Au final, lorsque le rapport bénéfice-risque a été bien évalué, la transplantation pulmonaire permet non seulement une amélioration nette de la survie quelle que soit l’indication mais aussi une amélioration de la qualité de vie.

Purpose Management of neutropenia, the main side effect of Valganciclovir, may affect final transplant results. The main objective of this study is to evaluate the safety of Valganciclovir in D+/R- patients. The secondary objectives are to assess the impact of neutropenia and Mycophenolate Mofetil (MMF) daily dosage modification on the outcomes of the transplant. Methods We performed a single-center retrospective study from 01/01/2010 to 12/31/2018 including 531 consecutive lung transplant patients. Results 59 of the 108 D+/R- patients (55%) experienced at least one episode of neutropenia during the first posttransplant year leading to its premature withdrawal for 31 patients (29%). Among D+/R- patients, subgroup of premature vGCV withdrawal experienced significantly more neutropenia and reduction of MMF in comparison with complete vGCV treatment subgroup (87% vs 42%, p Conclusion Considering adverse effects associated with Valganciclovir one-year treatment may have a negative impact on the outcomes of the transplant, an alternative should be proposed.

Introduction La transplantation (TxP) est le seul traitement curatif de la fibrose pulmonaire idiopathique (FPI). Des traitements antifibrosants (pirfenidone et nintedanib), qui ralentissent l’evolution de la maladie, ont ete developpes recemment. Ils pourraient augmenter le risque de complications post-operatoires lors de la TxP des patients traites. L’objectif de cette etude etait d’evaluer l’association entre la prise d’un traitement antifibrosant et les complications apres une TxP. Methodes Il s’agit d’une etude retrospective multicentrique francaise, ayant inclus des patients atteints de FPI et ayant beneficie d’une TxP entre 2011 et 2018. Nous avons compare l’incidence des complications post operatoires (complications bronchiques et hemorragiques) et la survie des patients ayant recu ou non des antifibrosants au minimum un mois avant la TxP. Resultats Parmi les 205 patients inclus, 57 (27,8%) ont recu un traitement antifibrosant: pirfenidone pour 36 patients (63%) et nintedanib pour 21 patients (37%). La duree mediane de traitement antifibrosant avant la TxP etait de 532 jours. Il n’y avait pas de difference entre les deux groupes dans la survenue de complications anastomotiques bronchiques (p = 0,90), hemorragiques (p = 0,14) ou de cicatrisation cutanee (p = 0,65). La mortalite a 90 jours post-TxP dans le groupe traite etait significativement inferieure (7%) a celle du groupe controle (18,2%, p = 0,04). La mortalite a 30 jours post-TxP des deux groupes ne differait pas (p = 0,18). Le groupe traite presentait egalement moins de dysfonction primaire du greffon (DPG) (29,8%) que le groupe controle (43,2%, p = 0,01). Conclusion Les antifibrosants ne sont pas associes a une augmentation du risque de complications post-TxP et peuvent donc etre utilises sans risque avant la transplantation. Leur utilisation semble etre associee a une diminution de la DPG et de la mortalite a 90 jours. Cette difference de mortalite, deja rapportee par une equipe australienne [1] , devra cependant etre confirmee par d’autres etudes.

In the context of lung transplant (LT), because of diagnostic difficulties, antibody-mediated rejection (AMR) remains a matter of debate. We retrospectively analyzed an LT cohort at Foch Hospital to demonstrate the impact of AMR on LT prognosis. AMR diagnosis requires association of clinical symptoms, donor-specific antibodies (DSAs), and C4d(+) staining and/or histological patterns consistent with AMR. Prospective categorization split patients into four groups: (i) DSA positive, AMR positive (DSA(pos) AMR(pos) ); (ii) DSA positive, AMR negative (DSA(pos) AMR(neg) ); (iii) DSA limited, AMR negative (DSA(Lim) ; equal to one specificity, with mean fluorescence intensity of 500-1000 once); and (iv) DSA negative, AMR negative (DSA(neg) ). AMR treatment consisted of a combination of plasmapheresis, intravenous immunoglobulin and rituximab. Among 206 transplanted patients, 10.7% were DSA(pos) AMR(pos) (n = 22), 40.3% were DSA(pos) AMR(neg) (n = 84), 6% were DSA(Lim) (n = 13) and 43% were DSA(neg) (n = 88). Analysis of acute cellular rejection at month 12 showed higher cumulative numbers (mean plus or minus standard deviation) in the DSA(pos) AMR(pos) group (2.1 ± 1.7) compared with DSA(pos) AMR(neg) (1 ± 1.2), DSA(Lim) (0.75 ± 1), and DSA(neg) (0.7 ± 1.23) groups. Multivariate analysis demonstrated AMR as a risk factor for chronic lung allograft dysfunction (hazard ratio [HR] 8.7) and graft loss (HR 7.56) for DSA(pos) AMR(pos) patients. Our results show a negative impact of AMR on LT clinical course and advocate for an early active diagnostic approach and evaluation of therapeutic strategies to improve prognosis.

Background: Idiopathic interstitial pneumonia (IIP) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality. They have been associated with an increased frequency of lung cancer. A genetic cause is identified in up to 20% of familial cases, telomerase and surfactant genes (SFTPA2, SFTPB, SFTPC, ABCA3) mutations being the first etiologies. Objectives:This study investigates the implication of SFTPA1 (NM_005411) in 12 families affected by IPF and lung cancer. Methods:SFTPA1 was sequenced by Sanger method in 12 unrelated index cases. An informed signed consent was obtained for each patient. New SFTPA1 variations were studied with functional experimentations. Results: A heterozygous missense disease-causing mutation (p.Trp211Arg, W211R), in SFTPA1, that encodes the Surfactant Protein (SP)-A1, was identified in a large family. The affected members, aged 7 months to 59 years, presented with various forms of IIP, and adenocarcinoma. The W211R mutation segregated in a dominant pathway with the disease. The mutation involved an amino-acid that is located in the carbohydrate recognition domain (CRD) of SP-A1 and involved a residue invariant throughout evolution in SP-A1, but also in SP-A2 and in other CRD-containing proteins. The W211R mutation impaired SP-A1 secretion, and an abnormal expression pattern of SP-A was found in the alveolar epithelium of lung tissue from a patient carrying the SFTPA1 mutation. Conclusion: This first report of the involvement of SFTPA1 in a Mendelian disorder unveils the key role of SP-A1 in the pathophysiology of IIP from infancy to elderly, and open up a new field of research on the mechanisms involved in IIP and lung cancer.

Antibody-mediated rejection (AMR) after lung transplantation (LTx) is associated with poor prognosis [1]. Recent ISHLT recommendation propose a standardised classification of lung AMR [2]. Based on the number of features present, these classification describe three different degree of certainty for the AMR diagnosis. However in the absence of a true gold standard, the management of potential AMR rely on a quite high degree of uncertainty. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr PARQUIN has nothing to disclose. Conflict of interest: Dr Cuquemelle has nothing to disclose. Conflict of interest: Dr Camps has nothing to disclose. Conflict of interest: Dr Devaquet has nothing to disclose. Conflict of interest: Dr Sage has nothing to disclose. Conflict of interest: Dr Longchampt has nothing to disclose. Conflict of interest: Dr MALARD has nothing to disclose. Conflict of interest: Dr Picard has nothing to disclose. Conflict of interest: Dr taupin has nothing to disclose. Conflict of interest: Dr Roux has nothing to disclose. Conflict of interest: Dr Leguen has nothing to disclose. Conflict of interest: Dr Phillips-Houlbracq has nothing to disclose. Conflict of interest: Dr Brugiere has nothing to disclose.

Background: Heterozygous mutations in the SFTPA1 and SFTPA2 genes, encoding the surfactant protein SP-A1 and SP-A2 have been associated with rare forms of familial IIP and lung adenocarcinoma. We previously described 11 new heterozygous SFTPA1 and SFTPA2 variations in 13 unrelated patients including one newborn. The study aims to analyze the pathogenicity of those variations. Methods: We first analyzed the intrafamilial segregation of the identified variations with IIP and lung cancer. The production and the secretion of the mutant proteins were subsequently studied in HEK293T cells transiently expressing the SP-A proteins carrying the variations. Finally, SP-A expression was assessed on lung tissues of the patients. Results: In the studied families (38 adults, 3 children), the variations segregated with either IIP and/or lung cancer (37%) with an incomplete penetrance of the disease phenotype. The mean age at onset of the IIP was 45 years (0-68). Nine of the variations were located in the highly conserved carbohydrate recognition domain of the protein. In vitro, the mutant proteins were produced but their secretion was absent (n=9) or altered (n=2). The lung expression of SP-A studied in 3 unrelated patients showed an increased expression of SP-A in the cytoplasm of hypertrophic type 2 alveolar cells. Discussion and conclusion: The 11 identified SFTPA1 and SFTPA2 variations are pathogenic. They are associated with IIP and with an increased risk of lung cancer. They were identified mainly in adults but also in children. The pathophysiological consequences of their abnormal secretion/expression remain to be elucidated.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations ( C 0 ) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were C 0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively ( P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C 0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively ( P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C 0 /dose ratio ( C 0 / D ) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution ( P = 0.034*). The ERL C 0 / D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

RésuméIntroductionLa transplantation pulmonaire (TP) accroît le risque d’infection, de cancer, d’insuffisance rénale, de complication cardiovasculaire, d’ostéoporose, souvent en continuité avec la situation clinique pré-existante.Patients et méthodeLes comorbidités et leur prise en charge à la première consultation pré-TP ont été recensées chez 157 patients ayant subi une TP entre 2008 et 2011.RésultatsL’âge médian était de 37ans [25 ; 51]. L’index de masse corporel médian était inférieur à 19kg/m2 chez 56 % des patients. Parmi les bronchopneumopathies chroniques obstructives (BPCO), seulement 50 % avaient réalisé une réhabilitation respiratoire au cours des deux années précédentes. Une ostéoporose était présente chez 42 % des patients dont 36 % étaient traités par biphosphonates. Une carence en vitamine D était présente chez 65 % des patients. Au plan cardiovasculaire, le bilan d’évaluation pré-TP révélait une HTA méconnue dans un cas, une hypercholestérolémie méconnue chez 6 % des patients et un diabète méconnu chez 4 % des patients. Des soins dentaires étaient nécessaires chez 41 % des patients. Des taux protecteurs d’anticorps anti-HB étaient acquis chez 50 % des patients.Discussion et conclusionLa prise en charge des troubles nutritionnels, de l’ostéoporose, des facteurs de risque infectieux et des facteurs de risque cardiovasculaires est perfectible. Il serait bénéfique d’intégrer précocement la notion de TP ultérieure à la gestion des insuffisants respiratoires chroniques.SummaryIntroductionLung transplantation (LT) is associated with an increased risk of infection, cancer, chronic renal failure, cardiovascular disease and osteoporosis. Some risk factors precede transplantation and could benefit for early diagnosis and optimised care.MethodsThe incidence of comorbidities and their treatment before referral were assessed in 157 consecutive lung transplant candidates between 2008 and 2011.ResultsThe median age was 37years [25; 51]. Fifty-six percent had a body mass index below 19kg/m2. In the COPD group, only 50 % had undergone a pulmonary rehabilitation program in the preceding 2 years. Osteoporosis was present in 42 %, of whom 36 % were on bisphophonate therapy. Vitamin D deficiency was present in 65 %. Previously undiagnosed cardiovascular risk factors were discovered during LT assessment: hypertension in one patient, hypercholesterolemia in 6 % and diabetes in 4 %. Poor dental condition necessitating extractions were found in 41 % of patients. Protective anti-HBs antibodies levels were present in 50 % of the patients at the time of referral.ConclusionThe assessment and early treatment of nutritional disorders, osteoporosis and risk factors for infection as well as addressing associated cardiovascular risk factors should be optimised in the care of patients with chronic respiratory insufficiency. The potential for becoming a lung transplant candidate in the future should be kept in mind early in the global management of those patients.

Background: The surfactant protein A (SP)-A is a collectin implicated in surfactant homeostasis, local alveolar immune response, and epithelial repair after lung injury. SP-A is encoded by the SFTPA1 and SFTPA2 genes. The aim of this study was to search for mutations in SFTPA1 and SFTPA2 in adult patients with ILD. Methods: All SFTPA1 and SFTPA2 exons and flanking intronic sequences were analyzed in a large prospective study population of 160 apparently unrelated ILD patients with no telomerase, SFTPC or ABCA3 mutations. Results: 86 patients were diagnosed with a familial form of ILD, of whom 20 presented an association with a familial lung cancer. 63 patients were Discussion and conclusion: Altered SP-A expression may contribute to ILD pathophysiology. Data reported herein indicate that patients with ILD and a personal or familial lung cancer, and/or

Resume L’augmentation en France du taux de prelevements pulmonaires et les evolutions techniques chirurgicales et d’anesthesie-reanimation, ont augmente le nombre de transplantations pulmonaires (TP) et ameliore le pronostic au moins a court terme. La liste des contre-indications classiques de la transplantation pulmonaire peut donc etre reconsideree a la lumiere de cette evolution. Cet article remet en perspective certaines des contre-indications medicales de la TP au regard notamment de l’experience acquise dans d’autres transplantations d’organe ou par certains centres de TP. Les problemes poses par des antecedents de cancer, l’infection VIH, les hepatites virales, les troubles nutritionnels, les complications aigues et l’âge sont notamment detailles. Les contre-indications chirurgicales ne sont pas abordees.

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007–2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40–60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.

Introduction: The incidence of venous thrombotic event (VTE ) after lung tansplantation was recently evaluated to approximately 44 % in a large series of patients (Neto et al., Transplantation. 2018; 102: 681). Cystic fibrosis (CF) is a devastating chronic inflammatory disease caused by a mutation in the gene encoding cystic fibrosis transmembrane regulator (CFTR), which is a chloride channel in epithelia cell membranes. Coagulation balance in patient with CF is complexed since there is both a decrease in vitamin K-dependent factor but also an excess of physiological inhibitors deficiencies. Lung fibrosis was also sometimes associated to a higher thrombotic risk. Aim: To analyse whether thrombin generation assay (TGA), which takes in account both pro-and anticoagulant factors, or the activity of soluble tissue factor (TFa) are able to discriminate the thrombotic risk of patients after bipulmonary lung transplantation (BLT) and are better discriminant than classical thrombophilia screening test [prothrombin time (PT), activated partial thromboplastin time (APTT), antithrombin (AT), protein C (PC) S (PS), Z (PZ) fibrinogen (FG) and FVIII levels (FVIIIc) measurements]. Methods: Thrombophilia screening (including TGT in the presence or absence of thrombomodulin (TM) and TFa quantification) was performed for 166 consecutive patients before BLT. Patients were divided in 3 categories : 100 with CF, 43 with chronic obstructive pulmonary disease (COPD) and 23 with idiopathic pulmonary fibrosis (IPF). Among them, 91 (51 with CF, 28 with COPD and 12 with IF) were transplanted. Proven VTE (positive duplex ultrasound) during the first trimester was registered. Results: Because of a defect in lipophilic vitamin absorption, prothrombin time below 70 % and a significant higher proportion of PZ deficiency was observed in patients with CF, in comparison to COPD. The frequency of AT, PC and PS were not significantly different between the 3 groups of patients. Because the chronic pulmonary contamination of the lung by bacteria, the frequency of elevated fibrinogen levels were significantly higher in patients with CF as compared to COPD and IPF groups (table 1). Median TFa values were significantly higher (p < 0.05) in patients with CF (median 0.24 pg/mL, range 0.1 - 7.7) than in patients with COPD (median 0.1 pg/ml, range 0.1 - 0.63). FTa was also elevated (median 0.24, range 0.1 - 6.15) in patients with IPF. Time to Peak (tt-Peak) was significantly shorter in patients with CF as compared to COPD or IPF, even in the presence of thrombomodulin (TM). MRI were higher in patients with CF than in patients with COPD or IPF, even in the presence of TM. Peak was higher in patients with CF as compared to patients with COPD (p < 0.05). In the presence of TM, Endogenous prothrombin potential (ETP) was significantly higher in patients with CF as compared to patients with COPD, and the ratio ETP/ETP with TM was higher in patients with CF as compared to patients with COPD or IPF, indicating a defective PC pathway in patients with CF (table 2). Among the 91 patients with BLT, a VTE was evidenced in 25 (27.5%) patients, with a similar frequency between the 3 groups (33.3 % in CF, 14.7 in COPD, 33.3 % in IPF, not significant). We analysed separately patients with CF from patients with COPD or IPF, since there were differences between coagulation parameters tested in patients with CF. Only APTT ratio was significantly lower (p < 0.01) in patients with CF who had a VTE (1.04) than in patients without VTE (1.12). No difference in the different parameters tested was evidenced in patients with COPD and IPF Conclusion: Even if TGA and TFa clearly evidence a more prothrombotic phenotype in patients with CF than in patients with COPD or IPF, thrombophilia screening before BLT fail to identify patients with a high post-operative thrombotic risk. Disclosures No relevant conflicts of interest to declare.

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection.

A diagnosis of PPFE is linked to pathogenic variants in three different telomere-related genes http://ow.ly/eGOq30aPkgx