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Objective Many prognostic factors of grade-3 primary graft dysfunction at post-operative day 3 (PGD3-T72) have been reported but intraoperative blood lactate level has not been studied. The present retrospective study was done to test the hypothesis that intraoperative blood lactate level (BLL) could be a predictor of PGD3-T72 after double-lung transplantation. Design Retrospective monocentric cohort study. Setting Foch University Hospital, Suresnes, France. Participants Patients having received a double-lung transplantation between 2012 and 2019. Patients transplanted twice during the study period, having undergone a multi-organ transplantation, or cardiopulmonary bypass, and those under preoperative extracorporeal membrane oxygenation were excluded. Interventions None. Measurements and Main Results Analysis was performed on a cohort of 449 patients. Seventy-two (16%) patients had a PGD3-T72. BLL increased throughout surgery to reach a median value of 2.2 [1.6-3.2] mmol/L in the No-PGD3-T72 group and 3.4 [2.3-5.0] mmol/L in the PGD3-T72 group after second lung implantation. The best predictive model for PGD3-T72 was obtained adding a lactate threshold of 2.6 mmol/L at the end of surgery to the clinical model, the AUC was 0.867 with a sensitivity =76.9%, specificity = 85.4%. Repeated-measures mixed-model of BLL during surgery remained significant after adjustment for covariates (F ratio= 4.22, p Conclusions Blood lactate level increases during surgery and reaches a maximum after the second lung implantation. A value below the threshold of 2.6 mmol/L at the end of surgery has a high negative predictive value for the occurrence of a grade-3 primary graft dysfunction at post-operative day 3.

The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient’s allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient’s CD4+T cells that recognize complexes of recipient’s MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4+T cells within the graft that recognize intact recipient’s MHC II molecules expressed by B cell receptor–activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4+T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient’s circulation; this, in turn, was associated with an early transient anti–MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.

International audience; Lung transplantation (LTx) is a steadily expanding field. The considerable developments have been driven over the years by indefatigable work conducted at LTx centers to improve donor and recipient selection, combined with multifaceted efforts to overcome challenges raised by the surgical procedure, perioperative care, and long-term medical complications. One consequence has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. The Francophone Pulmonology Society (Société de Pneumology de Langue Française, SPLF) set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force examined the most recent literature and evaluated the risk factors that limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while also improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

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

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.

AIMS Antibody-mediated rejection (AMR) is an emerging and challenging issue in transplantation. Endothelial deposition of C4d and microvascular inflammation (MI) are reliable markers of AMR in renal and cardiac transplantation, but remain controversial in the lung. Our aim was to assess C4d immunohistochemistry and histological patterns for the diagnosis of lung AMR. METHODS AND RESULTS We reviewed 158 transbronchial biopsies (TBBs) (n = 85 clinically indicated, and n = 73 surveillance TBBs) from 48 recipients, blinded to clinical and serological data. C4d was scored as 0, 1+ ( 50%). TBBs were reassessed for MI and acute lung injury (ALI). Donor-specific antibodies (DSAs), acute clinical graft dysfunction and chronic lung allograft graft dysfunction (CLAD) were recorded. C4d3+, C4d2+, C4d1+ and C4d0 occurred respectively in four (2.5%), six (3.8%), 28 (17.7%) and 120 (75.9%) TBBs. MI and ALI were rare but more frequent in C4d1-3+ TBBs than in the absence of C4d. C4d2+ was frequently observed with concomitant infection. Among the surveillance TBBs, only two (2.7%) showed MI. Neither ALI nor C4d3+ was diagnosed on surveillance TBBs. No significant association was found between histopathological findings and DSAs. All four patients with C4d3+ could retrospectively be diagnosed with AMR and developed CLAD. CONCLUSION Although rare, diffuse C4d deposition appears to be a strong indication of acute clinical AMR in lung transplant patients, whereas intermediate C4d2+ requires more investigations. In stable patients, histopathology and C4d may lack the sensitivity to diagnose subclinical AMR. This emphasises the need for a multidisciplinary evaluation of each suspected AMR case, and the need for complementary diagnostic tools.

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.

International audience; Background: Lung transplantation (LT) is an identified risk factor for Pneumocystis pneumonia (PCP). However, PCP management and outcomes remain poorly described in LT recipients and PCP incidence is rarely documented in this population.Methods: PCP episodes that occurred in 9 French LT centers between January 2010 and October 2017 were included in this analysis. PCP was defined as compatible clinical and radiologic findings associated with fungal identification.Results: Forty-seven PCP were included. The annual incidence rate of PCP was 2.7/1000 patients/year. Patients had a mean age of 53 +/- 14 years. Median time from LT was 2.4 +/- 3.0 years. Sixty-five percent of patients were not on prophylaxis at the time of PCP while all patients were receiving steroids at the time of PCP. Diagnosis was obtained by bronchoalveolar lavage in 91% (direct examination: 47%, PCR: 62%). The majority of patients were treated with trimethoprim-sulfamethoxazole (78%). Fifty-five percent of patients were hospitalized in ICU for organ failure (for which non-invasive ventilation was used for 21% and mechanical ventilation for 23%). Mortality rate was 15% at day 28 and reached 23% at day 90. Mortality was associated with decreased FEV1, everolimus treatment, Pseudomonas aeruginosa coinfection, fungal coinfection (especially Aspergillus sp.), mechanical ventilation and vasopressors. PCP primary prophylaxis, steroid modification during PCP and the number of immunosuppressive molecules were not associated with mortality.Conclusion: PCP is associated with a high mortality in LT. Our data suggest the need for a lifetime PCP prophylaxis in LT recipients. The benefit of adjuvant steroids remains unclear.

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.

New findings for the puzzle of bronchiolitis obliterans syndrome (BOS) are pointing to the role of CatB-procollagen-TGF-β signalling pathways, linked to fibrosis mechanisms and tissue damage controlhttps://bit.ly/3qQPax9

Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients.BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-β, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells.Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-β, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio).The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.

Aspergillus niger is usually considered to be a low virulence fungus, not commonly reported to cause invasive infections. Invasive pulmonary aspergillosis due to Aspergillus niger was diagnosed in a 43-year-old woman following bilateral lung transplantation. Intravenous voriconazole failed to control progression of the disease. Despite salvage therapy with a combination of voriconazole and caspofungin for 23 days, the patient developed massive hemoptysis leading to death. The authors report the clinical features and treatment of this case.

Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24

Introduction La survie apres transplantation pulmonaire (TxP) reste limitee par la survenue d’une dysfonction chronique du greffon (CLAD). Nous avons etudie le role potentiel du checkpoint inhibiteur HLA-G exprime par certaines populations lymphocytaires peripheriques, dans la prediction du developpement ulterieur du CLAD. Methodes Les donnees cliniques et les echantillons de sang de 150 patients TxP de la cohorte francaise COLT, suivis ≥ 3 ans et ayant ≥ 1 echantillon de sang disponible a 1, 6 ou 12 mois (M) post-TxP ont ete etudies. Les populations lymphocytaires (LT) peripheriques ont ete caracterisees en cytometrie en flux pour leur expression de 26 combinaisons de marqueurs, incluant ILT2, le recepteur d’HLA-G. Nous avons compare les 26 sous-populations de LT aux time points M1-M6-M12, et leur cinetique d’evolution la 1e annee (definie comme le ratio de M1 a M12) entre patients stables et patients CLAD. Resultats Les 150 patients analyses ont inclus 78 patients stables et 72 patients CLAD a 3 ans post-TxP. La survie sans CLAD a 3 ans etait inferieure chez les patients ayant un ratio M1-M12 de LT CD4 + CD57 + ILT2+ > 2,64 compare a celui des patients avec un ratio 0,069% (p = 0,04). Nous avons par ailleurs observe a M1 un taux de LT CD4 + CD25 + CD127low (% LT CD4 + ) plus important dans le groupe CLAD (1,8 + 2,3%), compare aux patients stables (0,9 + 1,2%, p = 0,02). En analyse multivariee, nous avons observe que: 1) Parmi les 26 sous-populations de LT, seule l’augmentation du ratio M1-M12 des LT CD4 + CD57 + ILT2+ etait un biomarqueur independant de survenue ulterieure de CLAD (HR = 1,25; 95% IC = 1,09–1,44; p = 0,001); 2). Parmi les sous-populations de LT etudiees a M1, seule l’augmentation du taux des LT CD4 + CD25 + CD127low etait un biomarqueur independant de la perte du greffon (HR = 1,1; 95% IC = 1,00–1,30; p = 0,01). Conclusion Cette etude suggere que la sous-population de LT CD4 + CD57 + ILT2+ est un facteur contribuant a un microenvironnement defavorable au maintien d’une fonction stable post-TxP et que son augmentation la 1re annee est un nouveau biomarqueur de CLAD a 3 ans post-TxP.

Introduction A l’ere de la prophylaxie anti-cytomegalovirus (CMV) systematique post transplantation (Tx), l’impact du statut serologique CMV du donneur et receveur sur la mortalite est debattu. L’objectif etait d’etudier la mortalite et la morbidite a 5 ans post-Tx chez des transplantes pulmonaires seronegatifs pour le CMV (R-) selon le statut serologique du donneur (D+ ou D-). Methodes Etude retrospective monocentrique realisee a l’Hopital Bichat (Paris). 42 patients R- recevant un greffon D+ (mismatch) entre 2007 et 2017 ont ete apparies sur l’âge, le sexe et la date de transplantation a 42 patients R- recevant un greffon D-. L’objectif principal etait de comparer la survie globale a 5 ans entre les deux groupes. Les objectifs secondaires etaient: rechercher des facteurs de risque de mortalite, decrire les infections/maladies a CMV et le taux de resistance, evaluer la tolerance des traitements prophylactiques systematiques anti-CMV dans le groupe D+/R-, comparer les rejets aigus, les dysfonctions chroniques du greffon, et la survenue de complications indirectes attribuables au CMV (analyse de survie par methode de Kaplan-Meier, comparaison par log-rank, modele de Cox pour estimer l’association entre statut D/R et survie). Resultats Les patients D+/R- et D-/R- avaient une survie a 5 ans post-Tx comparable, avec une tendance a une surmortalite de 15% dans le groupe D+/R- (49% vs 64% respectivement, p = 0,27). En analyse univariee, la dysfonction chronique du greffon et l’infection a CMV etaient des facteurs de risque de mortalite, non retrouves en analyse multivariee. Il y a eu plus d’infections (59%) et de maladies a CMV (21%) dans le groupe D+/R- que dans le groupe D-/R- (7% et 0 respectivement, p Conclusion Les patients D+/R- et D-/R- avaient une mortalite comparable, mais la morbidite notamment infectieuse etait plus importante dans le groupe D+/R-. Le statut D/R pour le CMV doit etre pris en compte dans le choix du donneur lors d’une Tx pulmonaire.

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.

Genetic testing is proposed for suspected cases of pulmonary fibrosis of genetics origin but clinicians and patients need advice about the related diagnostic and management issues. Because multidisciplinary team (MDT) has been shown to improve accuracy of ILD diagnosis, we evaluated the feasibility of an MDT dedicated to the indication and interpretation of genetic testing. The MDT met monthly, included pneumologists experts in ILD in adults, children, geneticists, radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend. Since 2016, 70 patients (37 males, 33 females) were discussed, from 31 different centers (7 countries). Mean age was 46.4 years [0-71] including 3 patients The MDT therapeutic proposals were: antifibrotic drugs (n=23), best supportive care (n=4), surgical lung biopsy (n=2), steroids (n=7), lung transplantation (n=16), or watch and wait (n=9). Our experience shows that a dedicated MDT with genetic analysis is feasible including patients of all ages and provides a unique opportunity to improve knowledge and to adapt patient management and therapy.

International audience; BACKGROUND: Chronic bronchiolitis obliterans syndrome (BOS) remains a major limitation for long-term survival after lung transplantation. The immune mechanisms involved and predictive biomarkers have yet to be identified. The purpose of this study was to determine whether peripheral blood T-lymphocyte profile could predict BOS in lung transplant recipients. METHODS: An in-depth profiling of CD4+and CD8+T cells was prospectively performed on blood cells from stable (STA) and BOS patients with a longitudinal follow-up. Samples were analyzed at 1 and 6 months after transplantation, at the time of BOS diagnosis, and at an intermediate time-point at 6 to 12 months before BOS diagnosis. RESULTS: Although no significant difference was found for T-cell compartments at BOS diagnosis or several months beforehand, we identified an increase in the CD4+CD25hiFoxP3+T-cell sub-population in BOS patients at 1 and 6 months after transplantation (3.39 ± 0.40% vs 1.67 ± 0.22% in STA, p \textless 0.001). A CD4+CD25hiFoxP3+T-cell threshold of 2.4% discriminated BOS and stable patients at 1 month post-transplantation. This was validated on a second set of patients at 6 months post-transplantation. Patients with a proportion of CD4+CD25hiFoxP3+T cells up to 2.4% in the 6 months after transplantation had a 2-fold higher risk of developing BOS. CONCLUSIONS: This study is the first to report an increased proportion of circulating CD4+CD25hiFoxP3+T cells early post-transplantation in lung recipients who proceed to develop BOS within 3 years, which supports its use as a BOS predictive biomarker.

Introduction Le syndrome restrictif du greffon (RAS) a recemment ete identifie comme le phenotype de dysfonction chronique associe au plus haut risque de mortalite. Les criteres fonctionnels diagnostiques de RAS ont ete proposes exclusivement apres Tx bi-pulmonaire, et leur validite chez les TX mono-pulmonaires (SLTx) n’est pas connue. En cas de mono-greffe, l’influence du poumon natif peut etre un facteur confondant dans la mesure du declin de la fonction. Par ailleurs, il est montre que la mesure volumetrique en scanner 3D est correlee a celle de la CPT, ce qui suggere son interet potentiel pour le diagnostic de RAS. But Evaluer les profils de declin fonctionnel et d’evolution scanographiques (volume/3D et score qualitatif de RAS) apres mono-greffe pulmonaire. Methodes Etude retrospective monocentrique (2006–2015, hopital Bichat), chez les mono-greffes pulmonaires, avec criteres diagnostiques de RAS suivant definis a priori : (1) CVF 0,7 et (2) scanner thoracique avec opacites evocatrices de RAS et score TDM (adapte de Suhling [1] ) > 2. Comparaison a un groupe patients stables ou avec syndrome de bronchiolite obliterante (BOS). Selection de 4 TDM/patient : no 1 baseline, no 2 apparition opacites, no 3 suivi, no 4 dernier TDM. Resultats Dix-sept monogreffes identifies avec un RAS. Mediane de survie apres diagnostic de RAS : 552 jours. Il est observe une augmentation precoce du score TDM (reticulations, condensation ; p 10 %, et sans score TDM > 3 etaient inferieures comparees a celle sans CVF 2 pour atteindre nos criteres diagnostiques de RAS. Conclusion Cette serie suggere que des criteres multidimensionnels associant CVF et score/volume TDM permettent d’identifier des patients monogreffes pulmonaires avec RAS. Ces criteres necessitent une validation sur une plus large cohorte.

International audience; BACKGROUND: Due to its multisystemic nature, scleroderma is considered a relative contraindication to lung transplantation at many centers. However, recent studies suggest similar post-transplant outcomes in patients with scleroderma compared to those with other causes of interstitial lung disease (ILD). Furthermore, it remains unknown whether scleroderma-associated pulmonary arterial hypertension (PAH) influences post-transplant outcomes. Our objective in this study was to assess the indications, survival, and prognostic factors of lung or heart lung transplantation for scleroderma lung disease. METHODS: We retrospectively reviewed the data of 90 patients with scleroderma who underwent lung or heart lung transplantation between 1993 and 2016 at 14 European centers. International criteria were used to diagnose scleroderma. Pulmonary hypertension (PH) was diagnosed during right heart catheterization based on international guidelines. RESULTS: Survival rates after 1, 3, and 5 years were 81%, 68%, and 61%, respectively. By univariate analysis, borderline-significant associations with poorer survival were found for female gender (hazard ratio 2.11; 95% confidence interval [CI] 0.99 to 4.50; p = 0.05) and PAH as the reason for transplantation (hazard ratio 1.90; 95% CI 0.96 to 3.92; p = 0.06). When both these factors were present in combination, the risk of death was 3-fold that in males without PAH. The clinical and histologic presentation resembled veno-occlusive disease in 75% of patients with PAH. CONCLUSIONS: Post-transplant survival rates and freedom from chronic lung allograft dysfunction in patients with scleroderma were similar to those in patients with other reasons for lung transplantation. Female sex and PAH in combination was associated with lower survival. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.

Presence of anti-human leukocyte antigen donor-specific antibodies (DSAs) is associated with poor outcome after lung transplantation. Currently, DSAs are detected using the Luminex technique, which may be overly sensitive. The new C1q assay allows for the exclusive detection of complement (C1q)-binding antibodies, involved in antibody-mediated rejection. We investigated whether early detection of complement-binding DSAs is associated with chronic lung allograft dysfunction (CLAD) and survival.From 2009 to 2012, lung transplant recipients from three transplantation centres were screened for the presence of DSA and their complement-binding capacity during the 6-12 months post-transplantation in a stable condition.The analysis included 168 patients. The 3-year rates of freedom from CLAD and graft survival were lower for patients with complement-binding DSAs (33.6% and 53.7%, respectively), as compared with patients with non-complement-binding DSAs (61.9% and 77.4%, respectively) and patients without DSA (70% and 84.9%, respectively) (p0.001 and p=0.001, respectively). Detection of complement-binding DSA was associated with a risk of graft loss that was nearly tripled after adjustment for clinical, functional, histological and immunological factors (hazard ratio 2.98, 95% CI 1.33-6.66; p=0.008).Assessment of the C1q-binding capacity of DSA appears to be useful in identifying stable lung transplant recipients at high risk of lung allograft loss.

Early acute renal failure (ARF) is a common complication after lung transplantation (LTx), and is associated with higher long-term mortality. Calcineurins inhibitors (CNIs) toxicity play a major role in ARF in the early phase post-LTx, and alternate nonnephrotoxic immunosuppressive (IS) regimen are needed in LTx. Belatacept, a novel immunosuppressant that blocks a T-cell costimulation pathway, is a nonnephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, a few cases of CNI-belatacept conversion have been reported so far, only in the late long-term follow-up (>3 years post-LTx). We here report a single-center series of 4 LTx recipients converted to a belatacept primary IS-regimen in the early-postoperative period after LTx (month [M] 2, M2, M2, M5). Causes of conversion were persistent severe renal failure, due to: [1] thrombotic microangiopathy; [2] CNI toxicity/acute tubular necrosis (ATN); [3] ATN/FSglomerulosclerosis; [4] CNI toxicity. Following belatacept-conversion, acute rejection (AR) episodes occurred in 2 high immunologic risk recipients, with detection of donor-specific antibodies (asymptomatic AR both in patient 1 [graded A2B0] and patient 2 [A2Bx], which were both resolved with pulsed steroids). All 4 recipients remained with stable pulmonary function and significant renal function improvement at last available follow-up postbelatacept (M2, M3, M3, and M4). Outcome at 9 months postbelatacept, including incidence of AR and chronic lung allograft dysfunction, graft survival, and renal function outcome will be presented at the ERS 2017 congress.

Chronic bronchiolitis obliterans syndrome (BOS) remains a major limitation for long-term survival after lung transplantation. The immune mechanisms involved and predictive biomarkers have yet to be identified. The purpose of this study was to determine whether peripheral blood T-lymphocyte profile could predict BOS in lung transplant recipients.An in-depth profiling of CD4Although no significant difference was found for T-cell compartments at BOS diagnosis or several months beforehand, we identified an increase in the CD4This study is the first to report an increased proportion of circulating CD4

International audience; OBJECTIVES: The aim of this study was to analyse characteristics and outcome of respiratory syncytial virus (RSV) infection in adults hospitalized with influenza-like illness (ILI). METHODS: Patients hospitalized with ILI were included in this prospective, multicentre study carried out in six French hospitals during three consecutive influenza seasons (2012-2015). RSV and other respiratory viruses were detected by multiplex PCR in nasopharyngeal swabs. Risk factors for RSV infection were identified by backward stepwise logistic regression analysis. RESULTS: A total of 1452 patients hospitalized with ILI were included, of whom 59% (861/1452) were >65 years and 83% (1211/1452) had underlying chronic illnesses. RSV was detected in 4% (59/1452), and influenza virus in 39% (566/1452). Risk factors for RSV infection were cancer (adjusted OR 2.1, 95% CI 1.1-4.1, p 0.04), and immunosuppressive treatment (adjusted OR 2.0, 95% CI 1.1-3.8, p 0.03). Patients with RSV had a median length of stay of 9 days (6-25), and 57% of them (30/53) had complications, including pneumonia (23/53, 44%) and respiratory failure (15/53, 28%). Fifteen per cent (8/53) were admitted to an intensive care unit, and the in-hospital mortality rate was 8% (4/53). Pneumonia was more likely to occur in patients with RSV than in patients with RSV-negative ILI (44% (23/53) versus 26% (362/1393), p 0.006) or with influenza virus infection (44% versus 28% (157/560), p 0.02). CONCLUSION: RSV is an infrequent cause of ILI during periods of influenza virus circulation but can cause severe complications in hospitalized adults. Risk factors for RSV detection in adults hospitalized with ILI include cancer and immunosuppressive treatment. Specific immunization and antiviral therapy might benefit patients at risk.

Belatacept is increasingly used in lung transplant (LTx) recipients intolerant to calcineurin inhibitors (CNIs), with satisfactory outcome.1 We describe a case of fatal acute respiratory distress syndrome (ARDS) that developed in a single LTx recipient after starting a belatacept-based immunosuppres

BACKGROUND New methods of solid-phase assays, such as Luminex assay, with high sensitivity in detecting anti-human leukocyte antigen (HLA) antibodies (Abs), have increased the proportion of sensitized candidates waiting for lung transplantation (LTx). However, how to apply these results clinically during graft allocation is debated: strict exclusion of candidates with Luminex-positive results can lead to lost opportunities for Tx. We retrospectively analyzed the clinical impact of pre-LTx Luminex-detected Abs on post-LTx outcomes for patients who underwent LTx before the availability of Luminex assay. METHODS We analyzed data for 56 successive patients who underwent LTx before 2008 and were considered to not have anti-HLA Abs by then-available methods of detection at the date of their LTx. Pre-LTx sera from these patients were retested by Luminex assay. Using log-rank test, freedom from bronchiolitis obliterans syndrome (BOS) and graft survival were compared between patients with and without pre-LTx Luminex-detected anti-HLA Abs classes I and II and donor-specific Abs (DSA) classes I and II. RESULTS Freedom from bronchiolitis obliterans syndrome was lower, and mortality was higher for patients with than those without pre-LTx Luminex-detected DSA class II (P=0.004 and P=0.007, respectively) but did not differ for patients with and without DSA class I or anti-HLA Abs class I or II. CONCLUSIONS It suggests to avoid attributing graft with forbidden antigens to sensitized candidates with Luminex-detected DSA class II and to evaluate the role of specific posttransplantation protocols for LTx candidates who require emergency LTx.

Survival after lung transplantation (LTx) remains limited by the occurrence of bronchiolitis obliterans (BO), thought to be a form of chronic rejection. In BO, an indirect allorecognition of both HLA and non-HLA antigens (Ags) expressed by bronchial epithelial cells (BEC) is highly suspected as a crucial trigger for BECs damages, although levels of proof remain weak. We here investigated the indirect allorecognition of Ags expressed by BEC in an original ex-vivo model established from samples of LTx recipients (LTxR). To reproduce the immune crosstalk that may occur in patients, 3 distinct cell types originated from the same LTxR were used: allogenic BECs (graft cells) in primary cultures, monocyte derived dendritic cells (DCs) and peripheral T cells. Mixed lymphocyte reactions were performed between T cells (responding cells) and DCs (stimulating cells) that had been or not previously loaded with Ags such as alloBECs lysates (n=10) or tetanus toxoid (TT) (n=6) as Ag positive control. Four healthy individuals were used as controls with TT-loaded DCs. In LTxR, T-cell proliferation was increased by 49% [16-87%] when DCs loaded with alloBEC lysates were used. TT-loaded DCs increased T-cell proliferation by 51% [9-97]% in controls, but only by 4% [0-76%] in LTxR. These measures were highly variable in both patients and controls. This ex-vivo model allowed us to demonstrate that LTxR display a specific T-cell response against alloBECs Ags through indirect allorecognition mechanism. Further objectives are the ability of this model to early predict BO in LTxR and to gain insight into the respective role of HLA and non-HLA Ags from BECs in alloreactivity.

Background. Endothelial C4d deposition is used as a reliable marker to diagnose antibody-mediated rejection (AMR) in renal and cardiac transplantation, but remains controversial in lung transplantation. Objectives. This study was planned to study the utility of C4d by immunohistochemistry (IHC) for the diagnosis of AMR in lung allograft transbronchial biopsies (TBBx). Methods. We evaluated C4d staining by IHC in a blinded fashion, on 158 consecutive formalin-fixed paraffin embedded (FFPE) TBBx, from a cohort of 48 lung transplant recipients. Capillary C4d staining was scored as 0, 1 ( 50% capillaries). C4d scoring was compared with microvascular inflammation (MI), acute lung injury (ALI), acute cellular rejection (ACR), concomitant donor specific antibodies (DSA) and graft dysfunction. Results. C4d3, C4d2, C4d1 and C4d0 occurred in 4 (2.5%), 6 (3.8%), 28 (17.7%) and 120 (75.9%) TBBx, respectively. Capillary staining ≥C4d2 was significantly associated with MI (50% vs 7.4%; p=0.001). C4d3 occurred more frequently with DSA (5.5% in DSA group vs 1.5% in non-DSA group) and was significantly associated with graft dysfunction (p=0.03). Histopathologic findings alone did not correlate with DSA. Three out of 4 patients with C4d3 developed bronchiolitis obliterans syndrome (BOS). Conclusions. Diffuse C4d deposition in endothelial capillaries was correlated with MI and graft dysfunction. It was closely related, but not significantly, with DSA and development of BOS in lung transplant recipients. Diffuse C4d deposition in the lung might be a specific marker for AMR, although lacking sensitivity.

Three weeks after single-lung transplantation for pulmonary fibrosis, a patient with high serum levels of de novo donor-specific antibodies received high-dose intravenous immunoglobulin (IVIG) infusion (scheduled dose: 2 g/kg on 2 days) to prevent antibody-mediated rejection. Within the first hours after completion of infusions, he experienced acute lung injury involving the transplanted lung. Given the clinical evolution and the absence of an alternative diagnosis, transfusion-related acute lung injury (TRALI) was diagnosed. The IVIG administered on each day was from the same batch. At day 110, because of an increase in the serum titers of donor-specific antibodies, IVIG therapy was reintroduced but from a different batch, with excellent clinical tolerance. The lung injury was explored biologically, but no mechanism was revealed. Given the increasing use of IVIG in solid-organ recipients, clinicians should be aware of possible TRALI after IVIG infusion.

International audience; BackgroundAspergillus colonisation is frequently reported after lung transplantation. The question of whether aspergillus colonisation is related to the hospital environment is crucial to prevention.MethodTo elucidate this question, a prospective study of aspergillus colonisation after lung transplantation, along with a mycological survey of the patient environment, was performed.ResultsForty-four consecutive patients were included from the day of lung transplantation and then examined weekly for aspergillus colonisation until hospital discharge. Environmental fungal contamination of each patient was followed weekly via air and surface sampling. Twelve patients (27%) had transient aspergillus colonisation, occurring 1–13 weeks after lung transplantation, without associated manifestation of aspergillosis. Responsible Aspergillus species were A. fumigatus (6), A. niger (3), A. sydowii (1), A. calidoustus (1) and Aspergillus sp. (1). In the environment, contamination by Penicillium and Aspergillus was predominant. Multivariate analysis showed a significant association between occurrence of aspergillus colonisation and fungal contamination of the patient’s room, either by Aspergillus spp. in the air or by A.fumigatus on the floor. Related clinical and environmental isolates were genotyped in 9 cases of aspergillus colonisation. For A. fumigatus (4 cases), two identical microsatellite profiles were found between clinical and environmental isolates collected on distant dates or locations. For other Aspergillus species, isolates were different in 2 cases; in 3 cases of aspergillus colonisation by A. sydowii, A. niger and A. calidoustus, similarity between clinical and environmental internal transcribed spacer and tubulin sequences was >99%.ConclusionTaken together, these results support the hypothesis of environmental risk of hospital acquisition of aspergillus colonisation in lung transplant recipients.

International audience; BACKGROUND: Both single and bilateral lung transplantation are recognised options for patients who have end-stage chronic obstructive pulmonary disease (COPD); however, which procedure leads to longer survival remains unclear. We aimed to compare survival after each procedure by analysing data from the registry of the International Society for Heart and Lung Transplantation. METHODS: We analysed data for 9883 patients with COPD, 3525 (35.7%) of whom underwent bilateral lung transplantation, and 6358 (64.3%) single lung transplantation, between 1987 and 2006. We accounted for possible selection bias with analysis of covariance, propensity-score risk adjustment, and propensity-based matching. FINDINGS: Median survival after either type of lung transplantation for patients with COPD was 5.0 years (95% CI 4.8-5.2). Survival for patients who had lung transplantation before 1998 was 4.5 years (4.3-4.8), compared with 5.3 years (5.0-5.5) for those who had it after 1998 (p

We studied the role of chronic exposure to ambiant air pollution on lung function level and evolution in lung transplant patients. The lung function of 525 lung transplant (LT) patients from the COLT cohort was followed-up. The 12-month average levels of air pollutants (Nitrogen dioxide (NO 2 ), fine particulate matters (PM 2.5 , PM 10 ) and ozone (O 3 )) were estimated at the home addresses of each patient. The effect of air pollutant exposure on FEV 1 level and change in FEV 1 both during the recovery and decline periodes were estimated using mixed linear regression models adjusted on recipient age, sex, smoking (donor and patient), body mass index, donor age, type of LT, underlying disease, sex and HLA mismatch, ischemia time, anti-HLA antibodies, Pseudomonas colonization, CMV infections, immunosuppression induction and acute rejection. The population included 54% of men and 81% of double LT (mean age 43yrs). The main underlying diseases were cystic fibrosis (40%), emphysema/COPD (34%) and pulmonary arterial hypertension (14%). Mean (sd) individual exposure levels were 15.2 (2.1), 22.1 (3.1), 18.1 (7.3) and 51.7 (8.2) µg/m 3 for PM 2.5 , PM 10 , NO 2 and O 3 , respectively. NO 2 exposure was significantly associated with lower FEV 1 levels measured during the recovery period and a non-significant trend was observed in the decline period (estimate (se) = -3.39(1.48) p=0.02 and -1.96(1.47) p=0.18). None of the air pollutants exposure was associated with change in FEV 1 . Our results suggest a potential deleterious effect of chronic exposure to NO 2 on FEV 1 level following LT and did not evidence an effect of air pollution on change in FEV 1 . Fundings: EU-FP7 SYSCLAD, Vaincre la Mucoviscidose, Association Gregory Lemarchal.

Chronic Lung Allograft Dysfunction (CLAD) manifests as Bronchiolitis Obliterans Syndrome (BOS) and the recently described Restrictive Allograft Syndrome (RAS). CLAD is unpredictable and irreversible. Thus predictive biomarkers of CLAD are needed to provide an early and personalized intervention. Our objective is to establish a predictive blood transcriptomic signature of CLAD. We hypothesized that gene and miRNA expression profiling of peripheral blood could uncover the early alterations of CLAD before the degradation of lung function. We selected 88 lung transplant recipients from the COLT (Cohort in Lung Transplantation) cohort. Patients were unequivocally phenotyped by an adjudication committee at 3 years post transplantation as stable (n=49), BOS (n=29) or RAS (n=10). Blood transcriptome (mRNA and microRNA) was investigated longitudinally at 6 months and 1 year post-transplantation, i.e . before the onset of CLAD. Integrated analysis of miRNA and mRNA expression was performed. Preliminary results show more than 500 differentially expressed genes (DEG) between Stable and BOS groups. Hierarchical clustering of DEG discriminates between stable and BOS patients with an accuracy approaching 80%. Gene ontology was conducted to categorize the function of the DEG. Analysis of KEGG pathways revealed several enrichment-related pathways including haematopoietic cell lineage or B cell receptor signaling pathway. As a conclusion, our work supports blood transcriptome analysis to predict and to explore the physiopathology of CLAD. Several biomarkers and pathways were identified. Investigations are ongoing to define the final gene-set predictor. Systems prediction of CLAD: http://www.sysclad.eu/