Search

Outcome in patients with congenital heart diseases and pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Two-dimensional echocardiographic parameters, such as strain imaging or RV end-systolic remodeling index (RVESRI) have emerged to quantify RV function.We prospectively studied 30 patients aged 48±12 years with pretricuspid shunt and PAH and investigated the accuracy of multiple echocardiographic parameters of RV function (tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity, RV systolic-to-diastolic duration ratio, right atrial area, RV fractional area change, RV global longitudinal strain and RVESRI) to RV ejection fraction measured by cardiac magnetic resonance.RV ejection fraction45% was observed in 13 patients (43.3%). RV global longitudinal strain (ρ [Spearman's correlation coefficient]=-0.75; P=.001; RRVESRI, right atrial area and RV global longitudinal strain are strong markers of RV dysfunction in patients with pretricuspid shunt and PAH.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Patients with end-stage pulmonary arterial hypertension due to congenital heart disease have limited access to heart-lung transplantation or double-lung transplantation. We aimed to assess the effects of a high-priority allocation program established in France in 2007. We conducted a retrospective study to compare waitlist and posttransplantation outcomes before versus after implementation of the high-priority allocation program. We included 67 consecutive patients (mean age at listing, 33.2 ± 10.5 years) with pulmonary arterial hypertension due to congenital heart disease listed for heart-lung transplantation or double-lung transplantation from 1997 to 2016. At one month, the incidences of transplantation and death before transplantation were 3.5% and 24.6% in 1997-2006, 4.8% and 4.9% for patients on the regular list in 2007-2016, and 41.2% and 7.4% for patients listed under the high-priority allocation program (p

Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002).Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.

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.

Pulmonary arterial hypertension (PAH) is rare but remains fatal in infants and children despite the advance of targeted therapies. Lung transplantation (LTx), first performed in pediatric patients in the 1980s, is, with the Potts shunt, the only potentially life-extending option in patients with end-stage PAH but is possible only in tightly selected patients. Size-matching challenges severely restrict the donor organ pool, resulting-together with peculiarities of PAH in infants-in high waitlist mortality. We aimed to investigate survival when using a high-priority allocation program (HPAP) in children with PAH listed for double-LTx or heart-LTx.We conducted a single-center, retrospective, before-after study of consecutive children with severe Group 1 PAH listed for double-LTx or heart-LTx between 1988 and 2019. The HPAP was implemented in France in 2006 and 2007 for heart-LTx and double-LTx, respectively.Fifty-five children with PAH were listed for transplantation. Mean age at transplantation was 15.8±2.8 years and 72% had heart-lung transplantation. PAH was usually idiopathic (65%) or due to congenital heart disease (25%). HPAP implementation resulted in the following significant benefits: Decreased cumulative incidence of waitlist death within 1 and 2 years (p0.0001); increased cumulative incidence of transplantation within 6 months, from 44% to 67% (p0.01); and improved survival after listing (at 1, 3, and 5 years: 61%, 50%, and 44% vs. 92%, 84%, and 72% before and after HPAP implementation, respectively; p = 0.02).HPAP implementation was associated with significant improvements in access to transplantation and in survival after listing in children with end-stage PAH.

Anticancer immune-checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs), including interstitial pneumonitis, which is managed chiefly with systemic corticosteroids. When corticosteroids fail, second-line immunosuppressive therapy is indicated. Our objective was to evaluate the prevalence and outcomes of ICI-induced pneumonitis requiring second-line immunosuppressive therapy (IS).We collected data form the REISAMIC pharmacovigilance registry and the multidisciplinary immunological toxicity board at Gustave Roussy (France). No response to steroids was called steroid-refractory pneumonitis and relapse after an initial response was defined as steroid-resistant pneumonitis.Of the 1187 patients screened from the REISAMIC register, 48 (4%) patients had pneumonitis treated with corticosteroids. Five of them (10%) had corticosteroid refractory/resistant disease but only 2 were treated with immunosuppressive therapy. Four additional patients requiring immunosuppressive therapy identified via the immunological toxicity board were included. Immunosuppressive therapy were cyclophosphamide (n=4 pts), infliximab (n=1 pt), intravenous immunoglobulins (n=1 pt). Five of these six patients had corticosteroid-refractory disease and one had corticosteroid-resistant pneumonitis. Five patients had severe pneumonitis (Common Terminology Criteria for Adverse Events grade ≥3) at initial pneumonitis diagnosis. Two months mortality rate in patients treated with IS was 67% (4/6). Among the patients treated with IS, the two patients alive at 5 months were treated with cyclophosphamide.Patients with ICI-pneumonitis treated by steroids received IS in 10% of cases. High mortality at 67% of patients was observed in ICI-pneumonitis after steroid failure. Cyclophosphamide could be a treatment option for pneumonitis after corticosteroid failure that requires further investigations.

Background. Anticancer immune-checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs), including interstitial pneumonitis, which is managed chiefly with systemic corticosteroids. When corticosteroids fail, second-line immunosuppressive therapy is indicated. Our objective was to evaluate the prevalence and outcomes of ICI-induced pneumonitis requiring second-line immunosuppressive therapy (IS).Methods. We collected data form the REISAMIC pharmacovigilance registry and the multidisciplinary immunological toxicity board at Gustave Roussy (France). No response to steroids was called steroid-refractory pneumonitis and relapse after an initial response was defined as steroid-resistant pneumonitis. Results. Of the 1187 patients screened from the REISAMIC register, 48 (4%) patients had pneumonitis treated with corticosteroids. Five of them (10%) had corticosteroid refractory/resistant disease but only 2 were treated with immunosuppressive therapy. Four additional patients requiring immunosuppressive therapy identified via the immunological toxicity board were included. Immunosuppressive therapy were cyclophosphamide (n=4 pts), infliximab (n=1 pt), intravenous immunoglobulins (n=1 pt). Five of these six patients had corticosteroid-refractory disease and one had corticosteroid-resistant pneumonitis. Five patients had severe pneumonitis (Common Terminology Criteria for Adverse Events grade ≥3) at initial pneumonitis diagnosis. Two months mortality rate in patients treated with IS was 67% (4/6). Among the patients treated with IS, the two patients alive at 5 months were treated with cyclophosphamide. Conclusion. Patients with ICI-pneumonitis treated by steroids needed IS in 10% of cases. High mortality at 67% of patients was observed in ICI-pneumonitis after steroid failure. Cyclophosphamide could be a treatment option for pneumonitis after corticosteroid failure.

BackgroundThe published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres.MethodsWe conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of “ARDS/pneumonia” were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed.Results55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015–2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977–55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation.ConclusionsLung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Do three COVID-19 vaccine doses induce a serological response in lung transplant recipients?We retrospectively included 1071 adults (551 [52%] males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre264 BAU·mLMedian follow-up after the first dose was 8.3 [6.7-9.3] months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination, and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders [47/898, 5%] and 4 [4/173, 2%] responders) experienced COVID-19, at a median of 6.6 [5.1-7.3] months after the third dose. No responders had severe COVID-19, compared to 15 non-responders, including six who died of the disease.Few lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protection

It is unknown whether pulmonary arterial hypertension (PAH) risk stratification instruments could be helpful to support the decision to list a patient for lung transplantation (LT). Our aim was to evaluate contemporary risk assessment tools in a cohort of PAH patients listed for LT.Consecutive PAH patients (without pulmonary veno-occlusive disease or unrepaired congenital heart disease) listed for LT at the French Pulmonary Hypertension Reference Center between January 2006 and December 2018 were included. At the time of listing, risk stratification was assessed using the ESC/ERS criteria, the REVEAL Lite 2 score and the COMPERA 2.0 method. The primary end point was overall survival after LT listing. Secondary outcome measures were mortality on waiting list and posttransplant survival.One hundred and two patients were enrolled (mean age 38 ± 13 years, 69% females). Overall survival after listing was 72%, 58% and 46% at 1, 3 and 5 years respectively. Survival after LT listing was lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0001) and the REVEAL Lite 2 score (p = 0.04). The COMPERA 2.0 method discriminated post-listing survival of patients at high-risk, intermediate-high and intermediate-low risk (p = 0.04). The proportion of patients requiring urgent transplantation and extracorporeal life support as a bridge to transplantation was higher in the "high-risk" patients. Posttransplant survival was significantly lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0004).High-risk PAH patients at the time of LT listing have poor outcomes, suggesting that LT should be considered earlier in the course of PAH remaining refractory to triple combination therapy with a parenteral prostacyclin.

Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.

Question addressed by the studyDo three coronavirus disease 2019 (COVID-19) vaccine doses induce a serological response in lung transplant recipients?MethodsWe retrospectively included 1071 adults (551 (52%) males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre >264 BAU·mL−1after the third dose (median (interquartile range (IQR)) 3.0 (1.7–4.1) months), was the primary outcome and adverse events were the secondary outcomes. Median (IQR) age at the first vaccine dose was 54 (40–63) years and median (IQR) time from transplantation to the first dose was 64 (30–110) months.ResultsMedian (IQR) follow-up after the first dose was 8.3 (6.7–9.3) months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders (47/898 (5%)) and four (4/173 (2%)) responders) experienced COVID-19, at a median (IQR) of 6.6 (5.1–7.3) months after the third dose. No responders had severe COVID-19 compared with 15 non-responders, including six who died of the disease.ConclusionsFew lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protectionviacellular immunity and/or good adherence to shielding measures.

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.

Introduction: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure. Methods: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models. Results: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.

International audience; Introduction Patients with short telomere-related interstitial lung disease (ILD) have worse outcomes after lung transplantation. We hypothesized that post-transplant airway complications, including dehiscence and bronchial stenosis, would be more common in the short telomere ILD lung transplant population. Methods We conducted a multi-institutional (Brigham and Women's Hospital, Groupe de Transplantation de la SPLF) retrospective cohort study of 63 recipients between 2009 and 2019 with ILD and short telomeres, compared to 4359 recipients from the Scientific Registry of Transplant Recipients with ILD and no known telomeropathy. Results In the short telomere cohort, six recipients (9.5%) developed dehiscence and nine recipients (14.3%) developed stenosis, compared to 60 (1.4%) and 149 (3.4%) in the control, respectively. After adjusting for age, sex, and bilaterality, the presence of short telomeres was associated with higher odds of dehiscence (odds ratio (OR) = 8.24, 95% confidence interval (CI) = 3.34 20.29, p < .001) and stenosis (OR = 4.63, 95% CI 2.21 9.69, p < .001). Conclusion The association between the presence of short telomeres and post-transplant dehiscence and stenosis suggest that airway complications may be a contributor to increased morbidity and mortality in patients with telomere-related ILD.

Background. We sought to determine whether invasive aspergillosis (IA) during the first year after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD). Methods. We retrospectively reviewed the records of 191 patients who underwent lung transplantation at our institution between January 2013 and December 2017. Screening for Aspergillus was with bronchial aspirates, bronchoalveolar lavage if indicated or during surveillance bronchoscopy, radiography, and computed tomography. We used Fine and Gray multivariable regression to identify potential risk factors for CLAD. Results. During the first posttransplant year, 72 patients had at least 1 deep-airway sample positive for Aspergillus; 63 were classified as having IA and were included in the study. Median number of endoscopies per patient during the first year was 9 (range, 1–44). Median time from transplantation to first Aspergillus-positive sample was 121 d. Bronchial aspirate samples and bronchoalveolar lavage fluid were positive in 71 and 44 patients, respectively. Aspergillus fumigatus (n = 36, 50%) predominated; bacterial samples were also positive in 22 (31%) patients. IA within 4 mo after transplantation was independently associated with CLAD development (subdistribution hazard ratio, 3.75; 95% confidence interval [CI], 1.61-8.73; P < 0.01) by regression analysis. Survival at 3 and 5 y conditional on 1-y CLAD-free survival was 37% (95% CI, 24%-58%), and 24% (95% CI, 11%-52%) in the IA

Background Infection is the most common cause of mortality within the first year after lung transplantation (LTx). The management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. Methods We sent by email a survey dealing with 5 daily clinical vignettes concerning perioperative antibiotic therapy to 180 LTx centers around the world. The invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center during a 3-month period. Results We received a total of 99 responses from 24 countries, mostly from Western Europe (n = 46) and the USA (n = 34). Systematic screening for bronchial recipient colonization before LTx was mostly performed with sputum samples (72%), regardless of the underlying lung disease. In recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin / tazobactam, cefepime, ceftazidime, carbapenems) were reported in 72% of the centers, and antibiotics with activity against methicillin-resistant Staphylococcus aureus (mainly vancomycin) were reported in 38% of the centers. For these recipients, the duration of antibiotics reported was 7 days (33%) or less (26%) or stopped when cultures of donor and recipients were reported negatives (12%). In recipients with previous colonization, antibiotics were adapted to the susceptibility of the most resistant strain and given for at least 14 days (67%). Conclusion Practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. The antibiotic duration reported was longer for colonized recipients.

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

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.

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al 6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases …

Summary Background Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function. Methods The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death. The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra). Findings From March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0·22 [95% CI 0·11–0·41; p

Summary RR secondary to ICI (nivolumab in all patients) were observed in the lung (n = 1) or skin (n = 3). All patients had a long-term response to ICI and are currently alive with no active disease (Median FU from ICI discontinuation: 30 months). RR could reflect a beneficial immune activation and constitute a predictive clinical biomarker of ICI long-term efficacy.

Purpose We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs). Experimental design The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019. Results Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216). Conclusion The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.

Objectives To analyse functional outcome parameters according to antimicrobial treatments after respiratory syncytial virus (RSV)-confirmed infection in adult lung transplant recipients. Methods A 9-year retrospective multicentre cohort study (2011–19) included adult lung transplant recipients with RSV-confirmed infection. The first endpoint determined new allograft dysfunction (acute graft rejection and chronic lung allograft dysfunction (CLAD)) 3 months after infection. Then baseline and 3 months' postinfection forced expiratory volume in 1 second (FEV1) values were compared according to antimicrobial treatment. Univariate logistic regression analysis was performed. Results RSV infection was confirmed in 77 of 424 lung transplant recipients (estimated incidence of 0.025 per patient per year; 95% confidence interval 0.018–0.036). At 3 months, 22 recipients (28.8%) developed allograft dysfunction: ten (13%) possible CLAD, six (7.9%) acute rejection and six (7.9%) CLAD. Recipients with the lowest preinfection FEV1 had a greater risk of developing pneumonia (median (interquartile range) 1.5 (1.1–1.9) vs. 2.2 (1.5–2.4) L/s, p 0.003) and a higher odds of receiving antibiotics (1.6 (1.3–2.3) vs. 2.3 (1.9–2.5) L/s, p 0.017; odds ratio 0.52, 95% confidence interval 0.27–0.99). Compared to tracheobronchitis/bronchiolitis, RSV-induced pneumonia led more frequently to hospitalization (91.7%, 22 vs. 58.0%, 29, p 0.003) and intensive care unit admission (33.3%, 8 vs. 0, p Conclusions At 3 months after RSV-confirmed infection, 22 recipients (28.8%) had new allograft dysfunction. Ribavirin treatment and azithromycin prophylaxis did not prevent FEV1 decline.

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.

Background Programmed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs. Materials and methods All consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs ≥2 were retrospectively included. Data were gathered from June 2014 to February 2017, and a central review was performed. The primary and secondary end-points were i) to evaluate the overall detection rate of irAEs by medical imaging and ii) to provide a comprehensive radiological description of irAEs. Results Fifty-three patients (31 women, 22 men; average age: 61 years) were included. The primary tumour was melanoma (n = 32), lung cancer (n = 18) and other (n = 3). Patients were treated with nivolumab (n = 27) or pembrolizumab (n = 26). Of 74 medical imaging procedures analysed (ratio = 1.4 medical imaging per patient), 55 irAE were detected. The detection rate was overall: 74% (95 confidence interval: 63–84%), positron emission tomography with 18F-fludeoxyglucose integrated with computed tomography (18F-FDG PET/CT): 83% (n = 10/12), magnetic resonance imaging: 83% (n = 5/6), computed tomography scan: 79% (n = 19/24), ultrasonography: 70% (n = 19/27), standard X-rays: 40% (n = 2/5), lung/mediastinum: 100% (n = 7/7), enterocolitis: 100% (n = 8/8), hypophysitis: 100% (n = 3/3), thyroiditis: 75% (n = 15/20), hepatitis: 67% (n = 2/3), arthralgia or arthritis: 40% (n = 2/5) and pancreas: 28% (n = 2/7). Conclusion Medical imaging detected 74% of irAE in patients treated with anti-PD1. Beyond response assessment, medical imaging can detect irAE and guide towards specific management. We described the most frequent sites and patterns of imaging findings.

Pulmonary arterial hypertension (PAH) is a rare but severe complication of unrepaired atrial septal defect (ASD) and appears to be among the strongest predictors of death in adults with Eisenmenger syndrome [1]. For decades, heart-lung transplantation (HLTx) has been considered the best treatment of last resort for patients with ASD-associated PAH and right ventricular failure. Nonetheless, over 25% of patients die within 1 year after the procedure [2]. In addition, the severe organ shortage results in long waitlist times, during which the frequency of clinical deterioration or death exceeds 30% [3]. Double-lung transplantation (DLTx) with concomitant surgical cardiac-defect repair has been suggested as an attractive alternative for patients with ASD-associated PAH [4]. However, due to the limited number of patients with ASD-associated PAH treated by HLTx or DLTx, the available scientific evidence is insufficient to define the best strategy. 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: None for any authors