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Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

Background: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. Objective: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. Methods: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. Results: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. Conclusion: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30–40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Background: Children with advanced pulmonary disease due to cystic fibrosis (CF) are at risk of acute respiratory failure due to pulmonary exacerbations leading to their admission to pediatric intensive care units (PICU). The objectives of this study were to determine short and medium-term outcomes of children with CF admitted to PICU for acute respiratory failure due to pulmonary exacerbation and to identify prognosis factors., Methods: This retrospective monocentric study included patients less than 18 years old admitted to the PICU of a French university hospital between 2000 and 2020. Cox proportional hazard regression methods were used to determine prognosis factors of mortality or lung transplant., Results: Prior to PICU admission, the 29 patients included (median age 13.5 years) had a severe lung disease (median Forced Expiratory Volume in 1 s percentage predicted at 29%). Mortality rates were respectively 17%, 31%, 34%, 41% at discharge and at 3, 12 and 36 months post-discharge. Survival rates free of lung transplant were 34%, 32%, 24% and 17% respectively. Risk factors associated with mortality or lung transplant using the univariate analysis were female sex and higher pCO2 and chloride levels at PICU admission, and following pre admission characteristics: home respiratory and nutritional support, registration on lung transplant list and Stenotrophomonas Maltophilia bronchial colonization., Conclusion: Children with CF admitted to PICU for acute respiratory failure secondary to pulmonary exacerbations are at high risk of death, both in the short and medium terms. Lung transplant is their main chance of survival and should be considered early., (© 2024. The Author(s).)

Objectives: Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD., Methods: This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort., Results: Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764)., Conclusions: Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT)., Methods and Results: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05)., Conclusions: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population., Methods and Results: Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years [95% confidence interval (CI), 9.7-15.9] in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53-0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048)., Conclusion: HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients., Material and Methods: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed., Results: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values., Conclusion: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Little is known about localized osteoarticular Scedosporiosis (LOS). Most data come from case reports and small case series. Here we present an ancillary study of the nationwide French Scedosporiosis Observational Study (SOS), describing 15 consecutive cases of LOS diagnosed between January 2005 and March 2017. Adult patients diagnosed with LOS defined by osteoarticular involvement without distant foci reported in SOS were included. Fifteen LOS were analyzed. Seven patients had underlying disease. Fourteen patients had prior trauma as potential inoculation. Clinical presentation was arthritis (n = 8), osteitis (n = 5), and thoracic wall infection (n = 2). The most common clinical manifestation was pain (n = 9), followed by localized swelling (n = 7), cutaneous fistulization (n = 7), and fever (n = 5). The species involved were Scedosporium apiospermum (n = 8), S. boydii (n = 3), S. dehoogii (n = 1), and Lomentospora prolificans (n = 3). The species distribution was unremarkable except for S. boydii, which was associated with healthcare-related inoculations. Management was based on medical and surgical treatment for 13 patients. Fourteen patients received antifungal treatment for a median duration of 7 months. No patients died during follow-up. LOS exclusively occurred in the context of inoculation or systemic predisposing factors. It has a non-specific clinical presentation and is associated with an overall good clinical outcome, provided there is a prolonged course of antifungal therapy and adequate surgical management., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Objective: Immunocompromised patients have an increased risk of a severe form of COVID-19. The clinical efficacy of the tixagevimab/cilgavimab monoclonal antibody combination as pre-exposure prophylaxis against BA.1 and BA.2 SARS-CoV-2 Omicron sublineages is unknown. We aimed to describe the incidence and outcomes of COVID-19 among immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis during the Omicron wave in France., Methods: This was an observational multicentre cohort study of immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis between December 28, 2021 and March 31, 2022. Patients received tixagevimab/cilgavimab 150/150 mg intramuscularly if they had impaired vaccine response and a high risk of severe form of COVID-19., Results: Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median (range) follow-up of 63 (49-73) days, COVID-19 was confirmed in 49/1112 (4.4%) ≥5 days after treatment. During the study period, mean weekly incidence rate was 1669 in 100 000 inhabitants in Ile-de-France and 530 in 100 000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to-moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19., Discussion: Our study reported a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: The value of Forrester's perfusion/congestion profiles assessed by invasive catheter evaluation in non-inotrope advanced heart failure patients listed for heart transplant (HT) is unclear. We aimed to assess the value of haemodynamic evaluation according to Forrester's profiles to predict events on the HT waitlist., Methods and Results: All non-inotrope patients (n = 837, 79% ambulatory at listing) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 with right heart catheterization (RHC) were included. The primary outcome was a combined criteria of waitlist death, delisting for aggravation, urgent HT or left ventricular assist device implantation. Secondary outcome was waitlist death. The 'warm-dry', 'cold-dry', 'warm-wet', and 'cold-wet' profiles represented 27%, 18%, 27%, and 28% of patients, respectively. At 12 months, the respective rates of primary outcome were 15%, 17%, 25%, and 29% (P = 0.008). Taking the 'warm-dry' category as reference, a significant increase in the risk of primary outcome was observed only in the 'wet' categories, irrespectively of 'warm/cold' status: hazard ratios, 1.50; 1.06-2.13; P = 0.024 in 'warm-wet' and 1.77; 1. 25-2.49; P = 0.001 in 'cold-wet'., Conclusions: Haemodynamic assessment of advanced HF patients using perfusion/congestion profiles predicts the risk of the combine endpoint of waitlist death, delisting for aggravation, urgent heart transplantation, or left ventricular assist device implantation. 'Wet' patients had the worst prognosis, independently of perfusion status, thus placing special emphasis on the cardinal prominence of persistent congestion in advanced HF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Little is known about targeted (antiviral or monoclonal antibody) anti-SARS-CoV-2 treatment in immunocompromised patients with COVID-19., Objectives: To assess the real-life efficacy and tolerance of targeted treatment of COVID-19 in immunocompromised patients., Patients and Methods: Single-centre retrospective case series of immunocompromised patients with COVID-19 between December 2021 and March 2022. We recorded all cases of COVID-19 among immunocompromised patients treatment between 20 December 2021 and 15 March 2022. Choice of treatment was left to the physician's decision, according to internal treatment protocol, treatment availability and circulating variants. Main outcome was death from COVID-19 after no treatment or targeted treatment., Results: Sixty-seven immunocompromised patients [38 male; median (IQR) age, 53 (43-63) years], with a median (IQR) follow-up of 60 (47-80) days. Ten patients did not receive any targeted treatment. Targeted treatment consisted of IV curative remdesivir (n = 22), sotrovimab (n = 16), tixagevimab/cilgavimab (n = 13) and casirivimab/imdevimab (n = 1). Ten patients (15%) presented severe COVID-19 and 2 (3%) died from Omicron COVID-19. Comparing patients who received targeted anti-SARS-CoV-2 treatment and no prophylaxis, (n = 42; 81%) with those who did not (n = 10; 19%), death rate was significantly lower in treated patients [n = 0 (0%) versus n = 2 (20%); P = 0.034]. No severe adverse events were reported among treated patients. Among 15 patients who received tixagevimab/cilgavimab as pre-exposure prophylaxis, 6 received an additional curative treatment and none died from COVID-19., Conclusions: Our results suggest that targeted COVID-19 treatment, including direct antivirals or monoclonal antibodies, is safe and efficient and could be proposed in high-risk immunocompromised patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Voriconazole is an antifungal treatment with central neurotoxicity. Modifications of the electroretinogram can explain some of its visual complications: visual hallucination, blurred vision, altered visual perception or photophobia. However, reports from the literature or the French pharmacovigilance centers evoked toxic optic neuropathy due to voriconazole. The aim of this report is to analyze the role of voriconazole in the occurrence of toxic optic neuropathy or the role of the combination of voriconazole with other neurotoxic drugs., Patients and Methods: We report the case of a 15-year-old young boy treated with voriconazole and ethambutol for a severe lung infection due to aspergillosis and mycobacterium tuberculosis in the mucoviscidosis and pulmonary transplantation who developed a toxic optic neuropathy. A review of the literature on the role of ethambutol on the activity of CYP2C19 and its relationship with the serum concentration of voriconazole was conducted., Results: In our patients, visual acuity recovered after discontinuation of voriconazole. Other cases of toxic optic neuropathy due to voriconazole were reported in pharmaco-vigilance databases, often in association with ethambutol., Conclusions: Ethambutol can reduce the activity of CYP2C19 leading to an increase of voriconazole concentration. Thus, it potentiates its risk of adverse event. Such mechanism leading to this neuro ophthalmological adverse effect would have an important clinical involvement. It would require a stricter monitoring and screening of patients treated by combination of neurotoxic molecules and VRZ to detect an adverse event.

Aim: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF., Methods and Results: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment., Conclusion: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans . A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans . Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans . The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

Background: Since the first successful facial transplantation in 2005, the benefits of this procedure in terms of aesthetics, functionality, and quality of life have been firmly established. However, despite immunosuppressive treatment, long-term survival of the allograft might be compromised by chronic antibody-mediated rejection (CAMR), leading to irreversible necrosis of the tissue. In the absence of therapeutic options, this complication is inevitably life-threatening., Methods: We report facial retransplantation in a man, 8 years after his first facial transplantation because of extensive disfigurement from type 1 neurofibromatosis and 6 weeks after complete loss of his allograft due to severe CAMR. We describe the chronology of immune-related problems that culminated in allograft necrosis and the eventual loss of the facial transplant, the desensitisation protocol used for this highly immunosensitised recipient, the surgical technicalities of the procedure, the specific psychological management of this patient, and the results from follow-up at 30 months., Findings: Although the patient had a complicated postoperative course with numerous immunological, infectious, cardiorespiratory, and psychological events, he was discharged after a hospital stay of almost 1 year. He has since been able to re-integrate into his community with acceptable restoration of his quality of life., Interpretation: This clinical report of the first documented human facial retransplantation is proof-of-concept that the loss of a facial transplant after CAMR can be mitigated successfully by retransplantation combined with an aggressive desensitisation process., Funding: Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development., Methods: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality., Results: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age ( P <0.001), donor male sex ( P <0.001), donor tobacco consumption ( P =0.001), recipient dyslipidemia ( P =0.009), class II anti-human leukocyte antigen donor-specific antibodies ( P =0.004), and acute cellular rejection ≥2R ( P =0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality ( P <0.001)., Conclusions: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m 2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation., Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed., Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB., Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection., (Copyright © 2019. Published by Elsevier Inc.)

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

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 hi CD38 hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24 hi CD38 hi transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9 + B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24 hi CD38 hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome-free survival., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: The purpose of this study was first to evaluate the imaging-related cumulative post-transplantation radiation dose in cystic fibrosis (CF) lung transplantation (LT) recipients and second, to identify the occurrence and type of malignancies observed after LT., Materials and Methods: A total of 52 patients with CF who underwent LT at our institution between January 2001 and December 2006 with at least 3 years of survival were retrospectively included. There were 27 men and 25 women with a mean age of 24.4±9.2 (SD) years (range: 7.6-52.9 years) at the time of LT. Calculation of cumulative effective and organ doses after LT were based on dosimetry information and acquisition parameters of each examination. Cumulative radiation doses were calculated until June 2016, but stopped at the time of de novomalignancy diagnosis, for patients developing the condition., Results: Patients received a mean cumulative effective dose of 110.0±51.6 (SD) mSv (range: 13-261.3 mSv) over a mean follow-up of 8.1±3.6 (SD) years (range: 0.5-13.5 years), with more than 100mSv in 5 years in 19/52 patients (37%). Chest CT accounted for 73% of the cumulative effective dose. Mean doses to the lung, breast and thyroid were 152.8±61.1 (SD) mGy (range: 21.2-331.6 mGy), 106.5±43.2 (SD) mGy (range: 11.9-221.4 mGy) and 72.7±31.8 (SD) mGy (range: 9.5-165.0 mGy), respectively. Nine out of 52 patients (17%) developed a total of 10 de novo malignancies, all but one attributable to immunosuppression after a mean post-transplantation follow-up period of 11.1±3.5 (SD) years (range: 3.7-16.3 years). Six-month cumulative effective dose was not greater in patients with de novomalignancies than in those without de novomalignancies (28.9±14.5 (SD) mGy (range: 13.0-53.4) vs 25.6±15.3 (range: 5.0-69.7), respectively, P>0.05)., Conclusion: The cumulative effective dose exceeded 100 mSv in 5 years in 37% of LT recipients, the reason why continuous efforts should be made to optimize chest CT acquisitions accounting for 73% of the radiation dose., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Club Cell Secretory Protein (CCSP) G38A polymorphism has recently been involved in lung epithelial susceptibility to external injuries. Lung transplantation (LT) is currently limited by ischemia-reperfusion injury leading to primary graft dysfunction (PGD). We thus hypothesized that donor CCSP G38A polymorphism might impact the risk of PGD after LT., Methods: We focused on LT included in the French multicentric Cohort in Lung Transplantation (COLT), performed between January 2009 and December 2014, and associated with preoperative blood samples from the donor and the recipient. Characteristics of the donors, recipients, procedures, early and late outcomes were prospectively recorded in COLT. The CCSP serum concentration and CCSP gene G38A polymorphism were retrospectively determined in a blind manner. Their association with grade 3 PGD was studied in univariate and multivariate analysis., Results: The study group included 104 LT donors and recipients, 84 with grade 0 to 2 PGD and 20 with grade 3 PGD. Preoperative CCSP serum concentration was significantly higher in the donors (median, 22.54 ng/mL; interquartile range, 9.6-43.9) than in the recipients (median, 7.03 ng/mL; interquartile range, 0.89-19.2; P < 0.001) but none impacted the risk of grade 3 PGD (P = 0.93 and P = 0.69, respectively). Donor CCSP G38A polymorphism was associated with a decreased risk of grade 3 PGD in univariate (AG + AA 3/21 = 14.2% vs GG 10/26 = 38.4%, P = 0.044) and multivariate analysis (odds ratio associated with AG + AA, 0.22; 95% confidence interval, 0.041-0.88; P = 0.045), but recipient CCSP G38A polymorphism was not., Conclusions: Donor CCSP G38A polymorphism is associated with a decreased risk of severe PGD after LT in the COLT study. These findings should be confirmed in the frame of a prospective study.

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 + CD25 hi FoxP3 + 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 < 0.001). A CD4 + CD25 hi FoxP3 + 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 + CD25 hi FoxP3 + 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 + CD25 hi FoxP3 + 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., (Copyright © 2018. Published by Elsevier Inc.)

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations ( C 0 ) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C 0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively ( P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C 0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively ( P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C 0 /dose ratio ( C 0 / D ) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution ( P = 0.034*). The ERL C 0 / D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients., (Copyright © 2018 American Society for Microbiology.)

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 ( POU2AF1 ), T-cell leukemia/lymphoma protein 1A ( TCL1A ), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p  < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

Objectives: Heart transplantation (HT) and ventricular assist devices (VAD) for the management of end-stage heart failure have not been directly compared. We compare the outcomes and use of resources with these 2 strategies in 2 European countries with different allocation systems., Methods: We studied 83 patients managed by VAD as the first option in Bad Oeynhausen, Germany (Group I) and 141 managed with either HT or medical therapy, as the first option, in Paris, France (Group II). The primary end-point was 2-year survival. Kaplan-Meier analyses were performed after the application of propensity score weights to mitigate the effects of non-random group assignment. The secondary end-points were resource utilization and costs. Subgroup analyses were performed for patients undergoing HT and patients treated with inotropes at the enrolment time., Results: The Group I patients were more severely ill and haemodynamically compromised, and 28% subsequently underwent HT vs 55% primary HT in Group II, P < 0.001. The adjusted probability of survival was 44% in Group I vs 70% in Group II, P <0.0001. The mean cumulated 2-year costs were €281 361 ± 156 223 in Group I and €47 638 ± 35 061 in Group II, P < 0.0001. Among patients who underwent HT, the adjusted probability of survival in Group I (n = 23) versus Group II (n = 78) was 76% versus 68%, respectively (0.09), though it differed in the inotrope-treated subgroups (77% in Group I vs 67% in Group II, P = 0.04)., Conclusions: HT should remain the first option for end-stage heart failure patients, associated with improved outcomes and better cost-effectiveness profile. VAD devices represent an option when transplant is not possible or when patient presentation is not optimal., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce., Objective: To assess the effect of leflunomide on BKvirus in kidney-transplanted children., Methods: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded., Results: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis., Conclusion: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients.

Background: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT., Methods: Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period., Results: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive., Conclusions: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described., Methods: LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis., Results: Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS., Conclusion: Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Antibody-mediated rejection (AMR) contributes to heart allograft loss. However, an important knowledge gap remains in terms of the pathophysiology of AMR and how detection of immune activity, injury degree, and stage could be improved by intragraft gene expression profiling., Methods: We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006-January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR. We characterized all patients using histopathology (ISHLT [International Society for Heart and Lung Transplantation] 2013 grades), immunostaining, and circulating anti-HLA donor-specific antibodies at the time of biopsy, together with systematic gene expression assessments of the allograft tissue, using microarrays. Effector cells were evaluated with in vitro human cell cultures. We studied a validation cohort of 98 heart recipients transplanted in Edmonton, AB, Canada, including 27 cases of AMR and 71 controls., Results: A total of 240 heart transplant endomyocardial biopsies were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculatory inflammation by monocytes/macrophages and natural killer (NK) cells. We also observed selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and interferon-γ-inducible genes. The AMR-selective gene sets accurately discriminated patients with AMR from those without and included NK transcripts (area under the curve=0.87), endothelial activation transcripts (area under the curve=0.80), macrophage transcripts (area under the curve=0.86), and interferon-γ transcripts (area under the curve=0.84; P <0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pathological AMR (pAMR) International Society for Heart and Lung Transplantation grade ( P <0.001) and association with donor-specific antibody levels. The unsupervised principal components analysis demonstrated a high proportion of molecularly inactive pAMR1(I+), and there was significant molecular overlap between pAMR1(H + ) and full-blown pAMR2/3 cases. Endothelial activation transcripts, interferon-γ, and NK transcripts showed association with chronic allograft vasculopathy. The molecular architecture and selective AMR transcripts, together with gene set discrimination capacity for AMR identified in the discovery set, were reproduced in the validation cohort., Conclusions: Tissue-based measurements of specific pathogenesis-based transcripts reflecting NK burden, endothelial activation, macrophage burden, and interferon-γ effects accurately classify AMR and correlate with degree of injury and disease activity. This study illustrates the clinical potential of a tissue-based analysis of gene transcripts to refine diagnosis of heart transplant rejection., (© 2017 American Heart Association, Inc.)

Background: Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A)., Methods: We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype., Results: PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003)., Conclusions: The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Lung transplantation (LTx) is an accepted therapy for selected infants, children and adolescents with end-stage lung and pulmonary vascular disease. It remains a challenge for a selected group of patients. In 2011, the number of paediatric lung transplantations (PLTxs) worldwide was 107. In France, a total of 131 PLTxs have been performed since 2000 (data from ABM: Agence de biomédecine), 65 of which were conducted at our institution., Methods: All patients under 18 (4.8-17.11) years of age matching inclusion and exclusion criteria, who underwent LTx at our institution were included in this study (n = 58). We analysed the outcomes of these patients in terms of survival rates, controlling for indications for transplantations and surgical procedures. Secondary outcomes were analysis of surgical and medical complications and identification of prognostic factors in the field of LTx in these categories of ages., Results: The 30-day mortality rate was 10%. Kaplan-Meier survival rates at 1 month, 1, 3, 5 and 10 years were 90, 81, 66, 60 and 57%, respectively; the median survival was 91 months. Reduced-size transplantation was performed in 33% of double-lung transplantation (DLTx) patients without negatively impacting survival. In our series, female sex, the presence of a sex mismatching and, in particular, the occurrence of a male donor to a female recipient (F/M group) have been poor prognostic factors after PLTx., Conclusions: The overall survival after PLTx was encouraging (57% at 10 years). A PLTx should be offered to the small number of patients with end-stage pulmonary disease. The limited number of paediatric donor organs can be overcome by using reduced-size organs without a survival disadvantage to the patients. In our series, male sex and sex matching seemed to be positive predictive prognostic factors after PLTx but further studies are required to confirm these results and to also clarify the role of age of donor, time of cold ischaemia and body mass index in PLTx., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: To investigate the temporal trends in profile and outcomes of adults with congenital heart disease (ACHD) undergoing heart transplantation (HT)., Methods and Results: Out of a multi-institutional series of 2257 HT from 1988 to 2012, 100 HT were performed in 97 ACHD. We evaluated clinical characteristics, underlying defect, surgical history, perioperative issues, and outcomes. We compared two eras: era 1 (1988-2005, n = 48) and era 2 (2006-2012, n = 49). Mean age at HT was 30.3 ± 10.5 years. Twenty-five patients (25.8%) had biventricular physiology with a systemic right ventricle and 43 patients (44%) had univentricular physiology. Adults with congenital heart disease severity were classified as great complexity (74.2%), moderate (21.7%), and simple (4.1%). During a median follow-up of 28.7 months [0-282], 44 patients died. Early mortality was high (34%; 95% CI 0.2536-0.4390). Survival was 63.9% at 1 year. The proportion of univentricular patients did not change. Biventricular patients with systemic right ventricle significantly increased in era 2 (16.7  vs. 34.7%, P = 0.04) due to increasing number of transposition of the great arteries with atrial switch. Although the proportion of great complexity ACHD did not change significantly in era 2 (81.6%  vs. and 66.7% in era 1, P = 0.09), ACHD recipients have more advanced disease, being more likely hospitalized (P = 0.03), receiving intravenous inotropes (P = 0.01), under assist devices (P = 0.04), or UNOS status 1 (P = 0.02) at the time of HT. Survival rates were comparable., Conclusion: Despite a worse risk profile, mortality after HT in ACHD did not increase. Improving survival of complex CHD will probably amplify the proportion of complex ACHD recipients with more advanced disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody-mediated injury and immune-mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor-specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody-mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody-mediated rejection occurred 4.5 ± 3.5 years before allograft loss. Explanted allografts with evidence of antibody-mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 ± 0.26 and 2.25 ± 0.28, respectively) compared with explanted allografts without antibody-mediated rejection (0.42 ± 0.11 and 0.36 ± 0.09, p = 0.046 and p < 0.0001, respectively). Antibody-mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody-mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody-mediated rejection episodes may be observed years before allograft failure., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance., Objectives: We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients., Methods: We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease., Results: This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation., Conclusions: We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients., (© 2015 European Academy of Dermatology and Venereology.)

Aims: Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells., Methods and Results: Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events., Conclusion: This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

This multicenter case-controlled pilot study evaluated myocardial inflammatory burden (IB) and phenotype in endomyocardial biopsies (EMBs) with and without pathologic antibody-mediated rejection (pAMR). Sixty-five EMBs from five European heart transplant centers were centrally reviewed as positive (grade 2, n = 28), suspicious (grade 1, n = 7) or negative (n = 30) for pAMR. Absolute counts of total, intravascular (IV) and extravascular (EV) immunophenotyped mononuclear cells were correlated with pAMR grade, capillary C4d deposition, donor specific antibody (DSA) status and acute cellular rejection (ACR). In pAMR+ biopsies, equivalent number of IV CD3+ T lymphocytes (23 ± 4/0.225 mm(2) ) and CD68+ macrophages (21 ± 4/0.225 mm(2) ) were seen. IB and cell phenotype correlated with pAMR grade, C4d positivity and DSA positivity (p < 0.0001). High numbers of IV T lymphocytes were associated with low grade ACR (p = 0.002). In late-occurring AMR EV plasma cells occurring in 34% of pAMR+ EMBs were associated with higher IB. The IB in AMR correlated with pAMR+, C4d positivity and DSA positivity. In pAMR+ equivalent numbers of IV T lymphocytes and macrophages were found. The presence of plasma cells was associated with a higher IB and occurrence of pAMR late after transplantation., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aim: Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection., Methods: We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity., Results: We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant., Conclusion: This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the Cardiac trAnsplantation and Renal INsufficiency (CARIN) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT, and to observe the renal profile of the prescriptions. CARIN was a French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at five time points: before HTx (T0), 1(T1), 6(T6), 12 (T12), and 36 (T36) months after HTx. Glomerular filtration rate (GFR) was estimated with aMDRD formula. RI was defined as GFR < 60 ml/min/1.73 m². Four hundred and forty-one patients from five HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), and 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR < 60 at T0 were independent risk factors of mortality. 48.7-64.7% of the nonimmunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients. RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken., (© 2014 Steunstichting ESOT.)

Introduction: Pediatric lung transplantations (LTx) remains a small part of LTx performed worldwide. The majority of these Tx concerns young adolescents, transplantations in infants being anecdotic. We conducted a retrospective study of LTx in children and adolescents in one center in Paris from the beginning of the 90's to 2013., Methods: Data from Broussais then HEGP were collected retrospectively from 1990 to 2013: 380 LTx were reported in 368 patients including 111 LTx performed among children from 5 to 18 years of age (30%)., Results: One hundred and eleven patients received 121 LTx: 86 bilateral LTx, 13 combined lung-liver, 3 monopulmonary, 5 heart-lung and 4 combined heart-lung-liver Tx. Eighty-eight percent of the patients had cystic fibrosis. Median age was 14 years, weight 34 kg and height 144 cm. Median age of donors was 27 years, weight 60 kg and height 167 cm. Conditional survival for children was not different than adults: 72% at one year, 42% at 5 years, 37% at 10 years and 26% at 15 years. There was not overall early mortality after transplantation. Era graft survival was significantly higher after year 2000 (53% at 5 years vs 32% P=0.03)., Conclusion: Lung transplantation among children under 18 years have similar outcome to those of adult patients., (Copyright © 2014. Published by Elsevier Masson SAS.)

Background: Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA)., Methods: From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP)., Results: AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%)., Conclusions: p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.