Conversion au bélatacept chez les transplantés rénaux stables : expérience dans la vraie vie

Calcineurin inhibitor (CNI) have renal toxicity and metabolic side effects affecting graft and patient survival. Belatacept, a new immunosuppressor without renal and metabolic side effect, has been recently approved for preventing allograft rejection. This treatment allows, in comparison with cyclosporin, a better kidney graft function, a reduced incidence of donor specific antibody, despite an increased acute cellular rejection rate. The main objective is to assess, in a real-life scenario, the effect of late conversion to belatacept in stable kidney transplant recipients under calcineurin inhibitors. We also assess if urinary CXCL-9 monitoring could highlight patients at risk of acute cellular rejection under belatacept. We realised a retrospective study on 35 kidney graft transplant recipients with mainly chronic graft dysfunction who were under CNI. Our study shows that late conversion to belatacept leads to kidney graft function stabilization, a decreased of HbA1c and systolic blood pressure at 12 months post conversion. Significantly renal function improvement was observed in sub-group of chronic graft dysfunction. After conversion, no side effect was observed. Only one acute rejection occured. Urinary CXCL-9 rate remains negative in all patients without renal event.Les inhibiteurs de la calcineurine (CNI) sont responsables de toxicité rénale et d’effets secondaires métaboliques qui impactent la survie des greffons et des patients. Le Bélatacept, un nouvel immunosuppresseur dépourvu d’effet secondaire rénal et métabolique, a été récemment approuvé comme traitement préventif du rejet d’allogreffe. Ce traitement permet d’obtenir, en comparaison à la cyclosporine, une meilleure fonction rénale, une moindre incidence de survenu des anticorps anti-donneur, au prix d’une augmentation du risque de rejet aigu cellulaire. L’objectif de notre étude est d’évaluer, dans la vraie vie, la conversion tardive vers le bélatacept chez les patients transplantés rénaux stables sous CNI. Par ailleurs, nous avons évalué si un monitorage par le dosage du CXCL-9 urinaire pouvait permettre de dégager les patients à risque de rejet cellulaire sous bélatacept. Nous avons réalisé une étude rétrospective portant sur 35 patients transplantés rénaux sous CNI, présentant majoritairement une dysfonction chronique du greffon. Notre étude montre que la conversion tardive vers le Bélatacept a permis une stabilisation de la fonction rénale, une amélioration de l’HbA1c, et de la pression artérielle systolique à 12 mois de la conversion. Une amélioration de la fonction rénale a par ailleurs été observée dans le sous-groupe de patient présentant une dysfonction chronique du greffon. Nous n’avons pas observé d’effet indésirable majeur. Un seul épisode de rejet aigu objectivé par biopsie rénale est survenu. Le taux urinaire de CXCL-9 est resté négatif chez l’ensemble des patients qui n’ont pas présenté d’événements rénaux durant le suivi

The eSpiro Ventilator: An Open-Source Response to a Worldwide Pandemic

International audienceObjective: To address the issue of ventilator shortages, our group (eSpiro Network) developed a freely replicable, open-source hardware ventilator. Design: We performed a bench study. Setting: Dedicated research room as part of an ICU affiliated to a university hospital. Subjects: We set the lung model with three conditions of resistance and linear compliance for mimicking different respiratory mechanics of representative intensive care unit (ICU) patients. Interventions: The performance of the device was tested using the ASL5000 lung model. Measurements and Main Results: Twenty-seven conditions were tested. All the measurements fell within the ±10% limits for the tidal volume (VT). The volume error was influenced by the mechanical condition (p = 5.9 × 10−15) and the PEEP level (P = 1.1 × 10−12) but the clinical significance of this finding is likely meaningless (maximum −34 mL in the error). The PEEP error was not influenced by the mechanical condition (p = 0.25). Our experimental results demonstrate that the eSpiro ventilator is reliable to deliver VT and PEEP accurately in various respiratory mechanics conditions. Conclusions: We report a low-cost, easy-to-build ventilator, which is reliable to deliver VT and PEEP in passive invasive mechanical ventilation

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial

International audienceBackground Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34–50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg −1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation.Methods The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO 2 /FiO 2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg −1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg −1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principlesDiscussion The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing.Trial registration ClinicalTrials.gov NCT04349618 . Registered on April 16, 202

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<p>Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients’ spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.</p

CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients’ spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal

Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the ICU: An Observational Study From the OUTCOMEREA Database, 1997–2018

International audienceObjectives: Our aim was to describe changes in the management of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) by ICUs and patient outcomes.Design: We extracted data from the OutcomeRea database concerning patients admitted for AECOPD between 1997 and 2018. We analyzed trends in the use of ventilatory support, corticosteroid therapy, antibiotic therapy, and patient survival.Setting: ICUs at 32 French sites.Patients: One thousand eight hundred sixteen patients in the database had a diagnosis of AECOPD.Interventions: None.Measurements and main results: Over time, there was a reduction in the prescription of corticosteroids and antibiotics. In a time-series analysis, these changes in practice were not linked with ICU mortality. The proportion of patients treated with invasive mechanical ventilation (IMV) also gradually declined (from 51% between 1997 and 2002 to 35% between 2013 and 2018) with an association between decrease in IMV use and reduction in ICU mortality in a time series analysis. Rates of noninvasive ventilation (NIV) failure decreased with an increase in NIV use to support weaning from IMV. There was a reduction in the median ICU length of stay (from 8 d in 1997-2002 to 4 d in 2013-2018) and in the median total duration of hospitalization (from 23 d in 1997-2002 to 14 d in 2013-2018). We observed an improvement in prognosis, with decreases in overall hospital mortality (from 24% between 1997 and 2002 to 15% between 2013 and 2018), ICU mortality (from 14% between 1997 and 2002 to 10% between 2013 and 2018), and 90-day mortality (from 41% between 1997 and 2002 to 22% between 2013 and 2018).Conclusions: The length of stay and mortality of patients with AECOPD admitted to ICUs has decreased over the last 20 years, with a wider use of NIV and a reduction in antibiotic and corticosteroid prescriptions