Dysfonctions lymphocytaires et perturbations immuno-métaboliques au cours des états infectieux sévères

Severe infectious states are characterized by the occurrence of immune perturbations responsible for an exacerbation of the susceptibility to secondary infections. The development of a standardized murine model of double sequential infections (a sepsis followed 5 days later by an acquired infection) allowed us to explore the T- cells disturbances showing an increase in apoptosis of these cells as well as a decrease in their capacity to proliferate in vitro. These dysfunctions were associated with the presence of an alteration of mitochondrial respiration. On the other hand, an increase in the concentration of regulatory T cells and MDSCs and a decrease in arginine concentration were observed. The correction of hypoargininemia by citrulline supplementation allowed the correction of all these perturbations as well as a decrease in the severity of secondary infections. In order to complete this experimental approach, we have initiated explorations in patients suffering from COVID-19, allowing us to observe, once again, the presence of lymphopenia correlated to the severity of the patients as well as T-cells dysfunctions associated with the occurrence of hypoargininemia and an increased risk of secondary infections. Finally, the presence of immunosuppressive cell populations was observed in severe patients. All these results underline the key role of arginine metabolism within the immunosuppressive mechanisms occurring during infectious states. The correction of hypoargininemia suggests new therapeutic perspectives to limit the consequences of immunosuppressive phenomena induced by sepsis.Les états infectieux sévères sont caractérisés par la survenue de perturbations immunitaires responsables d’une exacerbation de la susceptibilité aux infections secondaires. L’élaboration d’un modèle murin standardisé de double infections séquentielles (un sepsis suivi 5 jours après d’une infection acquise) nous a permis d’explorer les perturbations lymphocytaires T objectivant une majoration de l’apoptose de ces cellules ainsi qu’une diminution de leurs capacités à proliférer in vitro. Ces dysfonctions étaient associées à la présence d’une altération de la respiration mitochondriale. D’autre part, ont été observées une augmentation de la concentration de lymphocytes T régulateurs et de MDSC ainsi qu’une diminution de la concentration en arginine. La correction de l’hypoargininémie par supplémentation en citrulline a permis la correction de l’ensemble de ces perturbations ainsi qu’une diminution de la sévérité des infections acquises. Afin d’approfondir cette approche expérimentale, nous avons initié des analyses chez les patients atteints de COVID-19 permettant d’observer, là encore, la présence d’une lymphopénie corrélée à la sévérité ainsi que des dysfonctions lymphocytaires T associées à la survenue d’une hypoargininémie et à une majoration du risque d’infections secondaires. Enfin, a pu être objectivée la présence de populations cellulaires immunosuppressives préférentiellement chez les patients sévères. L’ensemble de ces résultats souligne le rôle clé du métabolisme de l’arginine au sein des mécanismes immunosupresseurs survenant au cours des états infectieux. La correction de l’hypoargininémie laisse entrevoir de nouvelles perspectives thérapeutiques afin de limiter les conséquences des phénomènes immunosuppresseurs induits par le sepsis

Lymphocyte dysfunctions and immuno-metabolic impairment during severe infectious states

Les états infectieux sévères sont caractérisés par la survenue de perturbations immunitaires responsables d’une exacerbation de la susceptibilité aux infections secondaires. L’élaboration d’un modèle murin standardisé de double infections séquentielles (un sepsis suivi 5 jours après d’une infection acquise) nous a permis d’explorer les perturbations lymphocytaires T objectivant une majoration de l’apoptose de ces cellules ainsi qu’une diminution de leurs capacités à proliférer in vitro. Ces dysfonctions étaient associées à la présence d’une altération de la respiration mitochondriale. D’autre part, ont été observées une augmentation de la concentration de lymphocytes T régulateurs et de MDSC ainsi qu’une diminution de la concentration en arginine. La correction de l’hypoargininémie par supplémentation en citrulline a permis la correction de l’ensemble de ces perturbations ainsi qu’une diminution de la sévérité des infections acquises. Afin d’approfondir cette approche expérimentale, nous avons initié des analyses chez les patients atteints de COVID-19 permettant d’observer, là encore, la présence d’une lymphopénie corrélée à la sévérité ainsi que des dysfonctions lymphocytaires T associées à la survenue d’une hypoargininémie et à une majoration du risque d’infections secondaires. Enfin, a pu être objectivée la présence de populations cellulaires immunosuppressives préférentiellement chez les patients sévères. L’ensemble de ces résultats souligne le rôle clé du métabolisme de l’arginine au sein des mécanismes immunosupresseurs survenant au cours des états infectieux. La correction de l’hypoargininémie laisse entrevoir de nouvelles perspectives thérapeutiques afin de limiter les conséquences des phénomènes immunosuppresseurs induits par le sepsis.Severe infectious states are characterized by the occurrence of immune perturbations responsible for an exacerbation of the susceptibility to secondary infections. The development of a standardized murine model of double sequential infections (a sepsis followed 5 days later by an acquired infection) allowed us to explore the T- cells disturbances showing an increase in apoptosis of these cells as well as a decrease in their capacity to proliferate in vitro. These dysfunctions were associated with the presence of an alteration of mitochondrial respiration. On the other hand, an increase in the concentration of regulatory T cells and MDSCs and a decrease in arginine concentration were observed. The correction of hypoargininemia by citrulline supplementation allowed the correction of all these perturbations as well as a decrease in the severity of secondary infections. In order to complete this experimental approach, we have initiated explorations in patients suffering from COVID-19, allowing us to observe, once again, the presence of lymphopenia correlated to the severity of the patients as well as T-cells dysfunctions associated with the occurrence of hypoargininemia and an increased risk of secondary infections. Finally, the presence of immunosuppressive cell populations was observed in severe patients. All these results underline the key role of arginine metabolism within the immunosuppressive mechanisms occurring during infectious states. The correction of hypoargininemia suggests new therapeutic perspectives to limit the consequences of immunosuppressive phenomena induced by sepsis

Organizing and Sharing Medical Knowledge Among Anesthesiology and Intensive care Residents: Evaluating Existing Practices and the Feasibility of Implementing a Dedicated Multiplatform Application

International audienceTreating patients with up-to-date medical knowledge is an ongoing goal for healthcare workers and implies efficient knowledge management at the point of care. Widely available mobile wireless technologies influence practices but a significant gap remains between technological possibilities and actual usage. The purpose of this study was to analyze residents’ baseline practices in managing medical knowledge and to evaluate the use and impact of an innovative multiplatform application dedicated to anesthesiology and intensive care residents. This study took place in Rennes Teaching Hospital and comprised two distinct surveys. First, in April 2018, all residents received a ten-items online survey focusing on managing medical knowledge. Then, through a second online survey constituted of ten items, we sought to assess the use of a new multiplatform cloud-based application named "DansMaBlouse", dedicated to sharing and indexing medical knowledge, in anesthesiology and intensive care residents. Among 148 residents that answered the evaluation survey, the most sought out pieces of information in clinical setting were a phone or fax number (74%), drugs’ characteristics (68%) and expert guidelines (57%). The main sources were senior staff (68%), medical databases (60%) and an Internet search engine (59%). Computers and smartphones were more frequently used than bound paper notebooks. After implementation of the multiplatform application DansMaBlouse, fifty-nine (82%) of the 72 residents that answered the evaluation survey reported using the application and 39% used it more than ten times. Among application users, 90% found it easy to use and 92% agreed that it improved point-of-care access to knowledge. Accessing appropriate medical knowledge at the point of care remains an issue for residents and can be improved by a multiplatform application combining personal and shared up-to-date resources

Assessing the entire landscape of antifungal immune response to COVID-19-associated pulmonary aspergillosis

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Selective digestive decontamination to reduce the high rate of ventilator-associated pneumonia in critical COVID-19

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Toward the personalized and integrative management of voriconazole dosing during COVID-19-associated pulmonary aspergillosis

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Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients

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Platelet-derived sCD40L: specific inflammatory marker for early-stage severe acute respiratory syndrome coronavirus 2 infection

International audienceBACKGROUND: The SARS-CoV-2 virus is the causing agent of the Coronavirus disease 2019 (COVID-19) characterized by a huge pro-inflammatory response and coagulation disorders that may lead to for its severe forms, in organ failure or even death. As major players of thrombo-inflammation, platelets release large amounts of immunomodulatory molecules and regulate leukocyte and endothelial activity, which are both altered in COVID-19. Altogether, this makes platelets a very likely actor of the thrombo-inflammatory complications of COVID-19. Thus, we propose to identify a platelet inflammatory signature of severe COVID-19 specifically modulated throughout the course of the disease. METHODS: Luminex technology and enzyme-linked immunosorbent assay were used to assess plasma levels of platelet inflammatory markers in patients with severe acute respiratory syndrome coronavirus 2 infection on admission and for 14 days afterwards. RESULTS: In accordance with the observations of other teams, we evidence that the plasma levels of the platelet soluble (s)CD40L is significantly elevated in the early stages of the disease. Interestingly we observe that the plasma level of sCD40L decreases overtime while that of sCD62P increases significantly. CONCLUSIONS: Our data suggest that there is a platelet signature of inflammatory response to SARS-COv-2 infection which varies overtime and could serve as monitoring biomarkers of patient inflammatory state. CLINICAL TRIAL REGISTRATION NUMBER: 2020-A01100-39; title: Human Ab Response and immunoMONItoring of COVID-19 Patients, registration date: 05/25/2020; URL of the registry: https://clinicaltrials.gov/ct2/history/NCT04373200?V_5=View

Herpesviridae systemic reactivations in COVID-19 associated ARDS patients

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1-hour t-piece spontaneous breathing trial vs 1-hour zero pressure support spontaneous breathing trial and reintubation at day 7: A non-inferiority approach

International audiencePurpose: Physiological data suggest that T-piece and zero pressure support (PS0) ventilation both accurately reflect spontaneous breathing conditions after extubation. These two types of spontaneous breathing trials (SBTs) are used in our Intensive Care Unit to evaluate patients for extubation readiness and success but have rarely been compared in clinical studies. Materials and methods: We performed a prospective observational study to confirm the hypothesis that 1-hour T-piece SBT and 1-h PS0 zero PEEP (ZEEP) SBT are associated with similar rates of reintubation at day 7 after extubation. A non-inferiority approach was used for sample size calculation. Results: The cohort consisted of 529 subjects invasively ventilated for more than 24 h and extubated after successful 1-hour T-piece SBT (n = 303, 57%) or 1-h PS0 ZEEP SBT (n = 226, 43%). The reintubation rate at day 7 was 14.6% with PS0 ZEEP and 17.5% with T-piece (difference - 2.6% [95% confidence interval, -8.3% to 4.3%]; p = 0.40). The reasons for reintubation did not differ significantly when compared between patients with 1-h PS0 ZEEP SBT and patients with 1-hour T-piece SBT. Conclusion: Our results suggest that successful 1-hour T-piece and 1-h PSO ZEEP SBTs are associated with similar reintubation rates at day 7. (c) 2021 Published by Elsevier Inc