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

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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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

Early discontinuation of combination antibiotic therapy in severe community-acquired pneumonia: a retrospective cohort study

Abstract Background Severe community-acquired pneumonia (SCAP) is commonly treated with an empiric combination therapy, including a macrolide, or a quinolone and a β-lactam. However, the risk of Legionella pneumonia may lead to a prolonged combination therapy even after negative urinary antigen tests (UAT). Methods We conducted a retrospective cohort study in a French intensive care unit (ICU) over 6 years and included all the patients admitted with documented SCAP. All patients received an empirical combination therapy with a β-lactam plus a macrolide or quinolone, and a Legionella UAT was performed. Macrolide or quinolone were discontinued when the UAT was confirmed negative. We examined the clinical and epidemiological features of SCAP and analysed the independent factors associated with ICU mortality. Results Among the 856 patients with documented SCAP, 26 patients had atypical pneumonia: 18 Legionella pneumophila (LP) serogroup 1, 3 Mycoplasma pneumonia (MP), and 5 Chlamydia psittaci (CP). UAT diagnosed 16 (89%) Legionella pneumonia and PCR confirmed the diagnosis for the other atypical pneumonia. No atypical pneumonia was found by culture only. Type of pathogen was not associated with a higher ICU mortality in the multivariate analysis. Conclusion Legionella pneumophila UAT proved to be highly effective in detecting the majority of cases, with only a negligible percentage of patients being missed, but is not sufficient to diagnose atypical pneumonia, and culture did not provide any supplementary information. These results suggest that the discontinuation of macrolides or quinolones may be a safe option when Legionella UAT is negative in countries with a low incidence of Legionella pneumonia

At-Risk Drinking Is Independently Associated With Acute Kidney Injury in Critically Ill Patients

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