Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study

International audienceBACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (Cblood)-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI Cblood within the therapeutic range. Other pharmacokinetic parameters, such as the intra-graft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intra-graft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intra-graft concentrations of CNI (CEMB). Cblood, and the concentration inside peripheral blood mononuclear cells (CPBMC), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the three matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. Cblood, CEMB and CPBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6 %) from 26 patients (76.5 %), all except one of low-grade. None of the PK parameters (Cblood, CEMB, CPBMC, CEMB/blood and CPBMC/blood) was associated with BPAR. CONCLUSION: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters including Cblood, with the occurrence of BPAR. However, a trend was noticed for the CEMB and CEMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of CEMB and CPBMC for CNI TDM in HTR

High-risk exposure without personal protective equipment and infection with SARS-CoV-2 in-hospital workers - The CoV-CONTACT cohort.

International audienc

High-risk exposure without personal protective equipment and infection with SARS-CoV-2 in-hospital workers - The CoV-CONTACT cohort

International audienc

High-risk exposure without personal protective equipment and infection with SARS-CoV-2 in-hospital workers - The CoV-CONTACT cohort

International audienc

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

International audienceMultisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of , , or in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

TLR7 and plasmacytoid dendritic cells are essential for type I IFN–dependent immunity to SARS-CoV-2 in the lungs.</jats:p

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Autoantibodies neutralizing type I IFNs increase in prevalence over 60 years of age and underlie about 20% of all fatal COVID-19 cases.</jats:p