Association Between Maintenance Immunosuppressive Regimens and COVID-19 Mortality in Kidney Transplant Recipients

Purpose: Kidney transplant recipients (KTR) are at increased risk of mortality from COVID-19. We conducted a cohort study among KTR from the French Solid Organ Transplant COVID-19 (SOT COVID) registry to investigate the association between maintenance immunosuppressive drugs and 60-day mortality in KTR with COVID-19. Method(s): Data from all KTR with COVID-19 included in SOT COVID 02/28/2020 and 12/30/2020 were retrieved. Among them, 116 were excluded because of missing data on immunosuppressive therapy. We evaluated associations between immunosuppressive drugs and death <=60 days of 1st symptoms using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. Benjamini-Hochberg correction was used for controlling false positive rate;40 multiple imputations were performed. Adjusted p-value <0.05 was considered statistically significant. Result(s): There were 1,451 KTR included. Median age was 58 years, 963 (66.4%) were men. Most frequent comorbidities were hypertension (n=1188, 81.9%), diabetes (501, 34.5%), cardiovascular disease (428, 29.5%). Median time since transplant was 71 months. Maintenance immunosuppression regimen included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), Mammalian Target of Rapamycin inhibitors (144, 9.9%) and belatacept (58, 4.0%). Among 1,451 KTR, 201 (13.9%) died <=60 days. Older age and baseline creatininemia were associated with mortality (OR: 1.09 [1.07-1.11];1.01 [1.005- 1.009], p<0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (OR: 0.48 [0.31;0.76], p=0.011). All other variables yielded non-significant adjusted p-values. Conclusion(s): Corticosteroid-free regimens were associated with a lower risk of death in KTR with COVID-19. While a short course of high-dose corticosteroids is beneficial in severely ill COVID-19 patients, prolonged maintenance corticosteroids expose to chronic immune disorders that may predispose KTR to severe forms of COVID-19.

Low T Cell Responsiveness in the Early Phase Of COVID-19 Associates with Progression to Severe Pneumonia in Kidney Transplant Recipients

Purpose: Kidney transplant (KT) recipients are more prone to developing lifethreatening forms of COVID-19 than the general population. Little is known about the immunological mechanisms underlying disease severity in these patients receiving T-cell targeting immunosuppressive drugs. We investigated the relationship between T cell responsiveness at the beginning of the infection and the risk to subsequently progress to respiratory failure. Method(s): We performed a multicentric prospective study in 45 KT recipients with a positive RT-PCR COVID-19 test and only mild symptoms at inclusion. Blood samples were collected at baseline directly in a cell culture system containing T cell stimuli. We assessed T cell responsiveness by computing the ratio between the levels of Th1, Th2, Th17 and Treg cytokines produced after polyclonal stimulation and the number of blood lymphocytes. We then used an unsupervised classification approach to stratify patients into low and high T cell responders and a penalized logistic regression to identify variables independently associated with progression to severe COVID-19. Result(s): Forty-five kidney transplant patients were included. Unsupervised clusterization identified 31 low and 14 high T cell responders. Patients who progressed to severe pneumonia were all low T cell responders (p=0.01). In multivariate analysis, we found that low T cell responsiveness at baseline was the main risk factor for subsequent progression to severe pneumonia. Conclusion(s): Low T cell reactivity in the early phase of COVID-19 is strongly associated with progression to severe pneumonia. This study provides new insights into the mechanisms underlying COVID-19 severity in organ transplant recipients and data of interest to clinicians managing immunosuppressive drugs in these patients.

L’immunosuppression et le défaut d’immunogénicité des vaccins à ARNm limitent la protection des patients transplantés vaccinés selon le schéma standard : plaidoyer pour une 3e dose

Introduction Les patients transplantés rénaux (TxR), à haut risque de développer une infection grave par le SARS-Cov2, bénéficient d’une priorité pour la vaccination. Cependant, comme les TxR reçoivent un traitement immunosuppresseur, ils sont connus pour présenter des réponses vaccinales défectueuses. Description Les TxR ayant des antécédents de COVID ne présentent pas de réinfection par le SARS-Cov2, indiquant qu’ils sont efficacement protégés par leur immunité, contrairement aux TxR ayant reçu 2 doses de vaccin à ARNm-1273 (Moderna Therapeutics). Méthodes Afin de comprendre pourquoi l’infection offre une protection plus robuste que le vaccin ARNm, nous avons comparé les réponses humorales et cellulaires anti-SARS-Cov2 chez les patients TxR après infection (n=22, TxR COVID) ou vaccination (n=29, TxR Vacc). Résultats Contrairement aux réponses lymphocytaires T CD8+, qui sont similaires, presque tous les TxR COVID (91 %) développent des IgG anti-RBD, contre seulement 41 % des TxR Vacc (p<0,001). Ce défaut de réponse humorale corrèle avec un nombre plus faible de lymphocytes Tfh1 et Tfh17 spécifiques de la spicule virale chez les TxR Vacc non-répondeurs. L’incapacité à générer un nombre suffisant de lymphocytes Tfh capables d’aider les cellules B semble lié aux doses plus élevées d’antimétabolites (MMF) chez ces patients. Cependant, les TxR COVID ont développé des taux satisfaisant d’IgG anti-RBD malgré des doses identiques aux TxR Vacc non-répondeurs, suggérant que le blocage induit par le MMF peut être surmonté si l’immunogénicité (virus>vaccin) est suffisante. Conformément à cette hypothèse, l’administration d’une troisième dose de vaccin induit une séroconversion en IgG anti-RBD chez 54 % des patients non-répondeurs après deux doses. Conclusion Ces données suggèrent qu’une meilleure protection vaccinale des TxR pourrait être obtenue en adaptant transitoirement l’immunosuppression et/ou en augmentant l’immunogénicité du vaccin par l’administration d’une troisième dose.

Complications neurologiques du COVID-19 chez les patients atteints de maladie renale.

Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets. Copyright © 2020

Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Resultats du Registre francais des transplantes renaux ayant developpe une infection a SARS-CoV-2.

Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets. Copyright © 2020

Prediction de la severite de la COVID-19 par les biomarqueurs du syndrome de relargage cytokinique au sein d'une population de transplantes renaux.

Declaration de liens d'interets: Pr. Caillard signale des frais personnels et le soutien non financier de Novartis, le soutien non financier de Sanofi et le soutien non financier d'Astellas, en dehors du travail soumis. Les autres auteurs declarent ne pas avoir de liens d'interets. Copyright © 2020