Caractéristiques et impact pronostique des différents types d immunodépression chez les patients admis en réanimation pour sepsis sévère ou choc septique

Introduction : les données actuelles sur les patients avec une immunodépression préalable et une infection grave sont limitées. Cette étude a pour objectifs de décrire ces patients lorsqu ils sont admis en réanimation pour sepsis sévère ou choc septique, les comparer aux immunocompétents et évaluer l impact pronostique du type d immunodépression. Matériel et Méthodes : étude observationnelle à partir d une base de données prospective en incluant tous les patients admis pour sepsis sévère ou choc septique de Janvier 1997 à Août 2011 dans 11 services de réanimation. Les patients immunodéprimés ont été classés en 6 profils d immunodépression. L analyse pronostique a utilisé un modèle à risque compétitifs (Fine et Gray), la sortie vivant avant J28 étant en compétition avec le décès. Résultats : 1981 patients ont été inclus parmi lesquels 607 (31%) sont immunodéprimés (cancer solide 27%, hémopathie maligne 46%, SIDA 11%, greffe d organes 9%, pathologie inflammatoire 13%, déficit primitif ou congénital 1%). Le taux de décès à J28 est de 31.3% chez l immunodéprimé (vs 28.8%). Après ajustement sur les autres facteurs pronostiques, l immunodépression est un facteur de risque indépendant de décès à J28 (sHR à 1.37 [1.12-1.67]). Analysée en classes, seuls le SIDA (sHR=1.9), l oncologie solide (sHR=1.8) ou en hématologie (sHR=1.4) non agranulocytaire et l agranulocytose (sHR=1.7) sont indépendamment associés au pronostic. Conclusion : l immunodépression est fréquente chez les patients présentant un sepsis sévère ou choc septique. L analyse de survie montre que certains profils d immunodépression, outre l agranulocytose déjà décrite, sont associés à une augmentation du risque de décès.Introduction: current data on patients with pre-existing immunosuppression and severe infection are limited. This study aims to describe these patients when admitted to ICU for severe sepsis or septic shock, to compare them with immunocompetent and to evaluate the prognostic impact of the type of immunosuppression. Materials and Methods: we conducted an observational study using a prospective multicenter database. All patients admitted for severe sepsis or septic shock from January 1997 to August 2011 in 11 French ICUs were included. Immunocompromised patients were classified into six profiles of immunosuppression. Prognostic analysis used a competitive risk model (Fine and Gray), in which ICU or hospital discharge being alive before D28 competed with death. Results: 1981 patients were included among whom 607 (31%) were immunocompromised (27% solid cancer, 46% hematological malignancy, 11% AIDS, 9% solid organ transplantation, 13% inflammatory disease, 1% primary or congenital deficiency). The death rate at D28 is 31.3% in immunocompromised (vs. 28.8%). After adjustment on other prognostic factors, immunosuppression (all causes) is an independent risk factor for death at D28 (sHR 1.37 [1.12-1.67]). When we analyzed immunosuppression in classes, only AIDS (sHR = 1.9), solid cancer (sHR = 1.8) or hematology (sHR = 1.4) without agranulocytosis and agranulocytosis (sHR = 1.7) are independently associated with prognosis. Conclusion: immunosuppression is common in patients with severe sepsis or septic shock. Survival analysis shows that some profiles of immunosuppression, in addition to agranulocytosis already described, are associated with an increased risk of death.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

International audienceObjectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.Conclusion: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Background Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design Open-label, randomized, adaptive, controlled trial. Setting Multi-center trial with patients from France. Participants 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. Results Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration NCT04315948. Funding PHRC 2020, Dim OneHealth, REACTin

Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial

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Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial.

Dear Editor, We read with great interest the recent article by Kamboj et al., in which they described the risk of developing moderate to severe Coronavirus Disease 2019 (COVID-19) in patients with hematological malignancies receiving tixagevimab-cilgavimab (T-C) during a period in which the dominant circulating variants of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) were resistant to T-C.1 The authors highlight the ongoing need to urgently address the mAb treatment gap, particularly for immunocompromised patients. The unmet need is further highlighted by the DisCoVeRy Phase 3, adaptive, multicentre European, randomized, double-blind, superiority trial that evaluated the efficacy and safety of intravenous T-C in SARS-CoV-2 antigenic positive patients (i.e those with a high SARS-CoV-2 viral load) hospitalized with COVID-19 and followed-up to day 90. [...

Cluster of Coronavirus Disease 2019 (COVID-19) in the French Alps, February 2020

International audienceAbstract Background On 7 February 2020, French Health authorities were informed of a confirmed case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an Englishman infected in Singapore who had recently stayed in a chalet in the French Alps. We conducted an investigation to identify secondary cases and interrupt transmission. Methods We defined as a confirmed case a person linked to the chalet with a positive reverse-transcription polymerase chain reaction sample for SARS-CoV-2. Results The index case stayed 4 days in the chalet with 10 English tourists and a family of 5 French residents; SARS-CoV-2 was detected in 5 individuals in France, 6 in England (including the index case), and 1 in Spain (overall attack rate in the chalet: 75%). One pediatric case, with picornavirus and influenza A coinfection, visited 3 different schools while symptomatic. One case was asymptomatic, with similar viral load as that of a symptomatic case. Seven days after the first cases were diagnosed, 1 tertiary case was detected in a symptomatic patient with from the chalet a positive endotracheal aspirate; all previous and concurrent nasopharyngeal specimens were negative. Additionally, 172 contacts were monitored; all contacts tested for SARS-CoV-2 (N = 73) were negative. Conclusions The occurrence in this cluster of 1 asymptomatic case with similar viral load as a symptomatic patient suggests transmission potential of asymptomatic individuals. The fact that an infected child did not transmit the disease despite close interactions within schools suggests potential different transmission dynamics in children. Finally, the dissociation between upper and lower respiratory tract results underscores the need for close monitoring of the clinical evolution of suspected cases of coronavirus disease 2019

A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial

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Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial

International audienceBackground We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. Methods This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. Results Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). Conclusions Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses