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1. Characteristics of the first immunocompromised patients to receive sipavibart as an early access treatment for COVID-19 pre-exposure prophylaxis in France

Author: Paul Loubet, Benjamin Gaborit, Mathilde Salpin, Hèlene Gardeney, Ilies Benotmane, and Thomas Systchenko
Subjects: COVID-19, prophylaxis, immunocompromised, Immunologic diseases. Allergy, RC581-607, Therapeutics. Pharmacology, RM1-950
Abstract: France was the first country to grant Sipavibart (AZD3152, an investigational long-acting monoclonal antibody) as a COVID-19 pre-exposure prophylaxis treatment in immunocompromised individuals in December 2023. The first patients to receive Sipavibart had different profiles, but they were all highly immunocompromised with frequently associated hypogammaglobulinemia and other chronic conditions. No adverse event was reported.
Published: 2024
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2. Comparative effectiveness of empirical antibiotic treatments in methicillin-susceptible Staphylococcus aureus infective endocarditis: A post hoc analysis of a prospective French cohort study

Author: Raphaël Lecomte, Colin Deschanvres, Alexis Bourreau, Louise Ruffier d'Epenoux, Paul Le Turnier, Benjamin Gaborit, Marie Chauveau, Magali Michel, Thierry Le Tourneau, Pascale Bémer, Stéphane Corvec, and David Boutoille
Subjects: Infective endocarditis, Staphylococcus aureus, Empiric treatment, Bacteraemia, Infectious and parasitic diseases, RC109-216
Abstract: Objectives: The empirical treatment of infective endocarditis is still debated. The aim of this study was to compare the impact of empirical treatment with antistaphylococcal penicillin (ASP) or cefazolin vs. other treatments in methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis. Methods: A post hoc analysis of a prospective cohort study of patients hospitalized in a French reference centre with MSSA endocarditis was conducted between 2013 and 2022. The primary outcome was the duration of bacteraemia under treatment. Results: Of the 208 patients included, 101 patients (48.6%) were classified in the reference group (ASP or cefazolin) and 107 (52.4%) in the non-reference group. Empirical treatment with ASP/cefazolin was associated with a shorter duration of bacteraemia compared to other treatments (3.6 d vs. 4.6 d, P = 0.01). This difference was not corrected by the addition of an aminoglycoside (3.6 d vs. 4.7 d, P < 0.01). In multivariate analysis, empirical treatment with ASP/cefazolin was associated with a duration of bacteraemia ≤72 h (P = 0.02), whereas endocarditis on native valves (P = 0.01), and intracardiac abscess were associated with longer duration of bacteraemia (P = 0.01). Conclusions: Empirical treatment of endocarditis with ASP or Cefazolin is more effective than other treatments in MSSA endocarditis, even when the other treatments are combined with aminoglycosides.
Published: 2024
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3. The Use and Effectiveness of Ceftazidime–Avibactam in Real-World Clinical Practice: EZTEAM Study

Author: Alex Soriano, Philippe Montravers, Matteo Bassetti, Galina Klyasova, George Daikos, Paurus Irani, Gregory Stone, Richard Chambers, Pascale Peeters, Mitesh Shah, Claire Hulin, Natalia Albuquerque, Efim Basin, Benjamin Gaborit, Irene Kourbeti, Francesco Menichetti, María Teresa Perez-Rodriguez, Mathias W. Pletz, Marisa Sanchez, Ivan Trompa, Anita Verma, Maria Lavinea N. de Figueiredo, and Claudie Charbonneau
Subjects: Bloodstream infection, Ceftazidime–avibactam, Europe, Intra-abdominal infection, K. pneumoniae, LATAM, Infectious and parasitic diseases, RC109-216
Abstract: Abstract Introduction Ceftazidime–avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime–avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime–avibactam in real-world clinical practice. Methods This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime–avibactam for an approved indication per country label since 01 January 2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime–avibactam for at least 72 h. Results Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72 h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K. pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime–avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K. pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K. pneumoniae) were resistant to ceftazidime–avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. Conclusion This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime–avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime–avibactam is one of the antibiotics to consider for treatment of MDR bacteria. Trial Registration ClinicalTrials.gov identifier, NCT03923426.
Published: 2023
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4. Corrigendum: XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants

Author: Bernard Vanhove, Stéphane Marot, Ray T. So, Benjamin Gaborit, Gwénaëlle Evanno, Isabelle Malet, Guillaume Lafrogne, Edwige Mevel, Carine Ciron, Pierre-Joseph Royer, Elsa Lheriteau, François Raffi, Roberto Bruzzone, Chris Ka Pun Mok, Odile Duvaux, Anne-Geneviève Marcelin, and Vincent Calvez
Subjects: COVID-19, polyclonal antibody (PAb), SARS-CoV-2, variants, neutralization, Immunologic diseases. Allergy, RC581-607
Published: 2023
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5. Potential Impact of Rapid Multiplex PCR on Antimicrobial Therapy Guidance for Ventilated Hospital-Acquired Pneumonia in Critically Ill Patients, A Prospective Observational Clinical and Economic Study

Author: Florian Guillotin, Cécile Poulain, Benjamin Gaborit, Marwan Bouras, Raphaël Cinotti, Karim Lakhal, Mickael Vourc’h, Bertrand Rozec, Karim Asehnoune, Marie-Anne Vibet, Valéry-Pierre Riche, Sophie-Anne Gibaud, Lise Crémet, and Antoine Roquilly
Subjects: pneumonia, biomolecular diagnosis, empiric treatment, intensive care unit, hospital-acquired pneumonia, Microbiology, QR1-502
Abstract: ObjectivesTo investigate the potential impact of the syndromic multiplex FilmArray® Pneumonia plus Panel (FAPP) on the antimicrobial treatment guidance of patients with ventilated hospital-acquired pneumonia (VHAP).MethodsRespiratory fluids from 100 adult patients with VHAP, receiving invasive mechanical ventilation in three intensive care units from one French university hospital, were tested prospectively using FAPP. Conventional cultures were performed in parallel as routine practice. Clinicians were left blinded to the FAPP results. Antimicrobial therapies based on FAPP results were simulated by independent blinded experts according to a predefined algorithm and compared to 1) those prescribed in practice according to local guidelines (real-life), and 2) those that complied with the international ERS/ESICM/ESCMID/ALAT recommendations. The primary endpoint was the number of days of broad-spectrum antimicrobial therapy. Secondary endpoints were the rates of microbiological treatment failure and cost-effectiveness ratio.ResultsThe predicted median duration of broad-spectrum antibiotics was 0 [0-1.25] day in the FAPP-based simulation, versus 2 [0-6] days in real-life (p
Published: 2022
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6. Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial

Author: Benjamin Gaborit, Bernard Vanhove, Marie-Anne Vibet, Aurélie Le Thuaut, Karine Lacombe, Vincent Dubee, Florence Ader, Virginie Ferre, Eric Vicaut, Jéremie Orain, Morgane Le Bras, Anne Omnes, Laetitia Berly, Alexandra Jobert, Pascale Morineau-Le Houssine, Karine Botturi, Régis Josien, Laurent Flet, Nicolas Degauque, Sophie Brouard, Odile Duvaux, Alexandra Poinas, François Raffi, and POLYCOR study group
Subjects: COVID-19, Anti-SARS-CoV-2 antibodies, Moderate pneumonia, Immunotherapy, Randomized controlled trial, Phase 2, Medicine (General), R5-920
Abstract: Abstract Background Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2. Methods Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population. Discussion This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis. Trial registration ClinicalTrials.gov NCT04453384 , registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.
Published: 2021
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7. Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

Author: Mohamed Hamidou, Antoine Néel, Joel Poupon, Zahir Amoura, Mikael Ebbo, Jean Sibilia, Jean-Francois Viallard, Benjamin Gaborit, Christelle Volteau, Jean Benoit Hardouin, Eric Hachulla, and François Rieger
Subjects: Systemic lupus erythematosus, Autoimmune diseases, Treatment, Arsenic trioxide, Phase II clinical trial, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Background Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. Methods This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). Results Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P
Published: 2021
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8. XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Author: Bernard Vanhove, Stéphane Marot, Ray T. So, Benjamin Gaborit, Gwénaëlle Evanno, Isabelle Malet, Guillaume Lafrogne, Edwige Mevel, Carine Ciron, Pierre-Joseph Royer, Elsa Lheriteau, François Raffi, Roberto Bruzzone, Chris Ka Pun Mok, Odile Duvaux, Anne-Geneviève Marcelin, and Vincent Calvez
Subjects: COVID-19, polyclonal antibody (PAb), SARS-CoV-2, variants, neutralization, Immunologic diseases. Allergy, RC581-607
Abstract: Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.
Published: 2021
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9. Contribution of lung ultrasound in diagnosis of community-acquired pneumonia in the emergency department: a prospective multicentre study

Author: François Javaudin, Emmanuel Montassier, Philippe Le Conte, Nicolas Marjanovic, Hugo de Carvalho, Benjamin Gaborit, Quentin Le Bastard, Estelle Boucher, and Denis Haroche
Subjects: Medicine
Published: 2021
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10. Ludwig’s angina: A diagnostic and surgical priority

Author: Maxime Vallée, Benjamin Gaborit, Jérémy Meyer, Olivier Malard, David Boutoille, François Raffi, Florent Espitalier, and Nathalie Asseray
Subjects: Infectious and parasitic diseases, RC109-216
Abstract: Ludwig’s angina has been known for two centuries as a rapidly and frequently fatal progressive gangrenous cellulitis or necrotizing fasciitis of the neck and the floor of the mouth. The management of the usually young patients affected requires a trained team combining medical skills in surgery, antibiotic therapy, and resuscitation. The prognosis is directly related to early surgical debridement and the experience of the team managing these patients. We present four cases of severe necrotizing cervical cellulitis notably associated with concomitant self-medication with non-steroidal anti-inflammatory drugs. Through these cases, we conclude that several surgical steps could be required, combined with broad-spectrum antibiotic therapy. An optimal surgery, draining all collections and excising all necrotic tissues, seems to be a condition needed for antibiotic efficacy and finally healing. Keywords: Ludwig Angina, Necrotizing fasciitis, NSAIDs, Medico-surgical cooperation
Published: 2020
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11. Influenza and associated co-infections in critically ill immunosuppressed patients

Author: Ignacio Martin-Loeches, Virginie Lemiale, Pierce Geoghegan, Mary Aisling McMahon, Peter Pickkers, Marcio Soares, Anders Perner, Tine Sylvest Meyhoff, Ramin Brandt Bukan, Jordi Rello, Philippe R. Bauer, Andry van de Louw, Fabio Silvio Taccone, Jorge Salluh, Pleun Hemelaar, Peter Schellongowski, Katerina Rusinova, Nicolas Terzi, Sangeeta Mehta, Massimo Antonelli, Achille Kouatchet, Pål Klepstad, Miia Valkonen, Precious Pearl Landburg, Andreas Barratt-Due, Fabrice Bruneel, Frédéric Pène, Victoria Metaxa, Anne Sophie Moreau, Virginie Souppart, Gaston Burghi, Christophe Girault, Ulysses V. A. Silva, Luca Montini, Francois Barbier, Lene B. Nielsen, Benjamin Gaborit, Djamel Mokart, Sylvie Chevret, Elie Azoulay, and For the Efraim investigators and the Nine-I study group
Subjects: Influenza, Respiratory failure, Sepsis, Critical illness, Immunosuppression, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P
Published: 2019
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12. Evaluation of the FilmArray® Pneumonia Plus Panel for Rapid Diagnosis of Hospital-Acquired Pneumonia in Intensive Care Unit Patients

Author: Lise Crémet, Benjamin Gaborit, Marwan Bouras, Thomas Drumel, Florian Guillotin, Cécile Poulain, Elise Persyn, Karim Lakhal, Bertrand Rozec, Marie-Anne Vibet, Antoine Roquilly, and Sophie Gibaud
Subjects: multiplex syndromic testing, hospital-acquired pneumonia, rapid diagnosis, coinfection, antibiotic resistance, Microbiology, QR1-502
Abstract: The FilmArray® Pneumonia plus Panel (FAPP) is a new multiplex molecular test for hospital-acquired pneumonia (HAP), which can rapidly detect 18 bacteria, 9 viruses, and 7 resistance genes. We aimed to compare the diagnosis performance of FAPP with conventional testing in 100 intensive care unit (ICU) patients who required mechanical ventilation, with clinically suspected HAP. A total of 237 samples [76 bronchoalveolar lavages (BALDS) and 82 endotracheal aspirates (ETADS) obtained at HAP diagnosis, and 79 ETA obtained during follow-up (ETATT)], were analyzed independently by routine microbiology testing and FAPP. 58 patients had paired BALDS and ETADS. The positivity thresholds of semi-quantified bacteria were 103–104 CFUs/mL or 104 copies/mL for BAL, and 105 CFUs/mL or copies/mL for ETA. Respiratory commensals (H. influenzae, S. aureus, E. coli, S. pneumoniae) were the most common pathogens. Discordant results for bacterial identification were observed in 33/76 (43.4%) BALDS and 36/82 (43.9%) ETADS, and in most cases, FAPP identified one supplemental bacteria (23/33 BALDS and 21/36 ETADS). An absence of growth, or polybacterial cultures, explained almost equally the majority of the non-detections in culture. No linear relationship was observed between bin and CFUs/mL variables. Concordant results between paired BALDS and ETADS were obtained in 46/58 (79.3%) patients with FAPP. One of the 17 resistance genes detected with FAPP (mecA/C and MREJ) was not confirmed by conventional testing. Overall, FAPP enhanced the positivity rate of diagnostic testing, with increased recognition of coinfections. Implementing this strategy may allow clinicians to make more timely and informed decisions.
Published: 2020
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13. Treatment of UTIs Due to Klebsiella pneumoniae Carbapenemase-Producers: How to Use New Antibiotic Drugs? A Narrative Review

Author: Caroline Chapelle, Benjamin Gaborit, Raphaëlle Dumont, Aurélien Dinh, and Maxime Vallée
Subjects: UTI, KPC, cefiderocol, meropenem-vaborbactam, ceftazidim-avibactam, imipenem-relebactam, Therapeutics. Pharmacology, RM1-950
Abstract: Background: K. pneumoniae is one of the bacteria most frequently causing health care-associated urinary tract infections, and increasingly incriminating Klebsiella pneumoniae carbapenemase producers (KPCp). Most infections caused by KPCp are nosocomial and might cause serious issues, even leading to death in half of the reported cases. Our aim was to identify the best strategy, based on available scientific data, for the use of new antibiotic treatments to manage KPCp UTIs. Methods: this narrative review of the literature was performed according to the criteria of preferred reporting items for systematic review and meta-analyses statement (PRISMA) (2020). Results and Conclusions: KPCp-UTIs are a real challenge for physicians. While cefiderocol, meropenem-vaborbactam, ceftazidim-avibactam, and imipenem-relebactam represent a major step forward in the treatment of these UTIs, no guidelines are currently available, in view of choosing the most appropriate treatment, in each specific case.
Published: 2021
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14. Treatment of Bone and Joint Tuberculosis in France: A Multicentre Retrospective Study

Author: Aurélie Guillouzouic, Claire Andrejak, Olivia Peuchant, Geneviève Hery-Arnaud, Farida Hamdad, Philippe Lanotte, Benjamin Gaborit, Louis Bernard, and Pascale Bémer
Subjects: spinal tuberculosis, extraspinal tuberculosis, bone and joint tuberculosis, diagnosis, treatment duration, Medicine
Abstract: Background: Nine percent of all cases of tuberculosis are bone and joint tuberculosis (BJTB). BJTB occurs in two main forms: spinal (STB) and extraspinal (ESTB). The aim of this study was to compare STB with ESTB in terms of diagnosis, treatment and outcomes. Methods: We collected demographic, clinical, microbiological, treatment duration and outcome data for patients with BJTB in a retrospective multicentre study over a 17-year period. Results: Of the 116 patients included in the study, 69 (59.5%) had STB and 47 (40.5%) had ESTB. The median age was higher in the ESTB group. There were significantly more foreign-born patients in the STB group. The median time for diagnosis was longer for ESTB (6 months) than STB (4 months) (p = 0.017). Magnetic resonance imaging was highly reliable for the diagnosis. Direct examination and histology allowed the diagnosis to be made in more than 80% of cases. The median treatment duration of 12 months, regardless of the type of BJTB, was longer than recommended. A favourable outcome was achieved in 91.9% of cases. Conclusion: The management of BJTB remains challenging. An earlier diagnosis should be more effective, reducing the total duration of treatment and leading to better tolerance.
Published: 2020
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15. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Claire Fougerou, Minh-Patrick Lê, Gilles Peytavin, Noémie Mercier, Priyanka Velou, Sarah Tubiana, Xavier Lescure, Emmanuel Faure, Saad Nseir, Jean-Christophe Richard, Florent Wallet, François Goehringer, Benjamin Lefèvre, Antoine Kimmoun, François Raffi, Benjamin Gaborit, Jean Reignier, Jean-Philippe Lanoix, Claire Andrejak, Yoann Zerbib, Firouzé Bani-Sadr, Bruno Mourvilliers, François Danion, Yvon Ruch, Raphaël Clere-Jehl, Vincent Le Moing, Kada Klouche, Karine Lacombe, Guillaume Martin-Blondel, Fanny Vardon-Bounes, André Cabié, Jean-Marie Turmel, Lionel Piroth, Mathieu Blot, Élisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Guillaume Thiery, François Bénézit, Rostane Gaci, Joy Mootien, Sébastien Gallien, Denis Garot, Kevin Bouiller, Loïc Epelboin, Stéphane Jauréguiberry, Alexandre Gaymard, Gil Verschelden, Sandra Braz, Joao Miguel Ferreira Ribeiro, Michael Joannidis, Thérèse Staub, Antoine Altdorfer, Richard Greil, Alexander Egle, Jérémie Guedj, Marion Noret, Roberto Roncon-Albuquerque, Jose-Artur Paiva, Bruno Lina, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Hospices Civils de Lyon (HCL), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: [SDV]Life Sciences [q-bio]
Abstract: BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.FundingEuropean Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.
Published: 2023

16. Characteristics, management, and outcomes of patients with infectious encephalitis requiring intensive care: A prospective multicentre observational study

Author: Pierre Fillatre, Alexandra Mailles, Jean Paul Stahl, Pierre Tattevin, Sophie Abgrall, Laurent Argaud, Xavier Argemi, Guillaume Baille, Aurélie Baldolli, Sarah Benghanem, Kevin Bertrand, Julien Biberon, Charlotte Biron, Geneviève Blanchet Fourcade, Mathieu Blot, Elisabeth Bothelo-Nevers, Frédéric Bourdain, David Boutoille, Hélène Brasme, Cédric Bruel, Fabrice Bruneel, Rodolphe Buzele, Emmanuel Canet, Etienne Canoui, Philippe Casenave, Bernard Castan, Charles Cazanave, Céline Cazorla, Pascal Chavanet, Catherine Chirouze, Tomasz Chroboczek, Johan Courjon, Daniel Da Silva, Thomas De Broucker, Arnaud De La Blanchardiere, Etienne De Montmollin, Eric Denes, Colin Deschanvres, Aurélien Dinh, Olivier Epaulard, Emmanuel Forestier, Thibaut Fraisse, Benjamin Gaborit, Amandine Gagneux-Brunon, Nicolas Gaillard, Arnaud Galbois, Mathieu Godement, François Goehringer, Pascale Goubin, Simon Gravier, Valentin Greigert, Isabelle Gueit, Thomas Guimard, Carole Henry, Maxime Hentzien, Pierre Jaquet, Fanny Jomier, Snejana Jurici, Solen Kerneis, Morgane Le Bras, Marion Le Marechal, Gwenael Le Moal, Paul Le Turnier, Anne-Sophie Lecompte, Raphael Lecomte, Stéphanie Lejeune, François-Xavier Lescure, Olivier Lesieur, Philippe Lesprit, Guillaume Louis, Rafael Mahieu, Alain Makinson, Guillaume Marc, Alexandre Maria, Nathalie Marin, Guillaume Martin-Blondel, Martin Martinot, Alexandre Mas, Philippe Mateu, Morgan Matt, Laurence Maulin, Frédéric Mechai, Eugénie Mutez, Jérémie Orain, Anne Pachart, Nathalie Pansu, Solene Patrat-Delon, Patricia Pavese, Hélène Pelerin, Véronique Pelonde-Erimée, Isabelle Pierre, Emilie Piet, Diane Ponscarme, Dimitri Psimaras, Mathilde Puges, Jean Reignier, Mathilde Reveillon Istin, Sylvain Rheims, Aurélie Richard-Mornas, Vincent Roubeau, Yvon Ruch, Isabelle Runge, Hélène Savini, Romain Sonneville, Jean-Marie Turmel, Louise Tyvaert, Marc-Olivier Vareil, Magali Vidal-Roux, Virginie Vitrat, Adrien Wang, Heidi Wille, Mathieu Zuber, Laurent Almoyna-Martinez, Jean-Louis Herrmann, Jérome Honnorat, Patrice Morand, France Roblot, Jean-Paul Stahl, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre Hospitalier Universitaire [Grenoble] (CHU), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and This work was supported by the French Infectious Diseases Society (Société de pathologie infectieuse de langue française, SPILF).
Subjects: Frailty, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV]Life Sciences [q-bio], Encephalitis, Intensive care unit, Functional outcome, Herpes simplex virus, Critical Care and Intensive Care Medicine
Abstract: International audience; PURPOSE: Infectious encephalitis (IE) is a severe disease which requires intensive care unit (ICU) admission in up to 50% of cases. We aimed to describe characteristics, management and outcomes of IE patients who required ICU admission. MATERIALS AND METHODS: Ancillary study focusing on patients with ICU admission within the ENCEIF cohort, a French prospective observational multicentre study. The primary criteria for outcome was the functional status at hospital discharge, categorized using the Glasgow outcome scale (GOS). Logistic regression model was used to identify risk factors for poor outcome, defined as a GOS ≤ 3. RESULTS: We enrolled 198 ICU patients with IE. HSV was the primary cause (n = 72, 36% of all IE, 53% of IE with microbiological documentation). Fifty-two patients (26%) had poor outcome at hospital discharge, including 22 deaths (11%). Immunodeficiency, supratentorial focal signs on admission, lower cerebrospinal fluid (CSF) white cells count (2 days were independent predictors of poor outcome. CONCLUSION: HSV is the primary cause of IE requiring ICU admission. IE patients admitted in ICU have a poor prognosis with 11% of in-hospital mortality and 15% of severe disabilities in survivors at discharge.
Published: 2023

17. Safety and risk of febrile recurrence after early antibiotic discontinuation in high-risk neutropenic patients with haematological malignancies: a multicentre observational study

Author: Raphael Paret, Amandine Le Bourgeois, Gaëlle Guillerm, Benoit Tessoulin, Schéhérazade Rezig, Thomas Gastinne, Marie Anne Couturier, David Boutoille, Raphael Lecomte, Florence Ader, Steven Le Gouill, Séverine Ansart, Jean Philippe Talarmin, and Benjamin Gaborit
Subjects: Pharmacology, Microbiology (medical), Leukemia, Myeloid, Acute, Neutropenia, Infectious Diseases, Hematologic Neoplasms, Neoplasms, Humans, Bacteremia, Pharmacology (medical), Prospective Studies, Fever of Unknown Origin, Anti-Bacterial Agents
Abstract: Background Early antibiotic discontinuation according to the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations is not systematically applied in high-risk neutropenic patients with haematological malignancies. Methods A retrospective multicentre observational study was conducted over 2 years to evaluate the safety of early antibiotic discontinuation for fever of unknown origin (FUO) during neutropenia after induction chemotherapy or HSCT, in comparison with a historical cohort. We used Cox proportional hazards models, censored on neutropenia resolution, to analyse factors associated with febrile recurrence. Results Among 147 included patients in the ECIL-4 cohort, mainly diagnosed with acute leukaemia (n = 104, 71%), antibiotics were discontinued during 170 post-chemotherapy neutropenic episodes. In comparison with the historical cohort of 178 episodes of neutropenia without antibiotic discontinuation, no significant differences were observed regarding febrile recurrences [71.2% (121/170) versus 71.3% (127/178), P = 0.97], admission in ICUs [6.5% (11/170) versus 11.2% (20/178), P = 0.17], septic shock [0.6% (1/170) versus 3.9% (7/178), P = 0.07] and 30 day mortality [1.4% (2/147) versus 2.7% (4/150), P = 0.084]. In the ECIL-4 cohort, the rate of bacteraemia in case of febrile recurrence was higher [27.1% (46/170) versus 11.8% (21/178), P Conclusions After an FUO episode in high-risk neutropenia, compliance with ECIL-4 recommendations for early antibiotic discontinuation appears to be safe and mucosal damage was associated with febrile recurrence and bacteraemia. Prospective interventional studies are warranted to assess this strategy in high-risk neutropenic patients.
Published: 2022

18. Pre-existing comorbidities shape the immune response associated with severe COVID-19

Author: Stefanie Kreutmair, Manuel Kauffmann, Susanne Unger, Florian Ingelfinger, Nicolás Gonzalo Núñez, Chiara Alberti, Donatella De Feo, Sinduya Krishnarajah, Ekaterina Friebel, Can Ulutekin, Sepideh Babaei, Benjamin Gaborit, Mirjam Lutz, Nicole Puertas Jurado, Nisar P. Malek, Siri Göpel, Peter Rosenberger, Helene A. Häberle, Ikram Ayoub, Sally Al-Hajj, Manfred Claassen, Roland Liblau, Guillaume Martin-Blondel, Michael Bitzer, Antoine Roquilly, and Burkhard Becher
Subjects: Metabolic Syndrome, SARS-CoV-2, Immunology, Immunity, Immunology and Allergy, COVID-19, Humans, Comorbidity, Renal Insufficiency, Chronic
Abstract: Comorbidities are risk factors for development of severe coronavirus disease 2019 (COVID-19). However, the extent to which an underlying comorbidity influences the immune response to severe acute respiratory syndrome coronavirus 2 remains unknown.Our aim was to investigate the complex interrelations of comorbidities, the immune response, and patient outcome in COVID-19.We used high-throughput, high-dimensional, single-cell mapping of peripheral blood leukocytes and algorithm-guided analysis.We discovered characteristic immune signatures associated not only with severe COVID-19 but also with the underlying medical condition. Different factors of the metabolic syndrome (obesity, hypertension, and diabetes) affected distinct immune populations, thereby additively increasing the immunodysregulatory effect when present in a single patient. Patients with disorders affecting the lung or heart, together with factors of metabolic syndrome, were clustered together, whereas immune disorder and chronic kidney disease displayed a distinct immune profile in COVID-19. In particular, severe acute respiratory syndrome coronavirus 2-infected patients with preexisting chronic kidney disease were characterized by the highest number of altered immune signatures of both lymphoid and myeloid immune branches. This overall major immune dysregulation could be the underlying mechanism for the estimated odds ratio of 16.3 for development of severe COVID-19 in this burdened cohort.The combinatorial systematic analysis of the immune signatures, comorbidities, and outcomes of patients with COVID-19 has provided the mechanistic immunologic underpinnings of comorbidity-driven patient risk and uncovered comorbidity-driven immune signatures.
Published: 2022
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19. Nocardiosis in graft recipients of kidneys from extended‐criteria donors following switch to belatacept complicated by acute rejection

Author: Simon Ville, Christophe Masset, Lescornet Tanguy, Benjamin Gaborit, Jeremy Meyer, and Claire Garandeau
Subjects: Graft Rejection, Transplantation, medicine.medical_specialty, business.industry, Graft Survival, Nocardiosis, Nocardia Infections, Kidney, Extended criteria, medicine.disease, Belatacept, Tissue Donors, Transplant Recipients, Surgery, Abatacept, Humans, Medicine, business, Immunosuppressive Agents, medicine.drug
Published: 2020

20. Complete post-mortem data in a fatal case of COVID-19: clinical, radiological and pathological correlations

Author: Renaud Clement, Mathilde Ducloyer, Pierre Paul Arrigoni, Louise Castain, Raphaël Lecomte, Claire Toquet, Benjamin Gaborit, Christine Sagan, and Antonin Bal
Subjects: Male, Pathology, medicine.medical_specialty, Pleural effusion, Post-mortem, Pneumonia, Viral, SARS-CoV-2 coronavirus, Autopsy, Case Report, medicine.disease_cause, Pathology and Forensic Medicine, Betacoronavirus, Fibrosis, medicine, Humans, Respiratory system, Diffuse alveolar damage, Pathological, Lung, Pandemics, Coronavirus, Aged, Fibrin, Hyperplasia, business.industry, SARS-CoV-2, COVID-19, medicine.disease, Post-mortem computed tomography, Pleural Effusion, Pulmonary Alveoli, medicine.anatomical_structure, Alveolar Epithelial Cells, business, Coronavirus Infections, Tomography, X-Ray Computed
Abstract: A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse crazy-paving lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.
Published: 2020

21. Switch from parenteral to oral antibiotics for brain abscesses: a retrospective cohort study of 109 patients

Author: Antoine, Asquier-Khati, Colin, Deschanvres, David, Boutoille, Maeva, Lefebvre, Paul, Le Turnier, Benjamin, Gaborit, Karim, Lakhal, Kevin, Buffenoir, Lydie, Khatchatourian, Nathalie, Asseray, and Chan, Ngohou
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Brain Abscess, Logistic regression, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Internal medicine, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, Brain abscess, Retrospective Studies, Pharmacology, business.industry, Glasgow Outcome Scale, Glasgow Coma Scale, Retrospective cohort study, Prognosis, medicine.disease, Comorbidity, Anti-Bacterial Agents, Regimen, Treatment Outcome, Infectious Diseases, Quality of Life, business
Abstract: Objectives Brain abscess is one of the most serious diseases of the CNS and is associated with high morbidity and mortality. With regard to the lack of data supporting an optimal therapeutic strategy, this study aimed to explore the prognostic factors of brain abscess, putting emphasis on the impact of therapeutic decisions. Methods We retrospectively included patients hospitalized for brain abscess during a period of 13 years. Comorbidities (Charlson scale), clinical presentation, microbiology culture, radiological features and therapeutic management were collected. Glasgow Outcome Scale (GOS) at 3 months and length of hospital stay were, respectively, the main and the secondary outcomes. Logistic regression was used to determine factors associated with outcome independently. Results Initial Glasgow Coma Scale (GCS) ≤14 and comorbidities (Charlson scale ≥2) were associated with poor neurological outcome while oral antibiotic switch was associated with better neurological outcome. Oral switch did not appear to be associated with an unfavourable evolution in the subset of patients without initial neurological severity (GCS >14) on admission. Duration of IV regimen and time to oral switch were associated with the length of inpatient stay. Conclusions This study confirms the role of GCS and comorbidities as prognostic factors and presents reassuring data regarding the safety of oral switch for the antibiotic treatment of brain abscesses. Oral switch could prevent catheter-induced iatrogenic complications and allow a higher quality of life for patients.
Published: 2020

22. Development and validation of a dosing nomogram for amoxicillin in infective endocarditis

Author: David Boutoille, Guillaume Deslandes, Anne-Gaëlle Leroy, Antoine Rambaud, Nathalie Asseray-Madani, Colin Deschanvres, Raphaël Lecomte, Paul Le Turnier, Eric Dailly, Matthieu Grégoire, Benjamin Gaborit, Pascale Jolliet, and Ronan Bellouard
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Urology, 03 medical and health sciences, 0302 clinical medicine, Elimination rate constant, Pharmacokinetics, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, education, Retrospective Studies, Pharmacology, Body surface area, education.field_of_study, Endocarditis, business.industry, Amoxicillin, Nomogram, Anti-Bacterial Agents, Nomograms, Infectious Diseases, Pharmacodynamics, business, medicine.drug
Abstract: BackgroundAmoxicillin is the first-line treatment for streptococcal or enterococcal infective endocarditis (IE) with a dose regimen adapted to weight.ObjectivesCovariates influencing pharmacokinetics (PK) of amoxicillin were identified in order to develop a dosing nomogram based on identified covariates for individual adaptation.Patients and methodsPatients treated with amoxicillin administered by continuous infusion for IE were included retrospectively. The population PK analysis was performed using the Pmetrics package for R (NPAG algorithm). Influence of weight, ideal weight, height, BMI, body surface area, glomerular filtration rate adapted to the body surface area and calculated by the CKD-EPI method (mL/min), additional ceftriaxone treatment and serum protein level on amoxicillin PK was tested. A nomogram was then developed to determine the daily dose needed to achieve a steady-state free plasma concentration above 4× MIC, 100% of the time, without exceeding a total plasma concentration of 80 mg/L.ResultsA total of 160 patients were included. Population PK analysis was performed on 540 amoxicillin plasma concentrations. A two-compartment model best described amoxicillin PK and the glomerular filtration rate covariate significantly improved the model when included in the calculation of the elimination constant Ke.ConclusionsThis work allowed the development of a dosing nomogram that can help to increase achievement of the PK/pharmacodynamic targets in IE treated with amoxicillin.
Published: 2020

23. A murine model of <scp> Staphylococcus aureus </scp> infected chronic diabetic wound: A new tool to develop alternative therapeutics

Author: Jean-François Huon, Benjamin Gaborit, Jocelyne Caillon, David Boutoille, and Dominique Navas
Subjects: Staphylococcus aureus, Time Factors, Spleen, Dermatology, medicine.disease_cause, Diabetes Complications, Mice, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Immune system, Diabetes mellitus, Skin Ulcer, medicine, Animals, Wound Healing, integumentary system, business.industry, Staphylococcal Infections, medicine.disease, Streptozotocin, Disease Models, Animal, Chronic infection, medicine.anatomical_structure, Bacteremia, Chronic Disease, Immunology, Wound Infection, Female, Surgery, Wound healing, business, medicine.drug
Abstract: Diabetic wound infection is a frequent complication that may result in limb amputation. To develop new treatment strategies in response to increasing bacterial resistance, animal models are needed. We created a diabetic mouse model with chronically infected wounds. Diabetes was induced using streptozotocin, and wounds were performed using a biopsy punch, and then infected with a clinical strain of Staphylococcus aureus. Chronification was reached by delaying healing thanks to chemical products (aminotriazole and mercaptosuccinic acid). Overall survival, as well as clinical, bacteriological and immunological data in skin, blood and spleens were collected at days 1, 7, and 14 after wounding. After a transient bacteremia proved by bacteria presence in spleen and kidneys in the first days after wounding, infected mice showed a chronic infection, with a bioburden impairing the healing process, and bacteria persistence compared to control mice. Infected mice showed gradual increasing skin levels of IL-17A compared to control mice that resulted in an IL-17/IFN-γ inbalance, pointing out a localized Th17 polarization of the immune response. Whether infected or not, the skin level of IL-10 decreased dramatically at days 1 and 7 after wounding, with an increase observed only in the control mice at day 14. After a decrease at day 1 in both groups, spleen IL-10 showed a rather steady level at days 7 and 14 in the control group compared with the decrease observed in the infected group. The spleen IL-10/IFN-γ ratio showed a systemic inflammatory response with Th1 polarization. Therefore, this model provides useful data to study wound healing. It is easy to reproduce, affordable and offers clinical and biological tools to evaluate new therapeutics.
Published: 2020

24. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, France Mentré, Charles Burdet, Jérôme Aboab, Hafid Ait-Oufella, Antoine Altdorfer, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, Drifa Belhadi, Leila Belkhir, François Benezit, Marc Berna, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Sandra Braz, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Dominique Costagliola, Sandrine Couffin-Cadièrgues, Johan Courjon, Flora Crockett, François Danion, Aline Dechanet, Agathe Delbove, Jean Dellamonica, Christelle Delmas, Alpha Diallo, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Alexander Egle, Olivier Epaulard, Loïc Epelboin, Hélène Esperou, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Joao-Miguel Ferreira Ribeiro, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Claire Fougerou, Vincent Fraipont, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Alexandre Gaymard, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Richard Greil, Didier Gruson, Jérémie Guedj, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Michael Joannidis, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Bernd Lamprecht, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Minh-Patrick Lê, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Bruno Lina, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Noémie Mercier, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Bruno Mourvilliers, Marlène Murris-Espin, Jean-Christophe Navellou, Marion Noret, Saad Nseir, Walid Oulehri, José-Artur Paiva, Thomas Perpoint, Gilles Peytavin, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Julien Poissy, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Jean Reuter, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Roberto Roncon-Albuquerque, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Juliette Saillard, Naomi Sayre, Eric Senneville, Albert Sotto, Thérèse Staub, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Sarah Tubiana, Jean-Marie Turmel, Florent Valour, Fanny Vardon-Bounes, Priyanka Velou, Gil Verschelden, Florent Wallet, Guilhem Wattecamps, Yazdan Yazdanpanah, Yoann Zerbib, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Hospitalization, Clinical Trials as Topic, Alanine, Infectious Diseases, COVID-19, Humans, Adenosine Monophosphate, COVID-19 Drug Treatment
Published: 2022

25. Contribution of lung ultrasound in diagnosis of community-acquired pneumonia in the emergency department: a prospective multicentre study

Author: Philippe Le Conte, Quentin Le Bastard, Denis Haroche, Benjamin Gaborit, Estelle Boucher, Hugo De Carvalho, François Javaudin, Nicolas Marjanovic, Emmanuel Montassier, Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier de Saint-Nazaire, Centre Hospitalier Départemental Vendée (CHDV), and Malbec, Odile
Subjects: Male, medicine.medical_specialty, Concordance, [SDV]Life Sciences [q-bio], infectious diseases, 03 medical and health sciences, respiratory infections, 0302 clinical medicine, Community-acquired pneumonia, Intensive care, accident & emergency medicine, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Medical prescription, Lung, Aged, Ultrasonography, Aged, 80 and over, business.industry, ultrasound, General Medicine, Emergency department, Pneumonia, Middle Aged, medicine.disease, 3. Good health, Community-Acquired Infections, [SDV] Life Sciences [q-bio], 030228 respiratory system, Radiological weapon, Emergency medicine, Emergency Medicine, Observational study, Female, business, Emergency Service, Hospital
Abstract: Lung ultrasound (LUS) can help clinicians make a timely diagnosis of community-acquired pneumonia (CAP).ObjectivesTo assess if LUS can improve diagnosis and antibiotic initiation in emergency department (ED) patients with suspected CAP.DesignA prospective observational study.SettingsFour EDs.ParticipantsThe study included 150 patients older than 18 years with a clinical suspicion of CAP, of which 2 were subsequently excluded (incorrect identification), leaving 148 patients (70 women and 78 men, average age 72±18 years). Exclusion criteria included a life-threatening condition with do-not-resuscitate-order or patient requiring immediate intensive care.InterventionsAfter routine diagnostic procedure (clinical, radiological and laboratory tests), the attending emergency physician established a clinical CAP probability according to a four-level Likert scale (definite, probable, possible and excluded). An LUS was then performed, and another CAP probability was established based on the ultrasound result. An adjudication committee composed of three independent experts established the final CAP probability at hospital discharge.Primary and secondary outcome measuresPrimary objective was to assess concordance rate of CAP diagnostic probabilities between routine diagnosis procedure or LUS and the final probability of the adjudication committee. Secondary objectives were to assess changes in CAP probability induced by LUS, and changes in antibiotic treatment initiation.ResultsOverall, 27% (95% CI 20 to 35) of the routine procedure CAP classifications and 77% (95% CI 71 to 84) of the LUS CAP classifications were concordant with the adjudication committee classifications. Cohen’s kappa coefficients between routine diagnosis procedure and LUS, according to adjudication committee, were 0.07 (95% CI 0.04 to 0.11) and 0.61 (95% CI 0.55 to 0.66), respectively. The modified probabilities for the diagnosis of CAP after LUS resulted in changes in antibiotic prescriptions in 32% (95% CI 25 to 40) of the cases.ConclusionIn our study, LUS was a powerful tool to improve CAP diagnosis in the ED, reducing diagnostic uncertainty from 73% to 14%.Trial registration numberNCT03411824.
Published: 2021

26. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Minh-Patrick Lê, Gilles Peytavin, Thérèse Staub, Richard Greil, Jérémie Guedj, Jose-Artur Paiva, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Alexander Egle, Michael Joannidis, Bernd Lamprecht, Antoine Altdorfer, Leila Belkhir, Vincent Fraipont, Gil Verschelden, Jérôme Aboab, Hafid Ait-Oufella, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, François Benezit, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Johan Courjon, Flora Crockett, François Danion, Agathe Delbove, Jean Dellamonica, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Olivier Epaulard, Loïc Epelboin, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Didier Gruson, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Marlène Murris-Espin, Jean-Christophe Navellou, Saad Nseir, Walid Oulehri, Thomas Perpoint, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Naomi Sayre, Eric Senneville, Albert Sotto, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Jean-Marie Turmel, Florent Valour, Florent Wallet, Guilhem Wattecamps, Yoann Zerbib, Marc Berna, Jean Reuter, Sandra Braz, Joao-Miguel Ferreira Ribeiro, José-Artur Paiva, Roberto Roncon-Albuquerque, Alexandre Gaymard, Bruno Lina, Sarah Tubiana, Sandrine Couffin-Cadièrgues, Hélène Esperou, Aline Dechanet, Christelle Delmas, Claire Fougerou, Noémie Mercier, Marion Noret, Juliette Saillard, Priyanka Velou, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Internal Medicine, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Universidade do Porto = University of Porto, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Antiviral Agents, law.invention, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, Internal medicine, Humans, Medicine, media_common.cataloged_instance, 030212 general & internal medicine, European union, education, Contraindication, ComputingMilieux_MISCELLANEOUS, Aged, media_common, Mechanical ventilation, education.field_of_study, Alanine, business.industry, COVID-19, Standard of Care, Odds ratio, Articles, Middle Aged, Respiration, Artificial, Adenosine Monophosphate, COVID-19 Drug Treatment, 3. Good health, Europe, Hospitalization, Oxygen, Clinical trial, Infectious Diseases, Clinical research, Female, business
Abstract: Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.
Published: 2021

27. Pharmacokinetics and Safety of XAV-19, a Swine Glyco-humanized Polyclonal Anti-SARS-CoV-2 Antibody, for COVID-19-Related Moderate Pneumonia: a Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study

Author: Vincent Dubée, Bernard Vanhove, Benjamin Gaborit, Alexandra Jobert, Richard Danger, Sophie Brouard, Florence Ader, Régis Josien, Virginie Ferré, Laurent Flet, Marie-Anne Vibet, Laetitia Berly, Eric Dailly, Anne Omnes, Anne Chiffoleau, Aurélie Le Thuaut, François Raffi, Karine Lacombe, Odile Duvaux, Centre hospitalier universitaire de Nantes (CHU Nantes), Xenothera [Nantes, France], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hospices Civils de Lyon (HCL), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques
Subjects: Adult, medicine.medical_specialty, polyclonal glyco-humanized anti-SARS-CoV-2 antibody, Swine, phase IIa, viruses, [SDV]Life Sciences [q-bio], Cmax, XAV-19, Placebo, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Pharmacokinetics, Internal medicine, medicine, Animals, Humans, pneumonia, Experimental Therapeutics, Pharmacology (medical), 030212 general & internal medicine, Adverse effect, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, SARS-CoV-2, business.industry, COVID-19, virus diseases, medicine.disease, 3. Good health, respiratory tract diseases, Pneumonia, Infectious Diseases, Tolerability, biology.protein, Antibody, business, Perfusion
Abstract: We assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in coronavirus disease 2019 (COVID-19)-related moderate pneumonia. The objective was to evaluate the optimal dose and safety of XAV-19 during this first administration to patients with COVID-19-related moderate pneumonia. In this phase IIa trial, adults with COVID-19-related moderate pneumonia with a duration of ≤10 days were randomized to receive an infusion of XAV-19 at 0.5 mg/kg of body weight at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), or 2 mg/kg at day 1 (group 3) or placebo. Eighteen patients (n = 7 for group 1, n = 1 for group 2, n = 5 for group 3, and n = 5 for placebo) were enrolled. Baseline characteristics were similar across groups; median XAV-19 serum concentrations (ranges) at the time of the maximum serum concentration of the drug (Cmax) and at day 8 were 9.1 (5.2 to 18.1) and 6.4 (2.8 to 11.9) μg/ml, 71.5 and 47.2 μg/ml, and 50.4 (29.1 to 55.0) and 20.3 (12.0 to 22.7) μg/ml for groups 1, 2, and 3, respectively (P = 0.012). The median terminal half-life (range) was estimated at 11.4 (5.5 to 13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 μg/ml (2-fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 at 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, and there were no discontinuations for adverse events and no serious adverse events related to the study drug. A single intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability. (This study has been registered at ClinicalTrials.gov under identifier NCT04453384.)
Published: 2021

28. A Prospective Cohort Study to Identify Clinical, Biological, and Imaging Features That Predict the Etiology of Acute Encephalitis

Author: Daniel Da Silva, Vincent Roubeau, Patricia Pavese, Jean-Paul Mira, Rafael Mahieu, Heidi Wille, Lydie Khatchatourian, Charlotte Biron, Geneviève Blanchet-Fourcade, Romain Lefaucheur, Laurent Argaud, Arnaud Seigneurin, Guillaume Baille, Eugénie Mutez, Hélène Brasme, Morgan Matt, Amandine Gagneux-Brunon, Alexandra Mailles, Thibaut Fraisse, Morgane Le Bras, Céline Cazorla, Isabelle Pierre, Anne Bonnetain, Hélène Savini, Nathalie Marin, Isabelle Runge, Pierre Fillatre, Mathilde Reveillon-Istin, Mathieu Godement, Cédric Bruel, Martin Martinot, Xavier Argemi, Saber Touati, Emmanuel Forestier, M. Hentzien, Jérome Honnorat, Capucine Diard-Detoeuf, Nathalie Pansu, Yvon Ruch, Thècle Degroote, Alexandre Mas, Guillaume Louis, Bernard Castan, Thomas Guimard, Aurélien Dinh, Marc-Olivier Vareil, Pierre Jaquet, Aurélie Richard-Mornas, Thibault Challan-Belval, Paul Le Turnier, Aurélie Martin, Frédéric Bourdain, Catherine Chirouze, Pascal Chavanet, Carole Henry, François Goehringer, Alain Makinson, Fabrice Bruneel, Anne Pachart, Manuela Le Cam, Johan Courjon, Elisabeth Botelho-Nevers, Pierre Tattevin, Emilie Piet, Eric Denes, Jean-Louis Herrmann, Philippe Casenave, Rodolphe Buzele, Marion Le Maréchal, Laurence Maulin, Thomas De Broucker, Agnès Riché, Sylvain Rheims, Olivier Epaulard, Solene Patrat-Delon, Aurélie Baldolli, Valentin Greigert, Isabelle Gueit, Anne-Sophie Lecompte, Nicolas Gaillard, Marie Froidure, Guillaune Marc, Dimitri Psimaras, Nathalie Asseray, Charles Cazanave, Etienne Canouï, Jean-Etienne Herbrecht, Alexandre Thibault Jacques Maria, Romain Sonneville, Patrice Morand, Jessica Krause, Jean-Marie Turmel, Tomasz Tchroboczek, Kelly Tiercelet, Gwenael Le Moal, Arnaud de la Blanchardiere, Thomas Baudry, Jean-Paul Stahl, Simon Gravier, Frédéric Méchaï, Diane Ponscarme, Christelle Lucas, Laurent Almoyna-Martinez, Colin Deschanvres, Olivier Lesieur, Véronique Pelonde-Erimée, Raphaël Lecomte, David Boutoille, Sophie Abgrall, Jérémie Orain, Philippe Lesprit, François Raffi, Magalie Vidal-Roux, Mathieu Blot, Michael Bonnan, Arnaud Galbois, V. Vitrat, Olivier Bouchaud, Guillaume Martin-Blondel, Mathieu Zuber, Stéphanie Lejeune, Solen Kernéis, Hélène Pellerin, Isabelle Tyvaert, Mathilde Puges, Xavier Lescure, Philippe Mateu, Marine Delaroche, Fanny Jomier, Julien Biberon, Pascale Goubin, Benjamin Gaborit, Etienne De Montmollin, Centre Hospitalier Universitaire [Grenoble] (CHU), Santé publique France - French National Public Health Agency [Saint-Maurice, France], CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), French Infectious Diseases Society, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Infectious Encephalitis, 0301 basic medicine, Microbiology (medical), Herpesvirus 3, Human, Pediatrics, medicine.medical_specialty, Lymphocytosis, diagnosis, viruses, encephalitis, etiology, [SDV]Life Sciences [q-bio], 030106 microbiology, factor analysis, Context (language use), medicine.disease_cause, Virus, 03 medical and health sciences, 0302 clinical medicine, medicine, Infectious encephalitis, Humans, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, business.industry, medicine.disease, herpes simplex virus, 3. Good health, Infectious Diseases, Herpes simplex virus, Etiology, Encephalitis, Herpes Simplex, France, medicine.symptom, business, Encephalitis
Abstract: Background New diagnostic tools have been developed to improve the diagnosis of infectious encephalitis. Using a prospective cohort of encephalitis patients, our objective was to identify possible clusters of patients with similar patterns among encephalitis of unknown cause (EUC) and to describe to what extent a patient’s initial presentation may be predictive of encephalitis etiology, particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). Methods The National Cohort of Infectious Encephalitis in France is an ongoing prospective cohort study implemented in France in 2016. Patients who present with documented or suspected acute infectious encephalitis were included. Focusing on the variables that describe the initial presentation, we performed a factor analysis of mixed data (FAMD) to investigate a pattern of association between the initial presentation of a patient and the etiologic pathogen. Results As of 1 August 2018, data from 349 patients were analyzed. The most frequent pathogens were HSV (25%), VZV (11%), tick-borne encephalitis virus (6%), Listeria (5%), influenza virus (3%), and EUC (34%). Using the FAMD, it was not possible to identify a specific pattern related to the group of EUC. Age, temporal or hemorrhagic lesions, and cerebral spinal fluid lymphocytosis were significantly associated with HSV/VZV encephalitis. Conclusions No initial clinical/imaging/biology pattern was identified at admission among EUC, despite the improvement in diagnostic tools. In this context, the recommendation for a universal, early, probabilistic, initial treatment against HSV and VZV is still relevant, regardless of the initial clinical presentation of the encephalitis.
Published: 2021

29. Pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, for COVID-19-related moderate pneumonia: a randomized, double-blind, placebo-controlled, phase IIa study

Author: Benjamin Gaborit, Odile Duvaux, Karine Lacombe, Aurélie Le Thuaut, Anne Omnes, Marie-Anne Vibet, François Raffi, Florence Ader, Régis Josien, Bernard Vanhove, Anne Chiffoleau, Richard Danger, Eric Dailly, Vincent Dubée, Alexandra Jobert, Virginie Ferré, Sophie Brouard, and Laetitia Berly
Subjects: medicine.medical_specialty, biology, business.industry, Cmax, medicine.disease, Placebo, Gastroenterology, Pneumonia, Pharmacokinetics, Tolerability, Internal medicine, medicine, biology.protein, Antibody, business, Adverse effect, Perfusion
Abstract: BackgroundWe assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2, in COVID-19-related moderate pneumonia. In vitro, 100% neutralization activity is seen with XAV-19 concentrations above 5 μg/mL.MethodsIn this phase 2a trial, adults with COVID-19-related moderate pneumonia of ≤10 days duration were randomized to infusion of XAV-19 0.5 mg/kg at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), 2 mg/kg at day 1 (group 3) or placebo.ResultsEighteen patients (n=7 for group 1, n=1 for group 2, n=5 for group 3, and n=5 for placebo) were enrolled. Baseline characteristics were similar across groups, XAV-19 serum concentrations (μg/mL, median, range) at Cmaxand at day 8 were 9.1 (5.2-18.1) and 6.4 (2.8-11.9), 71.5 and 47.2, and 50.4 (29.1-55.0) and 20.3 (12.0-22.7) for groups 1, 2 and 3, respectively (p=0.012). Terminal half-life (median, range) was estimated at 11.4 (5.5-13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 μg/mL (tow fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, there was no discontinuation for adverse events and no serious adverse events related to study drug.ConclusionsSingle intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability.Trial registrationClinicalTrials.gov Identifier:NCT04453384Main pointIn this first-in-human trial including patients with COVID-19-related pneumonia, a single 2mg/kg dose of a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, achieved serum concentrations above the target of neutralization threshold for 8 days in all patients, with good tolerability and safety.
Published: 2021

30. Lopinavir pharmacokinetics in COVID-19 patients

Author: David Boutoille, Gwenaelle Veyrac, Benjamin Gaborit, Emmanuel Canet, François Raffi, Ronan Bellouard, Paul Le Turnier, Berthe Marie Imbert, Raphaël Lecomte, Matthieu Grégoire, The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), DCNS Group [Nantes] (DCNS-Nantes), DCNS group, Université de Nantes (UN), and NantesU M, Dépôt
Subjects: Male, Microbiology (medical), 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), viruses, [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Lopinavir, Betacoronavirus, Pharmacokinetics, immune system diseases, Pandemic, Research Letter, MESH: Aged Betacoronavirus* COVID-19 Coronavirus Infections / blood* Coronavirus Infections / drug therapy Cytochrome P-450 CYP3A Inhibitors / administration & dosage Cytochrome P-450 CYP3A Inhibitors / blood Drug Therapy, Combination Female Humans Lopinavir / administration & dosage Lopinavir / blood* Male Middle Aged Pandemics Pneumonia, Viral / blood* Pneumonia, Viral / drug therapy Ritonavir / administration & dosage Ritonavir / blood* SARS-CoV-2, Humans, Medicine, Pharmacology (medical), Pandemics, Aged, Pharmacology, Ritonavir, biology, SARS-CoV-2, business.industry, COVID-19, virus diseases, Middle Aged, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Virology, [SDV] Life Sciences [q-bio], Infectious Diseases, Cytochrome P-450 CYP3A Inhibitors, Drug Therapy, Combination, Female, Coronavirus Infections, business, medicine.drug
Abstract: International audience; The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in late 2019. Therapeutic solutions are currently being tested for COVID-19, the SARS-CoV-2-associated pneumonia. Ritonavir-boosted lopinavir is included in the investigational therapies. A recent in vitro study reported that lopinavir inhibits SARS-CoV-2 replication with a 50% effective concentration (EC50) of 16 720 ng/mL.1Here we describe lopinavir pharmacokinetics in COVID-19 patients treated with ritonavir-boosted lopinavir at the Nantes University Hospital, France.
Published: 2020

31. Ludwig’s angina: A diagnostic and surgical priority

Author: Olivier Malard, Florent Espitalier, Nathalie Asseray, David Boutoille, Jérémy Meyer, François Raffi, Maxime Vallée, and Benjamin Gaborit
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Resuscitation, Floor of mouth, medicine.drug_class, business.industry, 030106 microbiology, Antibiotics, General Medicine, medicine.disease, lcsh:Infectious and parasitic diseases, Surgery, Angina, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Cellulitis, Concomitant, medicine, lcsh:RC109-216, 030212 general & internal medicine, Ludwig's angina, Fasciitis, business
Abstract: Ludwig’s angina has been known for two centuries as a rapidly and frequently fatal progressive gangrenous cellulitis or necrotizing fasciitis of the neck and the floor of the mouth. The management of the usually young patients affected requires a trained team combining medical skills in surgery, antibiotic therapy, and resuscitation. The prognosis is directly related to early surgical debridement and the experience of the team managing these patients. We present four cases of severe necrotizing cervical cellulitis notably associated with concomitant self-medication with non-steroidal anti-inflammatory drugs. Through these cases, we conclude that several surgical steps could be required, combined with broad-spectrum antibiotic therapy. An optimal surgery, draining all collections and excising all necrotic tissues, seems to be a condition needed for antibiotic efficacy and finally healing. Keywords: Ludwig Angina, Necrotizing fasciitis, NSAIDs, Medico-surgical cooperation
Published: 2020

32. Risk-benefit Assessment of Systematic Thoracoabdominal-pelvic Computed Tomography in Infective Endocarditis

Author: Colin Deschanvres, Nahema Issa, Philippe Bizouarn, Ousama Al Habash, Nathalie Asseray, Thierry Le Tourneau, Raphaël Lecomte, Paul Le Turnier, Benjamin Gaborit, David Boutoille, Fabrice Camou, and Magali Michel
Subjects: Adult, Male, Microbiology (medical), medicine.medical_specialty, 030204 cardiovascular system & hematology, Risk Assessment, Asymptomatic, Cohort Studies, Lesion, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Endocarditis, Prospective Studies, 030212 general & internal medicine, Pelvis, Aged, business.industry, Acute kidney injury, Endocarditis, Bacterial, Acute Kidney Injury, Middle Aged, medicine.disease, Infectious Diseases, medicine.anatomical_structure, Embolism, Echocardiography, Infective endocarditis, Female, Radiology, medicine.symptom, Tomography, X-Ray Computed, business, Cohort study
Abstract: Background In the management of infective endocarditis (IE), the presence of extracardiac complications has an influence on both diagnosis and treatment. Current guidelines suggest that systematic thoracoabdominal-pelvic computed tomography (TAP-CT) may be helpful. Our objective was to describe how systematic TAP-CT affects the diagnosis and the management of IE. Methods In this multicenter cohort study, between January 2013 and July 2016 we included consecutive patients who had definite or possible IE according to the Duke modified criteria, validated by endocarditis teams. We analyzed whether the Duke classification and therapeutic management were modified regarding the presence or the absence of IE-related lesion on CT and investigated the tolerance of this examination. Results Of the 522 patients included in this study, 217 (41.6%) had 1 or more IE-related lesions. On the basis of CT results in asymptomatic patients, diagnostic classification was upgraded from possible endocarditis to definite endocarditis for only 4 cases (0.8%). The presence of IE-related lesions on CT did not modify the duration of antibiotic treatment (P = .55), nor the decision of surgical treatment (P = .39). Specific treatment of the lesion was necessary in 42 patients (8.0%), but only 9 of these lesions (1.9%) were asymptomatic and diagnosed only on the TAP-CT. Acute kidney injury (AKI) within 5 days of CT was observed in 78 patients (14.9%). Conclusions The TAP-CT findings slightly affected diagnosis and treatment of IE in a very small proportion of asymptomatic patients. Furthermore, contrast media should be used with caution because of the high risk of AKI.
Published: 2019

33. Le VEXAS, un déficit immunitaire auto-inflammatoire ?

Author: Hélène Aubert, P. Le Turnier, Julie Graveleau, S. Riescher, Y. Lebris, Benjamin Gaborit, and Antoine Néel
Subjects: Gastroenterology, Internal Medicine
Published: 2021

34. Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

Author: Jean Sibilia, François Rieger, Christelle Volteau, Jean-François Viallard, Mikael Ebbo, Joel Poupon, Mohamed Hamidou, Jean-Benoit Hardouin, Antoine Néel, Benjamin Gaborit, Eric Hachulla, Zahir Amoura, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Université de Strasbourg (UNISTRA), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Université de Lille, Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Gestionnaire, Hal Sorbonne Université, Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, medicine.drug_class, Autoimmune diseases, [SDV]Life Sciences [q-bio], Neutropenia, Antibodies, Monoclonal, Humanized, Severity of Illness Index, 03 medical and health sciences, chemistry.chemical_compound, Systemic lupus erythematosus, 0302 clinical medicine, Arsenic trioxide, Internal medicine, Clinical endpoint, Humans, Lupus Erythematosus, Systemic, Medicine, Adverse effect, 030203 arthritis & rheumatology, business.industry, medicine.disease, Phase II clinical trial, Rheumatology, 3. Good health, [SDV] Life Sciences [q-bio], Treatment, Treatment Outcome, 030104 developmental biology, chemistry, Corticosteroid, lcsh:RC925-935, Osteitis, business, Immunosuppressive Agents, Research Article
Abstract: Background Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. Methods This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). Results Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P Conclusions A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. Trial registration ClinicalTrials.gov, NCT01738360 registered 30 November 2012
Published: 2021

35. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Author: François-Xavier Lescure, Hitoshi Honda, Robert A Fowler, Jennifer Sloane Lazar, Genming Shi, Peter Wung, Naimish Patel, Owen Hagino, Ignacio J. Bazzalo, Marcelo M. Casas, Sebastián A. Nuñez, Yael Pere, Carlos M. Ibarrola, Marco A. Solis Aramayo, Maria C. Cuesta, Andrea E. Duarte, Pablo M. Gutierrez Fernandez, Maria A. Iannantuono, Erica A. Miyazaki, Javier P. Silvio, Dario G. Scublinsky, Alessandra Bales, Daniela Catarino, Elie Fiss, Sara Mohrbacher, Victor Sato, Antonio Baylao, Adilson Cavalcante, Francini Correa, Celso A. de Andrade, Juvencio Furtado, Nelson Ribeiro Filho, Valéria Telles, Leopoldo T. Trevelin, Ricardo Vipich, Rodrigo Boldo, Paula Borges, Suzana Lobo, Graziela Luckemeyer, Luana Machado, Maysa B. Alves, Ana C. Iglessias, Marianna M. Lago, Daniel W. Santos, Hugo Chapdelaine, Emilia L. Falcone, Rahima Jamal, Me-Linh Luong, Madeleine Durand, Stephane Doucet, François-Martin Carrier, Bryan A. Coburn, Lorenzo Del Sorbo, Sharon L. Walmsley, Sara Belga, Luke Y. Chen, Allison D. Mah, Theodore Steiner, Alissa J. Wright, J. Hajek, Neill Adhikari, Robert A. Fowler, Nick Daneman, Kosar A. Khwaja, Jason Shahin, Carolina Gonzalez, Rafael Silva, Marcelo Lindh, Gabriel Maluenda, Patricia Fernandez, Maite Oyonarte, Martin Lasso, Alexandre Boyer, Didier Bronnimann, Hoang-Nam Bui, Charles Cazanave, Helene Chaussade, Arnaud Desclaux, Mailys Ducours, Alexandre Duvignaud, Denis Malvy, Lisa Martin, Didier Neau, Duc Nguyen, Thierry Pistone, Gaetane Soubrane-Wirth, Julie Leitao, Clotilde Allavena, Charlotte Biron, Sabelline Bouchez, Benjamin Gaborit, Antoine Gregoire, Paul Le Turnier, Anne-Sophie Lecompte, Raphael Lecomte, Maeva Lefebvre, Francois Raffi, David Boutoille, Pascale H. Morineau, Romain Guéry, Emmanuel Chatelus, Nathalie Dumoussaud, Renaud Felten, Florina Luca, Bernard Goichot, Francis Schneider, Marie-Caroline Taquet, Matthieu Groh, Mathilde Roumier, Mathilde Neuville, Antoine Bachelard, Valentina Isernia, F-Xavier Lescure, Bao-Chau Phung, Anne Rachline, Aurelie Sautereau, Dorothee Vallois, Yves Bleher, Delphine Boucher, Clémentine Coudon, Jean Esnault, Thomas Guimard, Sophie Leautez-Nainville, Dominique Merrien, Marine Morrier, Pauline Motte-Vincent, Romain Gabeff, Hélène Leclerc, Céline Cozic, Romain Decours, Ronan Février, Gwenhael Colin, Sophie Abgrall, Dorothee Vignes, Raluca Sterpu, Mira Kuellmar, Melanie Meersch-Dini, Raphael Weiss, Alexander Zarbock, Christiane Antony, Marc Berger, Thorsten Brenner, Christian Taube, Frank Herbstreit, Sebastian Dolff, Margarethe Konik, Karsten Schmidt, Markus Zettler, Oliver Witzke, Boris Boell, Jorge Garcia Borrega, Philipp Koehler, Thomas Zander, Fabian Dusse, Othman Al-Sawaf, Philipp Köhler, Dennis Eichenauer, Matthias Kochanek, Alexander Shimabukuro-Vornhagen, Sibylle Mellinghoff, Annika Claßen, Jan-Michel Heger, Charlotte Meyer-Schwickerath, Paul Liedgens, Katrin Heindel, Ana Belkin, Asaf Biber, Mayan Gilboa, Itzchak Levy, Vladislav Litachevsky, Galia Rahav, Anat Finesod Wiedner, Tal Zilberman-Daniels, Yonatan Oster, Jacob Strahilevitz, Sigal Sviri, Elena M. Baldissera, Corrado Campochiaro, Giulio Cavalli, Lorenzo Dagna, Giacomo De Luca, Emanuel Della Torre, Alessandro Tomelleri, Davide Bernasconi De Luca, Amedeo F. Capetti, Massimo Coen, Maria V. Cossu, Massimo Galli, Andrea Giacomelli, Guido A. Gubertini, Stefano Rusconi, Giulia J. Burastero, Margherita Digaetano, Giovanni Guaraldi, Marianna Meschiari, Cristina Mussini, Cinzia Puzzolante, Sara Volpi, Marina Aiello, Alarico Ariani, Alfredo A. Chetta, Annalisa Frizzelli, Andrea Ticinesi, Domenico Tuttolomondo, Stefano Aliberti, Francesco B. Blasi, Marta F. Di Pasquale, Sofia Misuraca, Tommaso Pilocane, Edoardo Simonetta, Alessio M. Aghelmo, Claudio Angelini, Enrico Brunetta, Giorgio W. Canonica, Michele Ciccarelli, Sara Dal Farra, Maria De Santis, Sebastian Ferri, Marco Folci, Giacomo M. Guidelli, Enrico M. Heffler, Ferdinando Loiacono, Giacomo Malipiero, Giovanni Paoletti, Rosa Pedale, Francesca A. Puggioni, Francesca Racca, Aurora Zumbo, Morihiko Satou, Tatyana Lisun, Denis Protsenko, Nikolay Rubtsov, Irina Beloglazova, Daria Fomina, Mariana Lysenko, Sofia Serdotetskova, Vitali Firstov, Ivan Gordeev, Ilia Kokorin, Ksenia Komissarova, Nina Lapochkina, Elena Luchinkina, Valentin Malimon, Sevinch Mamedguseyinova, Ksenia Polubatonova, Natalia Suvorova, Jose Arribas, Alberto M. Borobia Perez, Fernando de la Calle Prieto, Juan Carlos Figueira, Rocio Motejano Sanchez, Marta Mora-Rillo, Concepcion Prados Sanchez, Javier Queiruga Parada, Francisco Fernandez Arnalich, Maria Guerro Barrientos, Alejandro Bendala Estrada, Aranzazu Caballero Marcos, Maria E. Garcia Leoni, Rita García-Martínez, Ana María Collado, Patricia Munoz Garcia, Ana Torres do Rego, María V. Villalba García, Almudena Burrillo, Maricela Valerio Minero, Paloma Gijon Vidaurreta, Sonsoles Infante Herrero, Elena Velilla, Marina Machado, Maria Olmedo, Blanca Pinilla, Benito Almirante Gragera, Maria de la Esperanza Cañas Ruano, Sofia Contreras Medina, Alejandro Cortés Herrera, Vicenç Falcó Ferrer, Ricard Ferrer Roca, Xavier Nuvials Casals, Esteve Ribera Pascuet, Paula Suanzes Diez, Pedro Rebollo Castro, Felipe Garcia Alcaide, Alejandro Soriano, Aina Oliver Caldes, Ana González Cordón, Celia Cardozo, Lorena De la Mora Cañizo, Romina Pena López, Sandra Chamorro, Clara Crespillo-Andujar, Rosa Escudero Sanchez, Jesús Fortún-Abete, Begoña Monge-Maillo, Ana Moreno Zamora, Francesca Norman, Matilde Sanchez Conde, Sergio Serrano Villar, Pilar Vizcarra, Lescure, F. -X., Honda, H., Fowler, R. A., Lazar, J. S., Shi, G., Wung, P., Patel, N., Hagino, O., Bazzalo, I. J., Casas, M. M., Nunez, S. A., Pere, Y., Ibarrola, C. M., Solis Aramayo, M. A., Cuesta, M. C., Duarte, A. E., Gutierrez Fernandez, P. M., Iannantuono, M. A., Miyazaki, E. A., Silvio, J. P., Scublinsky, D. G., Bales, A., Catarino, D., Fiss, E., Mohrbacher, S., Sato, V., Baylao, A., Cavalcante, A., Correa, F., de Andrade, C. A., Furtado, J., Ribeiro Filho, N., Telles, V., Trevelin, L. T., Vipich, R., Boldo, R., Borges, P., Lobo, S., Luckemeyer, G., Machado, L., Alves, M. B., Iglessias, A. C., Lago, M. M., Santos, D. W., Chapdelaine, H., Falcone, E. L., Jamal, R., Luong, M. -L., Durand, M., Doucet, S., Carrier, F. -M., Coburn, B. A., Del Sorbo, L., Walmsley, S. L., Belga, S., Chen, L. Y., Mah, A. D., Steiner, T., Wright, A. J., Hajek, J., Adhikari, N., Daneman, N., Khwaja, K. A., Shahin, J., Gonzalez, C., Silva, R., Lindh, M., Maluenda, G., Fernandez, P., Oyonarte, M., Lasso, M., Boyer, A., Bronnimann, D., Bui, H. -N., Cazanave, C., Chaussade, H., Desclaux, A., Ducours, M., Duvignaud, A., Malvy, D., Martin, L., Neau, D., Nguyen, D., Pistone, T., Soubrane-Wirth, G., Leitao, J., Allavena, C., Biron, C., Bouchez, S., Gaborit, B., Gregoire, A., Le Turnier, P., Lecompte, A. -S., Lecomte, R., Lefebvre, M., Raffi, F., Boutoille, D., Morineau, P. H., Guery, R., Chatelus, E., Dumoussaud, N., Felten, R., Luca, F., Goichot, B., Schneider, F., Taquet, M. -C., Groh, M., Roumier, M., Neuville, M., Bachelard, A., Isernia, V., Phung, B. -C., Rachline, A., Sautereau, A., Vallois, D., Bleher, Y., Boucher, D., Coudon, C., Esnault, J., Guimard, T., Leautez-Nainville, S., Merrien, D., Morrier, M., Motte-Vincent, P., Gabeff, R., Leclerc, H., Cozic, C., Decours, R., Fevrier, R., Colin, G., Abgrall, S., Vignes, D., Sterpu, R., Kuellmar, M., Meersch-Dini, M., Weiss, R., Zarbock, A., Antony, C., Berger, M., Brenner, T., Taube, C., Herbstreit, F., Dolff, S., Konik, M., Schmidt, K., Zettler, M., Witzke, O., Boell, B., Garcia Borrega, J., Koehler, P., Zander, T., Dusse, F., Al-Sawaf, O., Kohler, P., Eichenauer, D., Kochanek, M., Shimabukuro-Vornhagen, A., Mellinghoff, S., Classen, A., Heger, J. -M., Meyer-Schwickerath, C., Liedgens, P., Heindel, K., Belkin, A., Biber, A., Gilboa, M., Levy, I., Litachevsky, V., Rahav, G., Finesod Wiedner, A., Zilberman-Daniels, T., Oster, Y., Strahilevitz, J., Sviri, S., Baldissera, E. M., Campochiaro, C., Cavalli, G., Dagna, L., De Luca, Giacomo., Della Torre, E., Tomelleri, A., Bernasconi De Luca, D., Capetti, A. F., Coen, M., Cossu, M. V., Galli, M., Giacomelli, A., Gubertini, G. A., Rusconi, S., Burastero, G. J., Digaetano, M., Guaraldi, G., Meschiari, M., Mussini, C., Puzzolante, C., Volpi, S., Aiello, M., Ariani, A., Chetta, A. A., Frizzelli, A., Ticinesi, A., Tuttolomondo, D., Aliberti, S., Blasi, F. B., Di Pasquale, M. F., Misuraca, S., Pilocane, T., Simonetta, E., Aghelmo, A. M., Angelini, C., Brunetta, E., Canonica, G. W., Ciccarelli, M., Dal Farra, S., De Santis, M., Ferri, S., Folci, M., Guidelli, G. M., Heffler, E. M., Loiacono, F., Malipiero, G., Paoletti, G., Pedale, R., Puggioni, F. A., Racca, F., Zumbo, A., Satou, M., Lisun, T., Protsenko, D., Rubtsov, N., Beloglazova, I., Fomina, D., Lysenko, M., Serdotetskova, S., Firstov, V., Gordeev, I., Kokorin, I., Komissarova, K., Lapochkina, N., Luchinkina, E., Malimon, V., Mamedguseyinova, S., Polubatonova, K., Suvorova, N., Arribas, J., Borobia Perez, A. M., de la Calle Prieto, F., Figueira, J. C., Motejano Sanchez, R., Mora-Rillo, M., Prados Sanchez, C., Queiruga Parada, J., Fernandez Arnalich, F., Guerro Barrientos, M., Bendala Estrada, A., Caballero Marcos, A., Garcia Leoni, M. E., Garcia-Martinez, R., Collado, A. M., Munoz Garcia, P., Torres do Rego, A., Villalba Garcia, M. V., Burrillo, A., Valerio Minero, M., Gijon Vidaurreta, P., Infante Herrero, S., Velilla, E., Machado, M., Olmedo, M., Pinilla, B., Almirante Gragera, B., Canas Ruano, M. D. L. E., Contreras Medina, S., Cortes Herrera, A., Falco Ferrer, V., Ferrer Roca, R., Nuvials Casals, X., Ribera Pascuet, E., Suanzes Diez, P., Rebollo Castro, P., Garcia Alcaide, F., Soriano, A., Oliver Caldes, A., Gonzalez Cordon, A., Cardozo, C., De la Mora Canizo, L., Pena Lopez, R., Chamorro, S., Crespillo-Andujar, C., Escudero Sanchez, R., Fortun-Abete, J., Monge-Maillo, B., Moreno Zamora, A., Norman, F., Sanchez Conde, M., Serrano Villar, S., and Vizcarra, P.
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Critical Care, International Cooperation, Population, Antibodies, Monoclonal, Humanized, Placebo, Severity of Illness Index, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Intensive care, Severity of illness, medicine, Clinical endpoint, Humans, Immunologic Factors, 030212 general & internal medicine, Mortality, education, Respiratory Distress Syndrome, education.field_of_study, Dose-Response Relationship, Drug, SARS-CoV-2, business.industry, Hazard ratio, COVID-19, Articles, Middle Aged, Receptors, Interleukin-6, Sarilumab, Treatment Outcome, 030228 respiratory system, Female, Drug Monitoring, Cytokine Release Syndrome, business
Abstract: Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.
Published: 2021

36. Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

Author: Mirjam Lutz, Ekaterina Friebel, Roland S. Liblau, Antoine Roquilly, Guillaume Martin-Blondel, Manfred Claassen, Benjamin Gaborit, Manuel Kauffmann, Sepideh Babaei, Donatella De Feo, Nicolás Gonzalo Núñez, Nisar P. Malek, Chiara Alberti, Sally Al-Hajj, Susanne Unger, Siri Goepel, Ikram Ayoub, Helene A. Häberle, Jakob Nilsson, Nicole Puertas Jurado, Peter Rosenberger, Stefanie Kreutmair, Sinduya Krishnarajah, Burkhard Becher, Michael Bitzer, Florian Ingelfinger, Pistre, Karine, Universität Zürich [Zürich] = University of Zurich (UZH), German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institute of Experimental Immunology [Zurich], Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), German Center for Infectious Research - partner site Tübingen [Tübingen, Allemagne] (DZIF), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University hospital of Zurich [Zurich], University of Zurich, and Becher, Burkhard
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, MESH: CD4-Positive T-Lymphocytes / immunology, MESH: Biomarkers / blood, [SDV]Life Sciences [q-bio], MESH: HLA Antigens / genetics, MESH: COVID-19 / pathology, 10263 Institute of Experimental Immunology, Hospital-acquired pneumonia, Severity of Illness Index, 0302 clinical medicine, MESH: Pneumonia / immunology, HLA Antigens, T-Lymphocyte Subsets, peptide binding strength, Immunopathology, Immunology and Allergy, MESH: Pneumonia / pathology, MESH: T-Lymphocyte Subsets / metabolism, COVID, high-dimensional single cell analysis, Antigen Presentation, MESH: Middle Aged, spectral flow cytometry, immune profiling, MESH: SARS-CoV-2 / immunology, Middle Aged, Acquired immune system, MESH: HLA Antigens / immunology, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, HLA typing, 030220 oncology & carcinogenesis, MESH: T-Lymphocyte Subsets / immunology, 2723 Immunology and Allergy, MESH: SARS-CoV-2 / pathogenicity, Biomarker (medicine), Cytokines, biomarker, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, Angiotensin-Converting Enzyme 2, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, Immunology, Antigen presentation, 610 Medicine & health, Human leukocyte antigen, Biology, Article, 03 medical and health sciences, MESH: Natural Killer T-Cells / immunology, Immune system, immunophenotyping, MESH: CD4-Positive T-Lymphocytes / metabolism, MESH: Angiotensin-Converting Enzyme 2 / metabolism, MESH: Severity of Illness Index, medicine, Humans, 2403 Immunology, SARS-CoV-2, COVID-19, GM-CSF, 2725 Infectious Diseases, Pneumonia, biochemical phenomena, metabolism, and nutrition, medicine.disease, MESH: COVID-19 / immunology, Immunity, Innate, 030104 developmental biology, MESH: Antigen Presentation, 10033 Clinic for Immunology, 570 Life sciences, biology, Natural Killer T-Cells, Biomarkers
Abstract: Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2-petides to the patients’ HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Towards clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19., Graphical Abstract, The pathogen-specific immune alterations in severe COVID-19 remain unknown. Using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided comparison of COVID-19 vs. non-SARS-CoV-2-pneumonia patient samples, Kreutmair et al. identify T and NK cell immune signatures specific to SARS-CoV-2. They furthermore reveal NKT cell frequency as a predictive biomarker for COVID-19 outcome prediction and link impaired virus recognition to HLA genetics.
Published: 2021

37. Pseudomonas aeruginosa Infection Impairs NKG2D-Dependent NK Cell Cytotoxicity through Regulatory T-Cell Activation

Author: Jocelyne Caillon, Gaëlle David, Benjamin Gaborit, Christelle Retière, Mickael Vourc'h, Karim Asehnoune, Tanguy Chaumette, Alexis Broquet, Antoine Roquilly, Cédric Jacqueline, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), EFS Centre-Pays de la Loire [Nantes], LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), RETIERE, Christelle, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes]
Subjects: CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, 0301 basic medicine, Adoptive cell transfer, CD3 Complex, [SDV]Life Sciences [q-bio], Cell, Lipopolysaccharide Receptors, NK cells, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Monocytes, regulatory T cells, 0302 clinical medicine, Cytotoxic T cell, Host Response and Inflammation, Cell sorting, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], Infectious Diseases, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, Pseudomonas aeruginosa, Regulatory T cell, Immunology, chemical and pharmacologic phenomena, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microbiology, 03 medical and health sciences, Lysosomal-Associated Membrane Protein 1, Signaling Lymphocytic Activation Molecule Family, Immunity, Cell Line, Tumor, medicine, Humans, cancer, Pseudomonas Infections, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cytotoxicity Tests, Immunologic, NKG2D, immunity, infection, 030104 developmental biology, Cell culture, Leukocytes, Mononuclear, Cancer research, Parasitology
Abstract: International audience; Natural killer (NK) cells play a key role in both antibacterial and antitumor immunity. Pseudomonas aeruginosa infection has already been reported to alter NK cell functions. We studied in vitro the effect of P. aeruginosa on NK cell cytotoxic response (CD107a membrane expression) to a lymphoma cell line. Through positive and negative cell sorting and adoptive transfer, we determined the influence of monocytes, lymphocytes, and regulatory T cells (Treg) on NK cell function during P. aeruginosa infection. We also studied the role of the activating receptor natural killer group 2D (NKG2D) in NK cell response to B221. We determined that P. aeruginosa significantly altered both cytotoxic response to B221 and NKG2D expression on NK cells in a Treg-dependent manner and that the NKG2D receptor was involved in NK cell cytotoxic response to B221. Our results also suggested that during P. aeruginosa infection, monocytes participated in Treg-mediated NK cell alteration. In conclusion, P. aeruginosa infection impairs NK cell cytotoxicity and alters antitumor immunity. These results highlight the strong interaction between bacterial infection and immunity against cancer.
Published: 2020

38. Respiratory Mechanics and Outcomes in Immunocompromised Patients With ARDS

Author: Alexandre Demoule, Massimo Antonelli, Peter Schellongowski, Peter Pickkers, Marcio Soares, Tine Meyhoff, Jordi Rello, Philippe R. Bauer, Andry van de Louw, Virgine Lemiale, David Grimaldi, Ignacio Martin-Loeches, Martin Balik, Sangeeta Mehta, Achille Kouatchet, Andreas Barratt-Due, Miia Valkonen, Jean Reignier, Victoria Metaxa, Anne-Sophie Moreau, Gaston Burghi, Djamel Mokart, Julien Mayaux, Michael Darmon, Elie Azoulay, Karin Amrein, Thomas Staundinger, Gottfried Heinz, Gürkan Sengölge, Christian Zauner, Peter Jaksch, Fabio S. Taccone, Anne Pascale Meert, Dominique Benoît, Ulysses V.A. Silva, Ana Paula Pierre de Moraes, Thiago Lishoa, Jorge Salluh, William Viana, Guilliana Moralez, Thiago Domingos Correa, Umesh Shah, Thomas Karvunidis, Balik Martin, Katerina Russinova, Anders Perner, Tine Sylvest Meyhoff, Nielsen Jonas, Ramin Brandt Bukan, Ann M. Moeller, Lene B. Nielsen, Amélie Seguin, Akli Chermak, Nicolas Terzi, Isabelle Vinatier, Florent Wallet, Kada Klouche, Laura Platon, Benjamin Gaborit, François Barbier, Frederic Pène, Antoine Rabbat, Virginie Lemiale, Martine N'Yunga, Christophe Girault, Caroline Lemaitre, Elise Artaud-Macari, F. Bruneel, Anne Sophie Moreau, Anne Kuitunen, Brian Marsh, Mater Misericordia, Aisling Mc Mahon, Gilda Cinnella, Antonella Cotoia, Ospedali Riuniti, Lucas Montini, Angélique Spoelstra de Man, Precious Pearl Landburg, Dennis Bergmans, Pleun Hemelaar, Thomas Kaufmann, Andreas Barrat-Due, Pål Klepstad, Belen Encina, Gabriel Moreno, Llorenç Socias Crespi, Emilio Rodriguez-Ruiz, Andry Van De Louw, Philippe Bauer, Yadav Hemang, Service de Pneumologie et Réanimation Médicale [CHU Pitié-Salpêtrière] (Département ' R3S '), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Medizinische Universität Wien = Medical University of Vienna, Radboud University Medical Centre [Nijmegen, The Netherlands], University of Copenhagen = Københavns Universitet (KU), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Mayo Clinic [Rochester], Penn State Health Milton S. Hershey Medical Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Trinity College Dublin, Charles Darwin University, University of Toronto, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Oslo University Hospital [Oslo], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), King's College Hospital (KCH), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, MESH: Respiratory Distress Syndrome, medicine.medical_treatment, Population, Respiratory physiology, Neutropenia, Critical Care and Intensive Care Medicine, Acute respiratory failure, MESH: Tidal Volume, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Prognosis, 03 medical and health sciences, MESH: Positive-Pressure Respiration, 0302 clinical medicine, Diagnosis, medicine, MESH: Immunocompromised Host, Renal replacement therapy, education, Immunocompromised, Tidal volume, Outcome, MESH: Aged, education.field_of_study, MESH: Humans, MESH: Middle Aged, business.industry, Mortality rate, 030208 emergency & critical care medicine, MESH: Follow-Up Studies, Plateau pressure, medicine.disease, MESH: Male, MESH: Prospective Studies, 3. Good health, 030228 respiratory system, Emergency medicine, Driving pressure, Etiology, MESH: Respiratory Mechanics, Cardiology and Cardiovascular Medicine, business, MESH: Female
Abstract: International audience; Background: In view of the high mortality rate of immunocompromised patients with ARDS, it is important to identify targets for improvement.Research question: This study investigated factors associated with mortality in this specific ARDS population, including factors related to respiratory mechanics (plateau pressure [Pplat,rs], compliance [Crs], and driving pressure [ΔPrs]).Study design and methods: This study consisted of a predefined secondary analysis of the EFRAIM data. Overall, 789 of 1,611 patients met the Berlin criteria for ARDS, and Pplat,rs, ΔPrs, and Crs were available for 494 patients. A hierarchical model was used to assess factors at ARDS onset independently associated with hospital mortality.Results: Hospital mortality was 56.3%. After adjustment, variables independently associated with hospital mortality included ARDS of undetermined etiology (OR, 1.66; 95% CI, 1.01-2.72), need for vasopressors (OR, 1.91; 95% CI, 1.27-2.88), and need for renal replacement therapy (OR, 2.02; 95% CI, 1.37-2.97). ARDS severity according to the Berlin definition, neutropenia on admission, and the type of underlying disease were not significantly associated with mortality. Before adjustment, higher Pplat,rs, higher ΔPrs, and lower Crs were associated with higher mortality. Addition of each of these individual variables to the final hierarchical model revealed a significant association with mortality: ΔPrs (OR, 1.08; 95% CI, 1.05-1.12), Pplat,rs (OR, 1.07; 95% CI, 1.04-1.11), and Crs (OR, 0.97; 95% CI, 0.95-0.98). Tidal volume was not associated with mortality.Interpretation: In immunocompromised patients with ARDS, respiratory mechanics provide additional prognostic information to predictors of hospital mortality. Studies designed to define lung-protective ventilation guided by these physiological variables may be warranted in this specific population.
Published: 2020

39. Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis

Author: Tanguy Chaumette, Jeremie Poschmann, Fanny Coulpier, Sophie Lemoine, Antoine Asquier, Jocelyne Caillon, Emilie Ronin, Benoît L. Salomon, Benjamin Gaborit, Virginie Le Mabecque, David Boutoille, Marie Chauveau, Cédric Jacqueline, Mickael Vourc'h, Alexandre Bourdiol, Karim Asehnoune, Antoine Roquilly, Benoit Tessoulin, Abderrahmane Sadek, Marion Davieau, Alexis Broquet, Cédric Louvet, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Hôtel-Dieu de Nantes - Centre Hospitalier Universitaire de Nantes (Hôpital Hôtel-Dieu de Nantes - CHU de Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique, Institut de Biologie de l’Ecole Normale Superieure, Paris, France
Subjects: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Staphylococcus aureus, Secondary infection, medicine.medical_treatment, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, medicine.disease_cause, T-Lymphocytes, Regulatory, Sepsis, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, Immunology and Allergy, Cells, Cultured, Immunosuppression Therapy, Mice, Knockout, Effector, business.industry, Immunosuppression, hemic and immune systems, medicine.disease, In vitro, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, CD4 Antigens, Immunology, Female, Tumor necrosis factor receptor 2, business
Abstract: Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.
Published: 2020

40. Plea for multitargeted interventions for severe COVID-19

Author: Cristina Mussini, Sharon Walmsley, Georg M. N. Behrens, Benjamin Gaborit, Jean-François Bergmann, Anton Pozniak, François Raffi, Jose R. Arribas, Department of Infectious Diseases [Nantes], Hôtel-Dieu de Nantes, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Internal Medicine Department [Paris], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Modena e Reggio Emilia (UNIMORE), Hospital Universitario La Paz [Madrid, Espagne], Hannover Medical School [Hannover] (MHH), Toronto General Hospital Research Institute [Canada] (TGHRI), Chelsea and Westminster Hospital, London School of Hygiene and Tropical Medicine (LSHTM), Bodescot, Myriam, and Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE)
Subjects: 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Psychological intervention, Antiviral Agents, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Plea, Pandemic, medicine, Humans, Immunologic Factors, Intensive care medicine, Pandemics, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, SARS-CoV-2, business.industry, COVID-19, medicine.disease, biology.organism_classification, COVID-19 Drug Treatment, Pneumonia, Infectious Diseases, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Drug Therapy, Combination, Immunotherapy, Coronavirus Infections, business, Immunosuppressive Agents
Abstract: International audience
Published: 2020
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41. Resurgence of BK virus following Covid‐19 in kidney transplant recipients

Author: Benjamin Gaborit, Amaury Dujardin, Lola Jacquemont, Franck Halary, Sabine Lebot, Jacques Dantal, Simon Ville, Delphine Kervella, Celine Bressolette‐Bodin, Lucille Figueres, Aurélie Meurette, Christophe Masset, Maryvonne Hourmant, Gilles Blancho, Clément Deltombe, Diego Cantarovich, Claire Garandeau, and Magali Giral
Subjects: Male, viruses, medicine.medical_treatment, Population, Viremia, 030230 surgery, medicine.disease_cause, Mycophenolic acid, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, education, Kidney transplantation, Immunosuppression Therapy, education.field_of_study, Polyomavirus Infections, Transplantation, business.industry, SARS-CoV-2, virus diseases, COVID-19, Immunosuppression, Middle Aged, medicine.disease, Kidney Transplantation, Transplant Recipients, BK virus, Calcineurin, Tumor Virus Infections, Infectious Diseases, BK Virus, Immunology, 030211 gastroenterology & hepatology, Female, business, Immunosuppressive Agents, medicine.drug
Abstract: Kidney transplant recipients have been supposed vulnerable to severe Covid-19 infection, due to their comorbidities and immunosuppressive therapies. Mild-term complications of Covid-19 are currently unknown, especially in this population. Herein, we report two cases of BKV replication after non-severe SARS-CoV-2 infection. The first case was a 59-year-old man, transplanted 3 months ago, with recent history of slight BKV viremia (3.3 log10 DNA copies/ml). Despite strong reduction of maintenance immunosuppression (interruption of mycophenolic acid and important decrease of calcineurin inhibitors), BKV replication largely increased after Covid-19 and viremia persisted at 4.5 log copy/ml few months later. The second case was a 53-year-old woman, transplanted 15 years ago. She had a recent history of BKV cystitis, which resolved with a decrease of MPA dosage. Few weeks after SARS-CoV-2 infection, she presented recurrence of lower urinary tract symptoms. Our reports highlight that SARS-CoV-2 infection, even without severity, could disrupt immune system and particularly lymphocytes, thus leading to viral replication. Monitoring of viral replications after Covid-19 in kidney transplant recipients could permit to confirm these preliminary observations.
Published: 2020
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42. Utility of hyposmia and hypogeusia for the diagnosis of COVID-19

Author: Sami Rehaiem, Jeanne Brochon, V. Rabier, Joël Jenvrin, Paul Le Turnier, Vincent Thibault, Anne Maillard, François Raffi, Pierre Abgueguen, Matthieu Revest, Vincent Dubée, Hélène Cormier, Faouzi Souala, Pauline Comacle, Cécile Paillé, Marie Chauveau, Benjamin Gaborit, Pierre Tattevin, Marine de la Chapelle, Rafael Mahieu, Charles Declerck, Mélanie Poinot, David Boutoille, Cédric Arvieux, Valérie Delbos, Marion Baldeyrou, Jean Marc Chapplain, Alexandra Ducancelle, Colin Deschanvres, Charlotte Pronier, François Bénézit, Yves Marie Vandamme, Solène Patrat-Delon, Maeva Lefebvre, Raphaël Lecomte, Charlotte Biron, CHU Pontchaillou [Rennes], and Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 2019-20 coronavirus outbreak, Pediatrics, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, MEDLINE, 03 medical and health sciences, Betacoronavirus, Olfaction Disorders, 0302 clinical medicine, Hyposmia, Surveys and Questionnaires, Pandemic, Medicine, Humans, 030212 general & internal medicine, Pandemics, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Internet, business.industry, SARS-CoV-2, Hypogeusia, COVID-19, 3. Good health, Infectious Diseases, France, medicine.symptom, business, Ageusia, Coronavirus Infections, 030217 neurology & neurosurgery
Abstract: International audience; [No abstract available]
Published: 2020
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43. Comparative outcomes of cefazolin versus antistaphylococcal penicillins in methicillin-susceptible Staphylococcus aureus infective endocarditis: a post hoc analysis of a prospective multicentre French cohort study

Author: Alexis Bourreau, Jocelyne Caillon, Paul Le Turnier, Raphaël Lecomte, Colin Deschanvres, Nahema Issa, Thierry Le Tourneau, Fabrice Camou, David Boutoille, Anne-Gaëlle Leroy, Marie Chauveau, and Benjamin Gaborit
Subjects: 0301 basic medicine, Microbiology (medical), Male, medicine.medical_specialty, Staphylococcus aureus, 030106 microbiology, Cefazolin, Penicillins, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, polycyclic compounds, Medicine, Endocarditis, Humans, 030212 general & internal medicine, Prospective Studies, Aged, Retrospective Studies, Antistaphylococcal penicillins, business.industry, Mortality rate, General Medicine, Odds ratio, Endocarditis, Bacterial, biochemical phenomena, metabolism, and nutrition, Middle Aged, Staphylococcal Infections, bacterial infections and mycoses, medicine.disease, Discontinuation, Anti-Bacterial Agents, Infectious Diseases, Treatment Outcome, Infective endocarditis, Female, business, medicine.drug, Cohort study
Abstract: Current guidelines recommend cefazolin as an alternative to antistaphylococcal penicillins (ASPs) in methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis despite the lack of comparative study. The objective of this study was to evaluate the comparative outcomes of cefazolin vs. ASPs in MSSA infective endocarditis.This was a retrospective analysis of an observational multicentre cohort study using prospectively collected data from patients with MSSA endocarditis confirmed by endocarditis team and treated either with cefazolin or ASPs between July 2013 and December 2018. Patients were excluded if they received both treatments. The primary outcome was 90-day all-cause mortality.Of 210 patients included, 53 patients (25.2%) received cefazolin and 157 (74.8%) received ASPs. The overall 90-day mortality rate was 27.6% (58/210 patients), 24.5% (13/53) in the cefazolin group vs. 28.7% (45/157) in the ASP group (p 0.561). Premature antimicrobial discontinuation due to adverse events occurred less frequently with cefazolin than with ASPs (0/53 vs. 13/157 patients; p 0.042). In multivariate analysis, there was no difference in 90-day mortality between cefazolin and ASPs (adjusted odds ratio (aOR), 1.2; 95% confidence interval (CI), 0.49-2.91; p 0.681), while age (aOR, 1.06; 95% CI, 1.03-1.09; p 0.001), Charlson comorbidity index (aOR, 1.18; 95% CI, 1.02-1.36 p 0.023), cerebral embolism (aOR, 2.83; 95% CI, 1.33-6.14; p 0.007) and intensive care unit admission (aOR, 4.16; 95% CI, 1.89-9.59; p 0.001) were factors significantly associated with higher mortality.Cefazolin seems to be a possible alternative to ASPs in MSSA endocarditis. More studies are needed to confirm these results and determine which treatment should be recommended as first-line therapy.
Published: 2020

44. Long-term outcome of patients with non-operated prosthetic valve infective endocarditis is relapse the main issue?

Author: Paul Le Turnier, Nahema Issa, Ousama Al Habash, François Raffi, Jean-Baptiste Laine, Colin Deschanvres, François Bénézit, Raphaël Lecomte, Nathalie Asseray, Matthieu Revest, Benjamin Gaborit, Thierry Le Tourneau, Sabine Pattier, Fabrice Camou, David Boutoille, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe hospitalier Saint-André, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Microbiology (medical), medicine.medical_specialty, Prosthetic valve, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 030204 cardiovascular system & hematology, Recurrence risk, 03 medical and health sciences, 0302 clinical medicine, Bacterial endocarditis, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, 030212 general & internal medicine, Relapse risk, Relapse, Prosthetic valve endocarditis, business.industry, Mortality rate, medicine.disease, 3. Good health, Surgery, Infectious Diseases, Infective endocarditis, business
Abstract: In nonoperated prosthetic valve endocarditis (PVE), long-term outcome is largely unknown. We report the follow-up of 129 nonoperated patients with PVE alive at discharge. At 1 year, the mortality rate was 24%; relapses and reinfection were rare (5% each). Enterococcal PVE was associated with a higher risk of relapse.
Published: 2020

45. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results

Author: Carlos Guijarro, Farid Zand, Mohamed solyman Kabil, Sven Trelle, Birgitte Tholin, Belén Comeche, Johan Alexander Azañero Haro, Gonzalo Sierra Torres, Quarraisha Abdool Karim, Kari Tikkinen, Jean-michel Molina, Atousa Hakamifard, George M Varghese, Oscar Josue Ponce Ponte, Mazin Barry, Pilar Vizcarra, Niccolo Riccardi, Natalia Pérez-Macias, Aynaa AlSharidi, Nelson Lee, Alexandra Binnie, Firouzé BANI-SADR, Beatriz Díaz-Pollán, Aldo Pietro Maggioni, Ilkka Kalliala, Florian Desgranges, Anders Benjamin Kildal, Katerina Nezvalova-Henriksen, Corinne Merle, Andrés Martín Alcántara, Benjamin Gaborit, Daniel Lozano Martín, Antonio Ramos-Martinez, Miguel Villegas-Chiroque, Fredy Orlando Guevara Pulido, Ana Fernández-Cruz, Cormac McCarthy, Thesla Palanee-Phillips, Annalisa Marinosci, Abdullah Assiri, Florent Wallet, Juan Pablo Balbuena, Avik Ray, Francesc Puchades, Rajarao Mesipogu, Marjatta Sinisalo, Jonathan Sterne, Antonio Portolés, Heike Cappel-Porter, Jussi Mustonen, Jeremy Nel, BRUNO MOURVILLIER, María Consuelo Miranda Montoya, Chiara Fanciulli, L Marjukka MyllÃ¤rniemi, Edinson Dante Meregildo Rodriguez, Alexy Inciarte, Mohamed Hassany, François Danion, Elena Muñez Rubio, Jean-Pierre QUENOT, Esperanza Merino de Lucas, Sheela Godbole, Luis Guillermo Barreto Rocchetti, Katerina Spasovska, William Connors, Kiana Shirani, Umang Agrawal, Srinivas Murthy, Bjorn Blomberg, Vasee Moorthy, Amith Balachandran, Antonio De Pablo Esteban, Mahnaz Amini, Dag Arne Lihaug Hoff, Zeinab Siami, Guillaume Martin-Blondel, Heng Gee Lee, Thrilok Chander Bingi, Vijay Krishnan, ANA BELEN RIVAS PATERNA, Eric D'Ortenzio, Samy Zaky, Carlos Arturo Alvarez-Moreno, Alonso Soto, VIKAS MARWAH, Marco Tulio Medina, Zaira R. Palacios-Baena, Jean-Sébastien Hulot, Miguel Angel Hueda Zavaleta, Felipe García, Francisco Fanjul, Hospices Civils de Lyon (HCL), INSERM UMR-S 606, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, PRES Sorbonne Paris-Cité, and Université Paris Denis Diderot, Université Paris Diderot - Paris 7 (UPD7), Michel-Avella, Amandine, Pan, H., Peto, R., Henao-Restrepo, A. -M., Preziosi, M. -P., Sathiyamoorthy, V., Karim, Q. A., Alejandria, M. M., Garcia, C. H., Kieny, M. -P., Malekzadeh, R., Murthy, S., Srinath Reddy, K., Periago, M. R., Hanna, P. A., Ader, F., Al-Bader, A. M., Alhasawi, A., Allum, E., Alotaibi, A., Alvarez-Moreno, C. A., Appadoo, S., Asiri, A., Aukrust, P., Barratt-Due, A., Bellani, S., Branca, M., Cappel-Porter, H. B. C., Cerrato, N., Chow, T. S., Como, N., Eustace, J., Garcia, P. J., Godbole, S., Gotuzzo, E., Griskevicius, L., Hamra, R., Hassan, M., Hassany, M., Hutton, D., Irmansyah, I., Jancoriene, L., Kirwan, J., Kumar, S., Lennon, P., Lopardo, G., Lydon, P., Magrini, N., Maguire, T., Manevska, S., Manuel, O., Mcginty, S., Medina, M. T., Mesa Rubio, M. L., Miranda-Montoya, M. C., Nel, J., Nunes, E. P., Perola, M., Portoles, A., Rasmin, M. R., Raza, A., Rees, H., Reges, P. P. S., Rogers, C. A., Salami, K., Salvadori, M. I., Sinani, N., Sterne, J. A. C., Stevanovikj, M., Tacconelli, E., Tikkinen, K. A. O., Trelle, S., Zaid, H., Rottingen, J. -A., Swaminathan S., &amp, Luzzati, R, Di Bella, S, Doctoral Programme in Population Health, Doctoral Programme in Biomedicine, HUS Abdominal Center, Department of Surgery, Urologian yksikkö, South Carelia Social and Health care District Eksote, HUS Heart and Lung Center, Department of Medicine, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Male, Kaplan Meier method, Intention to Treat Analysi, MESH: Treatment Failure, MESH: Hydroxychloroquine, remdesivir, Rate ratio, MESH: Intention to Treat Analysis, MESH: Length of Stay, law.invention, Lopinavir/*therapeutic use, 0302 clinical medicine, middle aged, Medicine, Hospital Mortality, MESH: Respiration, Artificial, Antiviral Agents/administration & dosage/adverse effects/*therapeutic use, comparative study, beta1a interferon, MESH: Middle Aged, Alanine, Respiration, adult, clinical trial, General Medicine, 3. Good health, Intention to Treat Analysis, [SDV] Life Sciences [q-bio], aged, health care quality, priority journal, drug withdrawal, Artificial, Interferon, Drug Therapy, Combination, medicine.medical_specialty, Initiation of ventilation, Interferon beta-1a/*therapeutic use, World Health Organization, Antiviral Agents, Article, Duration of hospital stay, antiviral drugs, 03 medical and health sciences, Drug Therapy, death, Humans, MESH: Hospital Mortality, human, MESH: Kaplan-Meier Estimate, Aged, MESH: Humans, treatment duration, extracorporeal oxygenation, Hydroxychloroquine, Length of Stay, major clinical study, mortality, Respiration, Artificial, Adenosine Monophosphate/*analogs & derivatives/therapeutic use, multicenter study, Alanine/*analogs & derivatives/therapeutic use, MESH: Interferon beta-1a, randomized controlled trial, MESH: Female, antivirus agent, [SDV]Life Sciences [q-bio], MESH: Hospitalization, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Lopinavir, Adenosine Monophosphate, COVID-19, Female, Hospitalization, Interferon beta-1a, Middle Aged, Treatment Failure, Randomized controlled trial, Interquartile range, law, MESH: COVID-19, MESH: Adenosine Monophosphate, 030212 general & internal medicine, antiviral drugs, Covid-19, MESH: Aged, Hydroxychloroquine/*therapeutic use, MESH: Lopinavir, Covid19, artificial ventilation, drug therapy, ritonavir, hospital patient, female, Combination, medicine.drug, MESH: Antiviral Agents, combination drug therapy, COVID-19/*drug therapy/mortality, Randomization, MESH: Alanine, drug repositioning, drug clearance, adenosine phosphate, coronavirus disease 2019, length of stay, Internal medicine, controlled study, Antiviral Agent, Intention-to-treat analysis, business.industry, MESH: Male, COVID-19 Drug Treatment, purl.org/pe-repo/ocde/ford#3.02.00 [https], MESH: Drug Therapy, Combination, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract: The authors report interim results of the WHO Solidarity trial of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with Covid-19. Effects on overall mortality, initiation of ventilation, and duration of hospital stay are compared. Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ; ClinicalTrials.gov number, .)
Published: 2020

46. Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study

Author: Rose-Anne Lavergne, Colin Deschanvres, Michael Vourch, Benoit Tessoulin, Emmanuel Canet, Christine Sagan, Florent Morio, Jean Reignier, L. Khatchatourian, Charlotte Garret, Benjamin Gaborit, Delphine Marest, David Boutoille, François Raffi, Nathalie Asseray, Raphaël Lecomte, and Paul Leturnier
Subjects: medicine.medical_specialty, High flow oxygen, medicine.medical_treatment, Direct examination, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Anesthesiology, Internal medicine, Cytology, Alveolitis, Medicine, Haematological malignancies, 030212 general & internal medicine, Mechanical ventilation, 0303 health sciences, medicine.diagnostic_test, 030306 microbiology, business.industry, Research, Mortality rate, lcsh:Medical emergencies. Critical care. Intensive care. First aid, lcsh:RC86-88.9, Early prognostic score, medicine.disease, Pneumocystis jirovecii pneumonia, Bronchoalveolar lavage, Primary immunodeficiency, SOFA score, business
Abstract: Background Pneumocystis jirovecii pneumonia (PJP) remains a severe disease associated with high rates of invasive mechanical ventilation (MV) and mortality. The objectives of this study were to assess early risk factors for severe PJP and 90-day mortality, including the broncho-alveolar lavage fluid cytology profiles at diagnosis. Methods We prospectively enrolled all patients meeting pre-defined diagnostic criteria for PJP admitted at Nantes university hospital, France, from January 2012 to January 2017. Diagnostic criteria for PJP were typical clinical features with microbiological confirmation of P. jirovecii cysts by direct examination or a positive specific quantitative real-time polymerase chain reaction (PCR) assay. Severe PJP was defined as hypoxemic acute respiratory failure requiring high-flow nasal oxygen with at least 50% FiO2, non-invasive ventilation, or MV. Results Of 2446 respiratory samples investigated during the study period, 514 from 430 patients were positive for P. jirovecii. Of these 430 patients, 107 met criteria for PJP and were included in the study, 53 (49.5%) patients had severe PJP, including 30 who required MV. All patients were immunocompromised with haematological malignancy ranking first (n = 37, 35%), followed by solid organ transplantation (n = 27, 25%), HIV-infection (n = 21, 20%), systemic diseases (n = 13, 12%), solid tumors (n = 12, 11%) and primary immunodeficiency (n = 6, 8%). By multivariate analysis, factors independently associated with severity were older age (OR, 3.36; 95% CI 1.4–8.5; p P. jirovecii microscopy-positive result from bronchoalveolar lavage (BAL) (OR, 1.3; 95% CI 1.54–9.3; p p p p p Conclusions Older age and P. jirovecii oocysts at microscopic examination of BAL were independently associated with severe PJP. Both initial PJP severity as evaluated by the SOFA score and viral co-infection predicted 90-day mortality. Alveolitis at BAL examination was associated with less severe PJP. The pathophysiological mechanism underlying this observation deserves further investigation.
Published: 2019

47. Listeria Endophthalmitis cured with Linezolid in an Immunocompetent Farmer Woman: Hazard of a Sweep of a Cow Tail

Author: Sophie Gibaud, Jean-Baptiste Ducloyer, L. Khatchatourian, David Boutoille, Benjamin Gaborit, Romain Lécuyer, and François Raffi
Subjects: 0301 basic medicine, medicine.medical_specialty, Listeria, 030106 microbiology, cow, linezolid, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endophthalmitis, Listeria monocytogenes, Internal medicine, medicine, 030212 general & internal medicine, ID Cases, biology, business.industry, medicine.disease, biology.organism_classification, immunocompetent, Infectious Diseases, endophthalmitis, Oncology, chemistry, Intravenous antibiotics, Linezolid, Immunocompetence, business
Abstract: We report the first case of an unexpected exogenous Listeria monocytogenes endophthalmitis in a previously healthy woman after a cow tail’s sweep, successfully treated with surgical and linezolid. It is the first case carried out with linezolid to treat Listeria endophthalmitis. Therefore, it may challenge the requirement for intravenous antibiotics for long-term treatment.
Published: 2019

48. Population Pharmacokinetic Study of Cefazolin Dosage Adaptation in Bacteremia and Infective Endocarditis Based on a Nomogram

Author: Nathalie Asseray, Matthieu Grégoire, David Boutoille, Colin Deschanvres, Ronan Bellouard, Eric Dailly, Guillaume Deslandes, Benjamin Gaborit, and Pascale Jolliet
Subjects: Male, medicine.medical_specialty, Population, Urology, Cefazolin, Renal function, Bacteremia, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, education, Aged, Aged, 80 and over, Pharmacology, Body surface area, 0303 health sciences, education.field_of_study, Endocarditis, 030306 microbiology, business.industry, Endocarditis, Bacterial, Middle Aged, Nomogram, medicine.disease, Anti-Bacterial Agents, Nomograms, Infectious Diseases, Lean body mass, Female, business, Glomerular Filtration Rate, medicine.drug
Abstract: Optimal dosing of continuous-infusion cefazolin can be challenging in patients being treated for bacteremia or infective endocarditis. The aim of this work is to describe and analyze the pharmacokinetics of cefazolin in those patients using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose. Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin for bacteremia or infective endocarditis. The influence of multiple parameters, including renal function, total body weight, body mass index, body surface area (BSA), ideal weight, lean body weight, height, and age, was tested. The probabilities of target attainment for selected target concentrations (40, 60, and 80 mg/liter) were calculated. A dosing nomogram was then developed, using the absolute value of the glomerular filtration rate (aGFR), to determine the optimal daily dose required to achieve the target concentrations in at least 90% of patients. In total, 346 cefazolin plasma concentrations from 162 patients were collected. A one-compartment model best described the data set. The only covariate was aGFR, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the patient’s body surface area, for the rate of elimination. Using the nomogram, achieving a cefazolin concentration target of 40 mg/liter with a success rate of at least 90% and with an aGFR of 30, 60, 90, and 120 ml/min requires a daily dose of 2.6, 4.3, 6.1, and 8.0 g/day, respectively. These results confirm the interest of posology adaptation of cefazolin according to aGFR.
Published: 2019

49. Comparaison de la céfazoline aux pénicillines anti-staphylococcique dans l’endocardite infectieuse à Staphylocoque doré sensible à la méticilline : analyse à partir d’une étude de cohorte prospective multicentrique

Author: A. Bourreau, Fabrice Camou, Benjamin Gaborit, Nahema Issa, J. Caillon, Colin Deschanvres, P. Le Turnier, Anne-Gaëlle Leroy, David Boutoille, and Raphaël Lecomte
Subjects: Infectious Diseases
Abstract: Introduction La cefazoline a ete montree comme etant une alternative efficace aux penicillines anti-staphylococciques (PAS) mais uniquement dans les bacteriemies a Staphylocoque dore sensible a la meticilline (SASM). Pourtant, les recommandations actuelles americaines et europeennes recommandent la cefazoline en alternative aux PAS dans l’endocardite infectieuse alors meme que cette molecule pourrait etre concernee par un effet inoculum. L’objectif de cette etude etait donc de comparer l’efficacite entre la cefazoline et les PAS dans les endocardites a SASM. Materiels et methodes Dans cette etude de cohorte bicentrique, tous les patients dont le diagnostic d’endocardite a SASM a ete retenu en reunion de concertation pluridisciplinaire endocardite entre juillet 2013 et decembre 2018 ont ete screenes. Les patients etaient inclus s’ils avaient recu soit un traitement par cefazoline, soit un traitement par PAS. Le critere de jugement principal etait la mortalite toute cause a 90 jours (J90). Les criteres de jugements secondaires etaient les emboles symptomatiques sous traitement, la rechute, la duree de la bacteriemie et les arrets de traitement pour effets indesirables. Resultats Dans cette etude, 225 patients ont ete inclus, 182 (72,0 %) dans le groupe PAS et 63 (28 %) dans le groupe cefazoline. La duree mediane de traitement etait la meme dans les deux groupes (32 jours). La mortalite globale a J90 etait de 28,4 % (64 sur 225 patients). Il n’y avait pas de difference de mortalite entre le groupe cefazoline et le groupe PAS (p = 0,91) en analyse multivariee. En revanche, l’âge (p Conclusion Nous n’avons pas retrouve de difference d’efficacite ou de tolerance entre cefazoline et penicilline anti-staphylococcique pour le traitement des endocardites a SASM. Les facteurs associes a une sur-mortalite ainsi que les facteurs protecteurs etaient ceux classiquement retrouves dans la litterature.
Published: 2020

50. Influenza and associated co-infections in critically ill immunosuppressed patients

Author: Pål Klepstad, Andry Van de Louw, Pierce Geoghegan, Elie Azoulay, Benjamin Gaborit, Jordi Rello, Ignacio Martin-Loeches, Nicolas Terzi, Pleun Hemelaar, Virginie Souppart, Katerina Rusinova, Lene B. Nielsen, Ulysses V. A. Silva, Mary Aisling McMahon, Gastón Burghi, Tine Sylvest Meyhoff, Djamel Mokart, Christophe Girault, Achille Kouatchet, Andreas Barratt-Due, Miia Valkonen, Sangeeta Mehta, Peter Schellongowski, Frédéric Pène, Anne Sophie Moreau, Fabrice Bruneel, Massimo Antonelli, Jorge I. F. Salluh, Philippe R. Bauer, Marcio Soares, Precious Pearl Landburg, Peter Pickkers, Ramin Brandt Bukan, Victoria Metaxa, Anders Perner, Sylvie Chevret, Fabio Silvio Taccone, François Barbier, Luca Montini, Virginie Lemiale, Anestesiologian yksikkö, Clinicum, HUS Perioperative, Intensive Care and Pain Medicine, and University of Helsinki
Subjects: PNEUMONIA, Male, ARDS, Soins intensifs réanimation, IMPACT, medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Respiratory failure, Critical Care and Intensive Care Medicine, Cohort Studies, 0302 clinical medicine, Risk Factors, INFECTION, Intubation, Hospital Mortality, Prospective Studies, Prospective cohort study, Hospital Mortality/trends, Critical Illness/epidemiology, Aged, 80 and over, Coinfection, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Critical illness, Immunosuppression, Influenza, Sepsis, virus diseases, Middle Aged, 3. Good health, Hospitalization, Length of Stay/statistics & numerical data, Female, medicine.medical_specialty, RESPIRATORY-FAILURE, Immunocompromised Host, 03 medical and health sciences, Influenza, Human/epidemiology, Internal medicine, Influenza, Human, Settore MED/41 - ANESTESIOLOGIA, MANAGEMENT, medicine, Humans, Coinfection/epidemiology, Immunocompromised Host/immunology, Risk factor, Propensity Score, Hospitalization/statistics & numerical data, Aged, MALIGNANCY, Performance status, business.industry, Research, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Length of Stay, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Pneumonia, 3121 General medicine, internal medicine and other clinical medicine, BACTERIAL COINFECTION, business
Abstract: Background: It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods: Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results: Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90-1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions: Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

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