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1. Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model.

Author

Jean-Philippe Barnier, Daniel Euphrasie, Olivier Join-Lambert, Mathilde Audry, Sophia Schonherr-Hellec, Taliah Schmitt, Sandrine Bourdoulous, Mathieu Coureuil, Xavier Nassif, and Mohamed El Behi

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.

Published
2021
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2. Airway Mucus Restricts Neisseria meningitidis Away from Nasopharyngeal Epithelial Cells and Protects the Mucosa from Inflammation

Author

Mathilde Audry, Catherine Robbe-Masselot, Jean-Philippe Barnier, Benoit Gachet, Bruno Saubaméa, Alain Schmitt, Sophia Schönherr-Hellec, Renaud Léonard, Xavier Nassif, and Mathieu Coureuil

Subjects
airway mucus, host-pathogen interaction, meningitis, nasopharynx, Neisseria meningitidis, Microbiology, QR1-502
Abstract

ABSTRACT Neisseria meningitidis is an inhabitant of the nasopharynx, from which it is transmitted from person to person or disseminates in blood and becomes a harmful pathogen. In this work, we addressed colonization of the nasopharyngeal niche by focusing on the interplay between meningococci and the airway mucus that lines the mucosa of the host. Using Calu-3 cells grown in air interface culture (cells grown with the apical domain facing air), we studied meningococcal colonization of the mucus and the host response. Our results suggested that N. meningitidis behaved like commensal bacteria in mucus, without interacting with human cells or actively transmigrating through the cell layer. As a result, type IV pili do not play a role in this model, and meningococci did not trigger a strong innate immune response from the Calu-3 cells. Finally, we have shown that this model is suitable for studying interaction of N. meningitidis with other bacteria living in the nasopharynx and that Streptococcus mitis, but not Moraxella catarrhalis, can promote meningococcal growth in this model. IMPORTANCE N. meningitidis is transmitted from person to person by aerosol droplets produced by breathing, talking, or coughing or by direct contact with a contaminated fluid. The natural reservoir of N. meningitidis is the human nasopharynx mucosa, located at the back of the nose and above the oropharynx. The means by which meningococci cross the nasopharyngeal wall is still under debate, due to the lack of a convenient and relevant model mimicking the nasopharyngeal niche. Here, we took advantage of Calu-3 cells grown in air interface culture to study how meningococci colonize the nasopharyngeal niche. We report that the airway mucus is both a niche for meningococcal growth and a protective barrier against N. meningitidis infection. As such, N. meningitidis behaves like commensal bacteria and is unlikely to induce infection without an external trigger.

Published
2019
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3. The metabolic enzyme fructose-1,6-bisphosphate aldolase acts as a transcriptional regulator in pathogenic Francisella

Author

Jason Ziveri, Fabiola Tros, Ida Chiara Guerrera, Cerina Chhuon, Mathilde Audry, Marion Dupuis, Monique Barel, Sarantis Korniotis, Simon Fillatreau, Lara Gales, Edern Cahoreau, and Alain Charbit

Subjects
Science
Abstract

The enzyme fructose-bisphosphate aldolase (FBA) plays central roles in glycolysis and gluconeogenesis. Here, Ziveri et al. show that FBA of the pathogen Francisella novicida acts, in addition, as a transcriptional regulator and is important for bacterial multiplication in macrophages.

Published
2017
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4. Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model

Author

Mathieu Coureuil, Taliah Schmitt, Xavier Nassif, Sandrine Bourdoulous, Mohamed El Behi, Daniel Euphrasie, Olivier Join-Lambert, Mathilde Audry, Sophia Schönherr-Hellec, Jean-Philippe Barnier, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Bourdoulous, Sandrine

Subjects
Bacterial Diseases, Bacterial Lethality, Physiology, Bacteremia, Mice, SCID, Meningococcal Disease, Pilus retraction, Neisseria meningitidis, Pathology and Laboratory Medicine, medicine.disease_cause, Bacterial Adhesion, Pilus, Mice, Medical Conditions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Biology (General), Immune Response, 0303 health sciences, Skin Transplantation, Bacterial Pathogens, Body Fluids, 3. Good health, Infectious Diseases, Blood, Medical Microbiology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Fimbriae Proteins, Pathogens, Cellular Structures and Organelles, Anatomy, medicine.symptom, Neisseria, Research Article, Pathogen Motility, QH301-705.5, Virulence Factors, Immunology, Inflammation, Biology, Meningococcal disease, Microbiology, Sepsis, 03 medical and health sciences, Signs and Symptoms, Virology, Genetics, medicine, Animals, Humans, Microbial Pathogens, Molecular Biology, 030304 developmental biology, Bacteria, 030306 microbiology, Organisms, Endothelial Cells, Biology and Life Sciences, Bacteriology, Cell Biology, RC581-607, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Meningococcal Infections, Disease Models, Animal, Pili and Fimbriae, Fimbriae, Bacterial, Humanized mouse, Parasitology, Immunologic diseases. Allergy, Clinical Medicine, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis., Author summary Invasive meningococcal diseases remain a major cause of fatal sepsis. A specific feature of Neisseria meningitidis is its ability to colonize the blood microvessels in a type IV pilus (TFP)-dependent mechanism. TFP are filamentous appendages that undergo retraction through a mechanism dependent on the PilT ATPase. Here, we assess the role of TFP retraction in the pathophysiology of meningococcal infection using a humanized model of SCID mice grafted with human skin. We show that human skin graft microvessels are replicative niches for N. meningitidis that promote sustained bacteremia and subsequent lethality. Intriguingly, although pilus retraction-deficient N. meningitidis (ΔpilT) efficiently colonizes human grafts, this mutant strain did not promote sustained bacteremia nor induce mouse lethality. This drastic decrease in virulence was not due to a decreased inflammatory response or to a defect in bacterial clearance by the innate immune system. Rather, we demonstrate that pilus retraction was crucial to obtain a sustained bacteremia by allowing the release of bacteria from colonized microvessels and that lethality was directly linked to sustained bacteremia. Altogether, these data demonstrate the important role of pilus retraction in meningococcal pathogenesis and infection outcome and open new questions regarding the impact of circulating bacteria on the host during lethal sepsis.

Published
2021

5. Airway Mucus Restricts Neisseria meningitidis Away from Nasopharyngeal Epithelial Cells and Protects the Mucosa from Inflammation

Author

Alain Schmitt, Bruno Saubaméa, Renaud Léonard, Benoit Gachet, Catherine Robbe-Masselot, Xavier Nassif, Mathieu Coureuil, Mathilde Audry, Jean-Philippe Barnier, Sophia Schönherr-Hellec, Université de Lille, CNRS, Université Paris Descartes - Paris 5 [UPD5], Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], CHU Necker - Enfants Malades [AP-HP], Plates-formes mutualisées du centre de recherche pharmaceutique de Paris [P-MIM - UMS 3612], Institut Cochin [IC UM3 (UMR 8104 / U1016)], Université Paris Descartes - Paris 5 (UPD5), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plates-formes mutualisées du centre de recherche pharmaceutique de Paris (P-MIM - UMS 3612), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, LillOA, Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Mucositis, Host–pathogen interaction, [SDV]Life Sciences [q-bio], 030106 microbiology, lcsh:QR1-502, Biology, host-pathogen interaction, medicine.disease_cause, Microbiology, Pilus, airway mucus, lcsh:Microbiology, Cell Line, Host-Microbe Biology, nasopharynx, Moraxella catarrhalis, 03 medical and health sciences, neisseria meningitidis, Streptococcus mitis, medicine, Humans, Immunologic Factors, Molecular Biology, Pathogen, Innate immune system, Neisseria meningitidis, meningitis, Epithelial Cells, Models, Theoretical, biology.organism_classification, Mucus, QR1-502, 3. Good health, [SDV] Life Sciences [q-bio], [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, 030104 developmental biology, Commentary, commensal
Abstract

The work presented by Audry et al. (M. Audry, C. Robbe-Masselot, J.-P. Barnier, B. Gachet, et al., mSphere 4:e00494-19, 2019, https://doi.org/10.1128/mSphere.00494-19) gives new insight into the interactions of Neisseria meningitidis and the human nasopharynx., The work presented by Audry et al. (M. Audry, C. Robbe-Masselot, J.-P. Barnier, B. Gachet, et al., mSphere 4:e00494-19, 2019, https://doi.org/10.1128/mSphere.00494-19) gives new insight into the interactions of Neisseria meningitidis and the human nasopharynx. Using an air interface tissue culture model of a polarized, mucus-secreting epithelium, Audry et al. demonstrate that N. meningitidis bacteria do not commonly invade epithelial cells. Rather, they are trapped in the mucus layer, where they are protected from dessication. In this model, meningicocci fail to elicit a pro-inflammatory immune response and show growth effects in response to another nasopharyngeal colonizer, Streptococcus mitis. These findings prompt new questions about pathobiont behaviors, the role of mucus in bacterium-host interactions, and modeling human infection.

Published
2019

6. Air-interfaced colonization model suggests a commensal-like interaction of Neisseria meningitidis with the epithelium, which benefit from colonization by Streptococcus mitis

Author

Benoit Gachet, Renaud Léonard, Mathilde Audry, Barnier J, Bruno Saubaméa, Alain Schmitt, Xavier Nassif, Sophia Schönherr-Hellec, Mathieu Coureuil, and Catherine Robbe-Masselot

Subjects
0303 health sciences, Innate immune system, biology, 030306 microbiology, Neisseria meningitidis, medicine.disease_cause, biology.organism_classification, Commensalism, Mucus, Microbiology, Moraxella catarrhalis, 03 medical and health sciences, Streptococcus mitis, medicine, Colonization, Pathogen, 030304 developmental biology
Abstract

Neisseria meningitidisis an inhabitant of the nasopharynx, from which it is transmitted from person to person or disseminates in the blood and becomes a harmful pathogen. In this work, we addressed the colonization of the nasopharyngeal niche by focusing on the interplay between meningococci and the mucus that lines the mucosa of the host. Using Calu-3 cells grown in air-interfaced culture, we studied the meningococcal colonization of the mucus and the host response. Our results suggested thatN. meningitidisbehaved like commensal bacteria in mucus, without interacting with human cells or actively transmigrating through the cell layer. As such, meningococci did not trigger a strong innate immune response from the Calu-3 cells. Finally, we have shown that this model is suitable for studying interaction ofN. meningitidiswith other bacteria living in the nasopharynx, and thatStreptococcus mitisbut notMoraxella catarrhaliscan promote meningococcal growth in this model.

Published
2019
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7. Analysis of drug transporter expression in human intestinal Caco-2 cells by real-time PCR

Author

Nathalie Maubon, Marc Le Vee, Lina Fossati, Mathilde Audry, Sébastien Bolze, Eric Le Ferrec, Olivier Fardel, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
ATP Binding Cassette Transporter, Subfamily B, MESH: P-Glycoprotein, Cell, Organic Anion Transporters, ATP-binding cassette transporter, Biology, 030226 pharmacology & pharmacy, MESH: Membrane Transport Proteins, 03 medical and health sciences, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, medicine, Humans, Pharmacology (medical), ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Messenger, Intestinal Mucosa, Caco-2 cells, intestine, 030304 developmental biology, MESH: RNA, Messenger, Pharmacology, MESH: Organic Anion Transporters, 0303 health sciences, Messenger RNA, MESH: Humans, Reverse Transcriptase Polymerase Chain Reaction, Multidrug resistance-associated protein 2, Membrane Transport Proteins, Transporter, Reference Standards, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Multidrug Resistance-Associated Protein 2, 3. Good health, medicine.anatomical_structure, Real-time polymerase chain reaction, Biochemistry, Caco-2, transporter, MESH: Reference Standards, Efflux, MESH: Caco-2 Cells, Multidrug Resistance-Associated Proteins, real-time PCR, absorption, MESH: Multidrug Resistance-Associated Proteins, MESH: Intestines
Abstract

International audience; Expression of drug transporters corresponds to a crucial parameter in intestinal Caco-2 cells widely used for investigating drug absorption. In order to characterize it in an accurate, reproducible and comparative manner, we analyzed mRNA levels of 19 influx and efflux drug transporters through real-time quantitative polymerase chain reaction assays combined with the use of a total RNA reference standard. Profiles of transporter expression were found to be significantly correlated in two independent Caco-2 cell clones and in human small intestine, which may support the use of Caco-2 cells for investigating intestinal drug transport. Several transporters were nevertheless quantitatively expressed at higher (MRP2, MRP3, MRP4, MRP5, MRP6, OATP-A, OATP-B, OCT1 and MCT1) or lower (BCRP) levels in Caco-2 cells comparatively to small intestine. Moreover, MDR1, MRP2, OATP-A and PEPT1 mRNA relative expression were found to differ in the two analyzed Caco-2 cell clones by at least a twofold factor, highlighting that some variations in transporter expression may occur in Caco-2 cells depending on cell origin, and therefore underlining the interest of carefully characterizing transporter levels in any Caco-2 cell clone before its use for drug transport assays.

Published
2007

8. Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial

Author

Zuily, Stéphane, Lefèvre, Benjamin, Sanchez, Olivier, Empis de Vendin, Ombeline, de Ciancio, Guillaume, Arlet, Jean-Benoît, Khider, Lina, Terriat, Béatrice, Greigert, Hélène, Robert, Céline, Louis, Guillaume, Trinh-Duc, Albert, Rispal, Patrick, Accassat, Sandrine, Thiery, Guillaume, Montani, David, Azarian, Réza, Meneveau, Nicolas, Soudet, Simon, Le Mao, Raphaël, Maurier, François, Le Moing, Vincent, Quéré, Isabelle, Yelnik, Cécile, Lefebvre, Nicolas, Martinot, Martin, Delrue, Maxime, Benhamou, Ygal, Parent, Florence, Roy, Pierre-Marie, Presles, Emilie, Goehringer, François, Mismetti, Patrick, Bertoletti, Laurent, Rossignol, Patrick, Couturaud, Francis, Wahl, Denis, Thilly, Nathalie, Laporte, Silvy, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), F-Crin Innovte [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHR de Metz-Thionville, Centre Hospitalier Agen-Nérac, Hôpital Bicêtre, Université Paris-Saclay, Centre Hospitalier de Versailles André Mignot (CHV), Department of Cardiology, University Hospital Jean Minjoz, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), UNEOS, Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Lapeyronie [Montpellier] (CHU), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lille, CHU Lille, Centre National de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpitaux Civils de Colmar, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA), CHU d'Angers [Département Urgences], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université Jean Monnet - Saint-Étienne (UJM), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Service de Chirurgie Vasculaire [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre Hospitalier Princesse Grace, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole., and COVI-DOSE investigators: Stéphane Zuily, Francis Couturaud, François Goehringer, Silvy Laporte, Patrick Mismetti, Emilie Presles, Patrick Rossignol, Nathalie Thilly, Denis Wahl, Thomas Lecompte, Emmanuel Oger, Marie-Antoinette Sevestre, Florence Parent, Ygal Benhamou, Pierre-Marie Roy, Tristan Gigante, Morgane Gilg, Pierre-Luc Maclot, Bénédicte Rossignol, Jonathan Udot, Hélène Bouteille, Andréa Buchmuller, Céline Peurière, El Mehdi Siaghy, Valérie Bouaziz, Charlotte Daguin, Benjamin Grosjean, Véronique Saunier, Laurence Verger, Madlyne Jacquot, Nadine Petitpain, Martin Charly, Laurent Tordella, Emilie Presles, Guillaume Baronnet, Elisabeth Baux, Athanase Benetos, Jean-Baptiste Blanvillain, Marie Conrad, Guilhem Courte, Aurélie Cravoisy-Popovic, Virginie Dufrost, Sébastien Gibot, Philippe Guerci, Laure Joly, Antoine Kimmoun, Matthieu Koszutski, Alexandrine Larue, Bruno Levy, Marie-Reine Losser, Mathieu Mattei, Lionel Nace, Emmanuel Novy, Pierre Perez, Jean-Pierre Pertek, Camille Rigaux, Alexis Sauvage, Evelyne Schvoerer, Carine Thivilier, Lev Volkov, Piotr Zieminski, Manil Benlounes, Charles Cheng, Jean-Baptiste de Fréminville, Grégoire Détriché, Emmanuel Flammarion, Guillaume Goudot, Amer Hamdan, Raphaël Hindré, Corina Manoli, Emmanuel Messas, Adrien Michon, Tristan Mirault, Jean Pastré, Marie-Aude Penet, Benjamin Planquette, Geoffroy Volle, Rémy Hamdan, Aline Laubriet-Jazayeri, Vincent Petit, Lionel Piroth, Jean Pierre Quenot, Mélissa Saccu, Damien Barraud, Zoé Cavalli, Rostane Gaci, Mathilde Andreu, Laurent Bertoletti, Andréa Buchmuller, Elodie De Magalhaes, Sophie Bulifon, Athénaïs Boucly, Nathan Ebstein, Marc Humbert, Xavier Jaïs, Mitja Jevnikar, Laurent Savale, Andrei Horia Seferian, Charlotte Colin, Timothée Ganem, Mehdi Roumila, Romain Chopard, Matthieu Besutti, Basile Mouhat, Claire Andrejak, Stéphane Dupas, Gaëlle Le Roy, Santhi Samy-Modeliar, Anne Coste, Alexandre Fauche, David Goetghebeur, Christophe Gut-Gobert, Clément Hoffmann, Baptiste Hourmant, Cécile L'hévéder, Emmanuelle Lemoigne, Olivier Nepveu, Raphaël Paret, Gaël Picart, Saïd Azerkan, Chadia Boudaa, Julien Campagne, Peter Eszto, Benoît Godbert, Jean-François Guichard, Marion Heschung, Antoine Legoff, Jacques Mariot, Pascale Martin, Magalie Mercy, Julie Perrin, Stéphane Raymond, Nathalie Vernier, Pierre Fesler, Pierrick Henneton, Cédric Mercuzot, Nathalie Pansu, Lucas Perez, Loïc Andre, Edgar Bakhache, Marie-Charlotte Chopin, Marie Gilbert, Marc Lambert, Mohammad Ryadh Pokeerbux, François Danion, Yves Hansmann, Estelle Rougier, Yvon Ruch, Dominique Stéphan, Axel Ursenbach, Isabelle Connerade, Simon Gravier, Damien Kayser, Jean-Marc Michel, Mahsa Mohseni, Waël Younes, Ruxandra Burlacu, Amanda Lopes, Stéphane Mouly, Kladoum Nassarmadji, Damien Sène, Virginie Siguret, Alain Stepanian, Cédric Annweiler, Antoine Brangier, Vincent Dubee, Samir Henni, Jeanne Hersant, Jocelyne Loison, Léa Kern, Jean-Baptiste Laine, Claire Neveux-Brecheteau, Lucia Perez, Ruben Benainous, Bénédicte Giroux-Leprieur, Marilucy Lopez-Sublet, Saïda Khaled-Jousselin, Yohann Bernard, Amélie Amiot, Jessica Breistroff, Emilie Detry, Kadidiatou Diallo, Agnès Didier, Nathalie Dumont, Julie Egensperger, Aurélie Emmerich, Nelly François, Fanny Gallo, Valérie George, Quentin Gérome, Aurélie Gutehrle, Laure Lehman, Séverine Petit, Vanessa Piard, Maximilien Saint-Gilles, Olivier Terenzi, Amélie Marquette, Hélène Mortelette, Mathilde Audry, Amélie Cransac, Marine Maillard, Anaïs Boyer, Floriana Gallo, Arielle Urbing, Imane Zahaf, Alexandra Byczko, Amina Chaalal, Georgette Berlier, Corinne Bernabe, Souad Bezzeghoud, Caroline Chaudier, Carole Chauvet, Marina Davier, Carine Labruyere, Estelle Perrin, Michaël Pierre, Claire-Annissa Chekirine, Florence Voivret, Ramdane Meftali, Ouaffa Sabri, Anaïs Beulaygue, Julie Gall, Laure Girard, Soumia Haddaoui, Scheherazade Rami, Auriane Couderc, Aude Le Breton, Marie-Line Perruche, Cindy Claudon, Ludivine Roussel, Aude Barnier, Tiphaine Blanchard, Bénédicte Le Gall, Mélanie Pelouin, Anne-Sophie Veillon, Quam Aquereburu, Charlène Delaygue, Zahoua Ait Idir, Jérémy Drugeon, Déborah Dubrulle, Rabah Tezkratt, Anne-Sophie Frantz, Julie Drouaine, Jacqueline Dubois, Magali Eyriey, Elina Haerrel, Mélinda Beaudenon, Mialy Guenet, Thibaud Lecerf, Stéphanie Marechal-Girault, Sami Rehaiem, Romain Simon, Florence Dangeul-Potier, Morgane Goulvent, Souha Fliss, Fadhila Messani, Béatrice Mizejewski, Brigitte Mugnier, Valérie Opderbeck, Brigitte Risse

Subjects
Anticoagulation, Heparin, [SDV]Life Sciences [q-bio], COVID-19, Venous thromboembolism
Abstract

International audience; Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.

Published
2023

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