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1. Sera neutralizing activities against SARS-CoV-2 and multiple variants six month after hospitalization for COVID-19

Author

Blandine Monel, David Veyer, Benoit Visseaux, Anne Blanchard, Antoine Fayol, David Lebeaux, Benoit Vedie, Maureen Betton, Hélène Péré, Jade Ghosn, Delphine Planas, Timothée Bruel, Marine Livrozet, Jean-Sébastien Hulot, Jean-Claude Manuguerra, Olivier Schwartz, Nicolas Robillard, Eric Tartour, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de biochimie [AP-HP Hôpital Européen Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], Service de Microbiologie [CHU GeorgesPompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cellule d'Intervention Biologique d'Urgence (Centre National de Référence) - Laboratory for Urgent Response to Biological Threats (National Reference Center) (CIBU), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris]-Institut Pasteur [Paris], Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), The French COVID cohort is funding by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n°20-0424). Work in OS lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. Outside the submitted work, JSH is supported by AP-HP, INSERM, the French National Research Agency (NADHeart ANR-17-CE17-0015-02, PACIFIC ANR-18-CE14-0032-01, CORRECT_LMNA ANR-19-CE17-0013-02), the ERA-Net-CVD (ANR-16-ECVD-0011-03, Clarify project), Fédération Française de Cardiologie, the Fondation pour la Recherche Médicale, and by a grant from the Leducq Foundation (18CVD05), and is coordinating a French PIA Project (2018-PSPC-07, PACIFIC-preserved, BPIFrance) and a University Research Federation against heart failure (FHU2019, PREVENT_Heart Failure)., The French COVID cohort study group : Laurent ABEL (Inserm UMR 1163, Paris, France), Claire ANDREJAK (CHU Amiens, France), François ANGOULVANT (Hôpital Necker, Paris, France), Delphine BACHELET, Krishna BHAVSAR, Lila BOUADMA, Anissa CHAIR, Camille COUFFIGNAL, Charlene DA SILVEIRA, Marie-Pierre DEBRAY, Diane DESCAMPS, Xavier DUVAL, Philippine ELOY, Marina ESPOSITO-FARESE, Nadia ETTALHAOUI, Nathalie GAULT, Jade GHOSN, Isabelle GORENNE, Isabelle HOFFMANN, Ouifiya KAFIF, Sabrina KALI, Antoine KHALIL, Cédric LAOUÉNAN, Samira LARIBI, Minh LE, Quentin LE HINGRAT, François-Xavier LESCURE, Jean Christophe LUCET, France MENTRÉ, Jimmy Mullaert, Nathan PEIFFER-SMADJA, Gilles PEYTAVIN, Carine ROY, Marion SCHNEIDER, Nassima SI MOHAMMED, Lysa TAGHERSET, Coralie TARDIVON, Marie-Capucine TELLIER, Jean-François TIMSIT, Théo TRIOUX, Sarah TUBIANA, Benoit VISSEAUX, Yazdan YAZDANPANAH (Hôpital Bichat, Paris, France), Romain BASMACI, Olivier PICONE (Hôpital Louis Mourier, Colombes, France), Sylvie BEHILILL, Sylvie VAN DER WERF, Vincent ENOUF, Hugo MOUQUET (Pasteur Institute, Paris, France), Marine BELUZE (F-CRIN Partners Platform, Paris, France), Dehbia BENKERROU, Céline DORIVAL, François TÉOULÉ, Amina MEZIANE (Inserm UMR 1136, Paris, France), François BOMPART (Drugs for Neglected Diseases initiative, Geneva, Switzerland), Maude BOUSCAMBERT (Inserm UMR 1111, Lyon, France), Minerva CERVANTES-GONZALEZ, Eric d’ORTENZIO, Oriane PUÉCHAL, Caroline SEMAILLE (REACTing, Paris, France), Catherine CHIROUZE (CHRU Jean Minjoz, Besançon, France), Alexandra COELHO (Inserm UMR 1018, Paris, France), Sandrine COUFFIN-CADIERGUES, Hélène ESPEROU, Ikram HOUAS, Salma JAAFOURA, Aurélie PAPADOPOULOS (Inserm sponsor, Paris, France), Dominique DEPLANQUE (Hôpital Calmette, Lille, France), Mathilde DESVALLÉE, Coralie KHAN (Inserm UMR 1219, Bordeaux, France), Alpha DIALLO, Marie BARTOLI, Soizic LE MESTRE, Noémie MERCIER, Christelle PAUL, Ventzislava PETROV-SANCHEZ (ANRS, Paris, France), Alphonsine DIOUF, Alexandre HOCTIN, Marina MAMBERT (Inserm UMR 1018, Paris, France), François DUBOS (CHU Lille, France), Manuel ETIENNE (CHU Rouen, France), Alexandre GAYMARD (Inserm UMR 1111, Lyon, France), Tristan GIGANTE, Morgane GILG, Bénédicte ROSSIGNOL (F-CRIN INI-CRCT, Nancy, France), Jérémie GUEDJ, Hervé LE NAGARD, Guillaume LINGAS, Nadège NEANT (Inserm UMR 1137, Paris, France), Jean-Sébastien HULOT (Hôpital Européen Georges Pompidou, Paris, France), Florentia KAGUELIDOU, Justine PAGES (Hôpital Robert Debré, Paris, France), Yves LEVY, Aurélie WIEDEMANN (Vaccine Research Insitute (VRI), Inserm UMR 955, Créteil, France), Claire LEVY-MARCHAL (F-CRIN INI-CRCT, Paris, France), Bruno LINA, Manuel ROSA-CALATRAVA, Olivier TERRIER (Inserm UMR 1111, Lyon, France), Denis MALVY (CHU Bordeaux, France), Marion NORET (RENARCI, Annecy, France), Patrick ROSSIGNOL (CHU Nancy, France), Christelle TUAL, Aurélie VEISLINGER (Inserm CIC-1414, Rennes, France), Noémie VANEL (Hôpital la Timone, Marseille, France), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-17-CE17-0015,NAD-HEART,Supplémentation en précurseur du NAD+ pour le traitement de l'insuffisance cardiaque(2017), ANR-18-CE14-0032,PACIFIC,Cellules PW1+ dans la fibrose cardiaque(2018), ANR-19-CE17-0013,Correct-LMNA,Édition génomique par CRISPR/Cas9 pour traiter les cardiomyopathies liées aux mutations du gène LMNA(2019), ANR-16-ECVD-0011,CLARIFY,Communication between cardiomyocytes and innate immune cells in failing hearts(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, and French COVID cohort study group

Subjects
0301 basic medicine, Microbiology (medical), [SDV]Life Sciences [q-bio], 030106 microbiology, Antibodies, Viral, medicine.disease_cause, Severity of Illness Index, Immunoglobulin G, Neutralization, law.invention, Serology, 03 medical and health sciences, 0302 clinical medicine, law, Intensive care, Major Article, Humans, Medicine, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Pandemics, Coronavirus, biology, SARS-CoV-2, business.industry, COVID-19, Antibodies, Neutralizing, Intensive care unit, 3. Good health, Hospitalization, Editorial Commentary, AcademicSubjects/MED00290, Infectious Diseases, Spike Glycoprotein, Coronavirus, Immunology, biology.protein, Antibody, business
Abstract

Background Humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurs within the first weeks after coronavirus disease 2019 (COVID-19). Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution over time after COVID-19 as well as efficiency against novel variants are poorly characterized. Methods In this prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3 and 6 months postinfection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-spike (S) and anti-nucleocapsid (NP) immunoglobulin G (IgG). Results Levels of seroneutralization and IgG rates against the ancestral strain decreased significantly over time. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect against SARS-CoV-2. IgG levels correlated with seroneutralization, and this correlation was stronger for anti-S than for anti-NP antibodies. The level of seroneutralization quantified at 6 months correlated with markers of initial severity, notably admission to intensive care units and the need for mechanical invasive ventilation. In addition, sera collected at 6 months were tested against multiple SARS-CoV-2 variants and showed efficient neutralizing effects against the D614G, B.1.1.7, and P.1 variants but significantly weaker activity against the B.1.351 variant. Conclusions Decrease in IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity. Our results indicate a sustained humoral response against the ancestral strain and the D614G, B.1.1.7, and P.1 variants for at least 6 months in patients previously hospitalized for COVID-19. A weaker protection was, however, observed for the B.1.351 variant.

Published
2021
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2. Colibactin‐positive Escherichia coli induce a procarcinogenic immune environment leading to immunotherapy resistance in colorectal cancer

Author

Al Hassan Casse, Guillaume Carrier, Pierre Sauvanet, Souad Naimi, Franck Pagès, Nicolas Barnich, Mathilde Bonnet, Romain Villeger, Elisabeth Billard, Arnaud Briat, Denis Pezet, Amélie Lopès, Gwenaëlle Roche, Julie Veziant, Bruno Dumas, Sanofi [Vitry-sur-Seine], SANOFI Recherche, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CIFRE grant [2015/622], Ligue contre le cancer 63/03 [2018], ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), European Project: AV001826/AV0010859,CPER, École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)

Subjects
Cancer Research, Lymphocyte T, Neutrophils, Colorectal cancer, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Microenvironnement immunitaire, Cancer colorectal, Mice, 0302 clinical medicine, T-cell, Tumor Microenvironment, Mesenteric lymph nodes, biology, Colibactin, Colibactine, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Immunotherapy, medicine.symptom, T cell, CD3, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, Escherichia coli, medicine, Animals, Humans, Lymphocyte Count, business.industry, E. coli, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Immune microenvironment, Drug Resistance, Neoplasm, Polyketides, Cancer research, biology.protein, Peptides, business, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Colibactin-producing E. coli (CoPEC) are frequently detected in colorectal cancer (CRC) and exhibit procarcinogenic properties. Because increasing evidence show the role of immune environment and especially of antitumor T-cells in CRC development, we investigated the impact of CoPEC on these cells in human CRC and in the APC(Min/+) mice colon. T-cell density was evaluated by immunohistochemistry in human tumors known for their CoPEC status. APC(min/+) mice were chronically infected with a CoPEC strain (11G5). Immune cells (neutrophils and T-cell populations) were then quantified by immunofluorescent staining of the colon. The quantification of lymphoid populations was also performed in the mesenteric lymph nodes (MLNs). Here, we show that the colonization of CRC patients by CoPEC is associated with a decrease of tumor-infiltrating T lymphocytes (CD3(+) T-cells). Similarly, we demonstrated, in mice, that CoPEC chronic infection decreases CD3(+) and CD8(+) T-cells and increases colonic inflammation. In addition, we noticed a significant decrease in antitumor T-cells in the MLNs of CoPEC-infected mice compared to that of controls. Moreover, we show that CoPEC infection decreases the antimouse PD-1 immunotherapy efficacy in MC38 tumor model. Our findings suggest that CoPEC could promote a procarcinogenic immune environment through impairment of antitumor T-cell response, leading to tumoral resistance to immunotherapy. CoPEC could thus be a new biomarker predicting the anti-PD-1 response in CRC.

Published
2020
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3. Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation

Author

Mathilde Cailliez, Christelle Barbet, Alexandre Karras, Aude Servais, Julien Hogan, Marc Fila, Fadi Fakhouri, Valérie Châtelet, Véronique Frémeaux-Bacchi, Chantal Loirat, Feriell Louillet, Cédric Rafat, Raifah Makdassi, Jean-Philippe Coindre, Yahsou Delmas, Eric Rondeau, François Provôt, Le Bihan, Sylvie, 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), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de néphrologie pédiatrique [CHU Montpellier], Hôpital Lapeyronie [Montpellier] (CHU), Service de Néphrologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Service de Néphrologie-Dialyse-Transplantation rénale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], CHU Tenon [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), Département de néphrologie pédiatrique [Marseille], CHU Marseille, Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Département de Néphrologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de néphrologie [Hôpital Européen Georges Pompidou - APHP], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Néphrologie [Amiens], CHU Amiens-Picardie-hôpital Sud, Service de Néphrologie pédiatrique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service Néphrologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Epidemiology, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Complement inhibitor, 0302 clinical medicine, Recurrence, Monoclonal, complement, Prospective Studies, Registries, Prospective cohort study, Child, Humanized, CD46, Atypical Hemolytic Uremic Syndrome, Hematologic Tests, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, creatinine, Middle Aged, Eculizumab, 3. Good health, Nephrology, Child, Preschool, Factor H, Complement Factor H, renal dialysis, Retreatment, Female, eculizumab, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Antibodies, Monoclonal, Humanized, Antibodies, Membrane Cofactor Protein, Young Adult, 03 medical and health sciences, Internal medicine, Atypical hemolytic uremic syndrome, medicine, Humans, Antigens, Aged, Retrospective Studies, Transplantation, business.industry, Retrospective cohort study, Original Articles, Complement System Proteins, medicine.disease, Discontinuation, Complement Inactivating Agents, Withholding Treatment, hemolytic uremic syndrome, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; BACKGROUND AND OBJECTIVES: The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome.DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse.RESULTS: Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (

Published
2017
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4. Insights From the Use in Clinical Practice of Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome Affecting the Native Kidneys: An Analysis of 19 Cases

Author

Valérie Châtelet, Jean-Michel Goujon, Catherine Allard, Véronique Frémeaux-Bacchi, Aude Servais, François Provôt, Alexandre Karras, Guillaume Laurent, Christelle Barbet, Yahsou Delmas, Khair Rifard, Raifah Makdassi, Virginie Besson, Maud Cousin, Fadi Fakhouri, Chantal Loirat, Cécile Courivaud, Jean-Philippe Coindre, 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), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de néphrologie et d'immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de Néphrologie et Transplantation rénale [CHRU-lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Service de néphrologie [Hôpital Européen Georges Pompidou - APHP], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Néphrologie [Amiens], CHU Amiens-Picardie-hôpital Sud, Service de Néphrologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Néphrologie [CH Bourges], CH de Bourges, Département de Néphrologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie [CHR Metz-Thionville], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Service de Néphrologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Néphrologie-Dialyse-Transplantation rénale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Pathologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service Néphrologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Néphrologie [CH Perpignan], Centre Hospitalier Saint Jean de Perpignan, Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Le Bihan, Sylvie, Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours-Hôpital Bretonneau

Subjects
Nephrology, Male, Atypical hemolytic uremic syndrome, medicine.medical_treatment, Biopsy, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Kidney, Kidney Function Tests, Gastroenterology, 0302 clinical medicine, complement, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Acute kidney injury, Eculizumab, Acute Kidney Injury, 3. Good health, thrombotic microangiopathy, Treatment Outcome, Creatinine, Female, eculizumab, France, Drug Monitoring, medicine.drug, Adult, medicine.medical_specialty, Thrombotic microangiopathy, Renal function, Antibodies, Monoclonal, Humanized, Risk Assessment, 03 medical and health sciences, Renal Dialysis, Internal medicine, medicine, Humans, Immunologic Factors, Dialysis, Retrospective Studies, business.industry, Platelet Count, medicine.disease, Surgery, Hemolytic-Uremic Syndrome, Kidney Failure, Chronic, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract

International audience; BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys.STUDY DESIGN: A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 μmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included.SETTING & PARTICIPANTS: 19 patients were identified through a query sent to all French nephrology centers.OUTCOMES & MEASUREMENTS: Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy.RESULTS: All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls.LIMITATIONS: Retrospective study and use of historical controls.CONCLUSIONS: Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.

Published
2014
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5. Atypical hemolytic uremic syndrome: from the rediscovery of complement to targeted therapy

Author

Fadi Fakhouri, Chantal Loirat, Véronique Frémeaux-Bacchi, Le Bihan, Sylvie, 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), Université de Nantes (UN)-Université de Nantes (UN), Département de néphrologie et d'immunologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
medicine.medical_specialty, Thrombotic microangiopathy, medicine.medical_treatment, Complement Pathway, Alternative, 030232 urology & nephrology, Complement, urologic and male genital diseases, Antibodies, Monoclonal, Humanized, Targeted therapy, 03 medical and health sciences, Complement inhibitor, 0302 clinical medicine, hemic and lymphatic diseases, Atypical hemolytic uremic syndrome, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Plasma therapy, Intensive care medicine, Atypical Hemolytic Uremic Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Eculizumab, medicine.disease, 3. Good health, Clinical Practice, Complement Inactivating Agents, Hemolytic-Uremic Syndrome, Alternative complement pathway, Kidney Diseases, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience; Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. In the last five years, we have finally witnessed a dramatic improvement in the management of aHUS patients, and three breakthroughs in our understanding of aHUS have led to such an improvement. The first breakthrough was the emergence of a new clinical picture of aHUS (frequency of adult cases, and overall poor renal prognosis despite plasma therapy). The second breakthrough was the identification of complement alternative pathway dysregulation as a major risk factor for aHUS. The third breakthrough was the availability in clinical practice of the first complement inhibitor, the anti-C5 monoclonal antibody, eculizumab. Available data from case series and prospective studies indicate that eculizumab use has dramatically improved the renal prognosis of aHUS. These breakthroughs have prompted the French working group on aHUS to propose a new algorithm for the management of aHUS in children and in adults. This algorithm will evolve as we gain new insights in the path-ogenesis and evolution of aHUS in the eculizumab era.

Published
2013
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6. Obstetric Nephrology: AKI and Thrombotic Microangiopathies in Pregnancy

Author

Caroline Vercel, Véronique Frémeaux-Bacchi, Fadi Fakhouri, 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), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Alexion., and Le Bihan, Sylvie

Subjects
HELLP Syndrome, Thrombotic microangiopathy, Complications of pregnancy, Epidemiology, 030232 urology & nephrology, Thrombotic thrombocytopenic purpura, Receptors, Cell Surface, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Antigens, CD, Pregnancy, Atypical hemolytic uremic syndrome, medicine, Animals, Humans, Eclampsia, Transplantation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Vascular Endothelial Growth Factor Receptor-1, business.industry, Thrombotic Microangiopathies, Endoglin, Eculizumab, Acute Kidney Injury, medicine.disease, 3. Good health, Nephrology, Immunology, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience; AKI in pregnancy remains a cause of significant fetomaternal mortality and morbidity, particularly in developing countries. Hypertensive complications of pregnancy (preeclampsia/eclampsia or hemolysis, elevated liver enzymes, and low platelets count syndrome) are the leading cause of AKI in pregnancy worldwide. Thrombotic microangiopathy is another peculiar and devastating cause of AKI in pregnancy. During the last decade, our understanding, and in some cases, our management, of these causes of AKI in pregnancy has dramatically improved. For instance, convincing data have linked pre-eclampsia/eclampsia to an increase in circulating antian-giogenic factors soluble Flt 1 and endoglin, which induce endothelial cell dysfunction, hypertension, and proteinuria. Several distinct pathogenic mechanisms underlying thrombotic microangiopathy, including throm-botic microangiopathy occurring during pregnancy, have been established. Thrombotic microangiopathy, which can present as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, can be reclassified in four potentially overlapping subtypes: disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency-related thrombotic microangiopathy, complement alternative pathway dysregulation-related thrombotic microangiopathy, secondary thrombotic microangiopathy (verotoxin and antiangiogenic drugs), and thrombotic microangiopathy of undetermined mechanism. In most cases, pregnancy is only a precipitating factor for thrombotic microangiopathy. Treatment of thrombotic microangiopathy occurring during pregnancy should be tailored to the underlying pathogenic mechanism: (1) restoration of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 serum activity in the setting of thrombotic thrombocytopenic purpura through plasma exchanges and in some cases, B cell-depleting therapy and (2) inhibition of complement alternative pathway activation in atypical hemolytic uremic syndrome using antiC5 blocking antibody (eculizumab).

Published
2012
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