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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. Impact of hypertensive emergency and complement rare variants on presentation and outcome of atypical hemolytic uremic syndrome

Author

Karoui, Khalil, Boudhabhay, Idris, Petitprez, Florent, Vieira-Martins, Paula, Fakhouri, Fadi, Zuber, Julien, Aulagnon, Florence, Matignon, Marie, Rondeau, Eric, Mesnard, Laurent, Halimi, Jean-Michel, Frémeaux-Bacchi, Véronique, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Immunotherapy in Transplantation And Autoimmunity (Team 3 - U1064 Inserm - CRTI), 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 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), Service de néphrologie et transplantation rénale [Hôpital Necker Enfants Malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, This work was supported by grants from the SFNDT (société francophone de Néphrologie, Dialyse et Transplantation) (to KEK), from the Délégation Régionale à la Recherche Clinique, Assistance Publique – Hôpitaux de Paris (Programme Hospitalier de Recherche Clinique (AOM08198) (to VFB), by the EU FP7 Grant 2012-305608 (EURenOmics) (to VFB), the Fondation Du Rein (FRM, Prix 2012 FDR) (to VFB), the Association pour l’Information et la Recherche dans les maladies Rénales génétiques (AIRG France). FP is supported by a CARPEM (CAncer Research for PErsonalized Medicine) doctoral fellowship., 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 néphrologie et immunologie clinique [CHRU Tours], and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)

Subjects
Platelets, complement gene variant, hypertensive emergency, hemolytic uremic syndrome, Thrombotic Thrombocytopenic Purpura, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Atypical hemolytic uremic syndrome is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180mmHg) or diastolic (>120mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic atypical hemolytic uremic syndrome. We sought to retrospectively evaluate the clinical, biological and complement genetic characteristics of 76 and 61 atypical hemolytic uremic syndrome patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-hemolytic uremic syndrome were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one complement rare variant was identified in 51.3% (39/76) and in 67% (41/61) patients with or without hypertensive emergency, respectively (p=0.06). In both group, renal prognosis was severe with 23% and 40% of patients reaching end stage renal disease after a 5-year follow-up (p=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency nor complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or complement variant (p=0.02). In patients without hypertensive emergency, 5-year renal survival was 100% vs 40% with or without Eculizumab, respectively (p

Published
2019
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4. 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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5. 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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6. Malignancy and thrombotic microangiopathy or atypical haemolytic and uraemic syndrome?

Author

Véronique Frémeaux-Bacchi, Vincent L.M. Esnault, Hervé Hyvernat, Fadi Fakhouri, Guillaume Favre, Maxime Touzot, Viviane Queyrel, Jean-Pierre Gueffet, Pierre Rohrlich, Service de Néphrologie [Hôpital Pasteur, Nice], Hôpital Pasteur [Nice] (CHU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), 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), Service de Néphrologie [Nantes], 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), Unité de Soins Intensifs [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Cardiologie [CHU Nantes], Service Hématologie [CHU Nice], Service de médecine interne [Nice], COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Le Bihan, Sylvie

Subjects
medicine.medical_specialty, Thrombotic microangiopathy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Acute kidney injury, Hematology, medicine.disease, Malignancy, Gastroenterology, 3. Good health, thrombotic microangiopathy, Uraemic syndrome, acute kidney injury, Internal medicine, medicine, Carcinoid tumour, acute myeloid leukaemia, business, carcinoid tumour, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, atypical haemolytic and uraemic syndrome
Abstract

International audience

Published
2014

7. 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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8. 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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9. Humoral complementomics - exploration of noninvasive complement biomarkers as predictors of renal cancer progression.

Author

Revel M, Rezola Artero M, Hamidi H, Grunenwald A, Blasco L, Vano YA, Marie Oudard S, Sanchez-Salas R, Macek P, Rodriguez Sanchez L, Cathelineau X, Vedié B, Sautes-Fridman C, Herman Fridman W, Roumenina LT, and Dragon-Durey MA

Subjects
Humans, Prospective Studies, Biomarkers metabolism, Autoantibodies, Carcinoma, Renal Cell diagnosis, Kidney Neoplasms diagnosis, Kidney Neoplasms metabolism
Abstract

Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2024
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10. Clinical Relevance of Anti-C3 and Anti-C4 Autoantibodies in Lupus Nephritis.

Author

Vasilev V, Artero MR, Petkova M, Mihaylova G, Dragon-Durey MA, Radanova M, and Roumenina LT

Abstract

Introduction: Complement system overactivation is pivotal in lupus nephritis (LN) pathophysiology. Considering that anti-C3 autoantibodies play a significant role in LN pathophysiology, we explored them as disease activity biomarkers and compared them to the ones against the homologous protein, C4., Methods: We investigated the presence of anti-C3 and anti-C4 IgG autoantibodies in a LN cohort ( N  = 85 patients) and monitored their changes over time. We correlated autoantibody presence with clinical parameters. We conducted cross-sectional and longitudinal analyses ( N  = 295 samples, 8 years follow-up) to explore associations between autoantibodies and disease progression. Antigen-specific anti-C3 or anti-C4 IgG were purified from plasma by affinity chromatography and their reactivity was tested for cross-reactivity against purified C3 or C4 by enzyme-linked immunosorbent assay (ELISA)., Results: The reactivity against C3 was independent of C4. Our study revealed distinct roles for anti-C3 and anti-C4 in LN. Anti-C3 IgG exhibited stronger clinical correlations than anti-C4, showing associations with hypocomplementemia, anti-dsDNA, class IV LN, and active disease according to British Isles Lupus Assessment Group (BILAG) renal score. In a longitudinal analysis, anti-C3 positivity at initial sampling predicted present and future disease exacerbation alone and even better when combined with anti-dsDNA, as indicated by a transition to BILAG category A., Conclusion: Our research provides insights into anti-C3/C3b and anti-C4 autoantibodies in LN, revealing that they are often not cross-reactive. Anti-C3 utility as disease activity biomarkers is underscored by its stronger clinical associations and predictive value for future flares. Combining anti-C3 and anti-dsDNA out-performs the 2 factors alone, suggesting that the incorporation of anti-C3/C3b quantification into routine clinical practice could improve LN management., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Published
2024
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11. [Advice in autoimmunity biological diagnosis: guidelines for drafting comments on biological results].

Author

Sénant M, Dragon-Durey MA, Dumestre-Perard C, Musset L, Guis-Cabanne L, Alyanakian MA, Allenbach Y, Goncalves D, and Fabien N

Subjects
Humans, Reference Standards, Autoimmunity, Accreditation
Abstract

The ISO 15189 accreditation of biological analysis requires the presence of interpretation in the analysis report. The interpretation in the field of autoimmunity which includes many analyses and methods can be complex for biologists who may not have clinical data and for clinicians who may not be aware of technical difficulties. The French group of the european group EASI (European autoimmunity standardisation initiative) proposes a list of comments and advice in order to help biologists when interpreting auto-immune analyses results in several situations. These comments should be adapted to the clinical and biological situation (other biological results, clinical data…) and should alert the clinician. A dialogue between the biologist and the clinician is essential to adjust the interpretation on clinical data in order to provide a better health care for the patient.

Published
2023
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12. Repository of intra- and inter-run variations of quantitative autoantibody assays: a European multicenter study.

Author

Dragon-Durey MA, Bizzaro N, Senant M, Andreeva H, Bogdanos DP, Bonroy C, Bossuyt X, Eriksson C, Fabien N, Heijnen I, Herold M, Musset L, Kuhi L, Lopez-Hoyos M, Berki T, Roozendaal C, Sack U, Sundic T, Taylor L, Kuna AT, and Damoiseaux J

Subjects
Humans, Laboratories, Quality Control, Reference Standards, Autoantibodies, Clinical Laboratory Services
Abstract

Objectives: No reference data are available on repositories to measure precision of autoantibody assays. The scope of this study was to document inter- and intra-run variations of quantitative autoantibody assays based on a real-world large international data set., Methods: Members of the European Autoimmunity Standardisation Initiative (EASI) group collected the data of intra- and inter-run variability obtained with assays quantifying 15 different autoantibodies in voluntary participating laboratories from their country. We analyzed the impact on the assay performances of the type of immunoassay, the number of measurements used to calculate the coefficient of variation (CVs), the nature and the autoantibody level of the internal quality control (IQC)., Results: Data were obtained from 64 laboratories from 15 European countries between February and October 2021. We analyzed 686 and 1,331 values of intra- and inter-run CVs, respectively. Both CVs were significantly dependent on: the method of immunoassay, the level of IQC with higher imprecision observed when the antibody levels were lower than 2-fold the threshold for positivity, and the nature of the IQC with commercial IQCs having lower CVs than patients-derived IQCs. Our analyses also show that the type of autoantibody has low impact on the assay' performances and that 15 measurements are sufficient to establish reliable intra- and inter-run variations., Conclusions: This study provides for the first time an international repository yielding values of intra- and inter-run variation for quantitative autoantibody assays. These data could be useful for ISO 15189 accreditation requirements and will allow clinical diagnostic laboratories to assure quality of patient results., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Published
2022
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13. Precision of autoantibody assays in clinical diagnostic laboratories: What is the reality?

Author

Senant M, Musset L, Chyderiotis G, Guis-Cabanne L, Damoiseaux J, Fabien N, and Dragon-Durey MA

Subjects
Accreditation, Autoimmune Diseases blood, Autoimmune Diseases diagnosis, France, Humans, Quality Control, Reference Standards, Reproducibility of Results, Sensitivity and Specificity, Surveys and Questionnaires, Autoantibodies analysis, Clinical Laboratory Techniques standards, Immunoassay standards
Abstract

Background: ISO 15189 accreditation remains a challenge for specialized laboratories. In the field of autoimmunity, beside the crucial problem of absence of standardization, laboratories have to manage the analytical performances of the large panel of assays in terms of sensitivity and specificity, but also on their measurement precision for which no reference values are available on biorepositories., Methods: As an initiative of the French EASI (European Autoimmunity Standardization Initiative) group, French clinical diagnostic laboratories were requested to participate in a survey aiming to analyze the coefficients of variation (CVs) of intra-run and inter-run variability obtained with assays quantifying 14 different autoantibodies. Two performance goals corresponding to the 90th percentile and the 50th percentile (lowest CV values reached by 90% and 50% of laboratories respectively) defined for three levels of concentration were calculated. The impact on the assay performances of the number of measurements, of the nature of the internal quality control (IQC) and the type of immunoassay, was also analyzed., Results: 414 and 616 values of intra-run and inter-run CVs were collected, respectively. The 50th percentile performance goals were comprised between 1.0% and 8.9% for the intra-run CVs, and between 1.8% and 14.6% for the inter-run CVs. At 90th percentile, the performance goals were comprised between 3.2% and 13.5% for the intra-run CVs, and between 7.3% and 30.8% for the inter-run CVs. CVs calculated from 10 values were similar to those obtained from more values. Higher imprecision was observed when the antibody levels of the IQC was lower than 2 fold the positive threshold. Commercial IQCs gave lower CVs than IQCs derived from patient samples., Conclusion: Our results allow proposing some acceptability limits for the precision performances of the autoantibody assays, compatible with the reality of life in diagnostic laboratories and clinical care., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Published
2020
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14. Gastrointestinal pathogens in anti-FH antibody positive and negative Hemolytic Uremic Syndrome.

Author

Togarsimalemath SK, Si-Mohammed A, Puraswani M, Gupta A, Vabret A, Liguori S, Mariani-Kurkdjian P, Bagga A, and Dragon-Durey MA

Subjects
Atypical Hemolytic Uremic Syndrome microbiology, Atypical Hemolytic Uremic Syndrome parasitology, Atypical Hemolytic Uremic Syndrome virology, Child, Child, Preschool, Clostridioides difficile, Cohort Studies, Complement Factor H immunology, Entamoeba histolytica, Female, Giardia lamblia, Humans, India, Infant, Intestines microbiology, Intestines parasitology, Intestines pathology, Intestines virology, Male, Multiplex Polymerase Chain Reaction, Mutation, Norovirus, Rotavirus, Salmonella, Shigella, Atypical Hemolytic Uremic Syndrome immunology, Autoantibodies immunology, Complement Activation
Abstract

Background: Prodromal symptoms are frequently reported in the atypical form of Hemolytic uremic syndrome (aHUS) suggesting implication of infectious triggers. Some pathogens may also play a role in the mechanisms of production of autoantibody directed against Factor H (FH), a complement regulator, leading to aHUS., Methods: The presence of 15 gastrointestinal (GI) pathogens was investigated by using xTAG-based multiplex PCR techniques on stools collected at the acute phase in a cohort of Indian HUS children classified according to the presence or absence of anti-FH autoantibodies., Results: Prevalence of pathogens in patients with anti-FH antibody (62.5%) was twice that in those without (31.5%). Different pathogens were detected, the most frequent being Clostridium difficile, Giardia intestinalis, Salmonella, Shigella, Rotavirus, Norovirus and Entamoeba histolytica. No stool was positive for Shigatoxin., Conclusion: This study reveals a higher prevalence of GI pathogens in anti-FH positive than in negative patients. No single pathogen was implicated exclusively in one form of HUS. These pathogens may play a role in the disease initiation by inducing complement activation or an autoimmune response.

Published
2018
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15. Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the α3 chain of type IV collagen.

Author

Clavarino G, Gauthier A, Hellmark T, Carron PL, Giovannini D, Colliard S, Dragon-Durey MA, Segelmark M, Cesbron JY, and Dumestre-Pérard C

Subjects
Aged, Anti-Glomerular Basement Membrane Disease immunology, Autoantibodies blood, Autoantigens isolation & purification, Collagen Type IV isolation & purification, Diagnostic Tests, Routine, Female, Humans, Immunoassay, Immunodominant Epitopes isolation & purification, Male, Protein Conformation, Anti-Glomerular Basement Membrane Disease diagnosis, Autoantigens immunology, Collagen Type IV immunology, Fluorescent Antibody Technique, Indirect methods, Immunodominant Epitopes immunology, Kidney pathology, Lung pathology
Abstract

Detection of circulating anti-GBM antibodies has a key role for the diagnosis of Goodpasture syndrome but immunoassays using purified or recombinant alpha3(IV)NC1 as antigen do not recognize all anti-GBM antibodies. We show that anti-GBM antibodies directed against epitopes in their native conformation or cryptic epitopes are detected by indirect immunofluorescence., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2018
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