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Jeremy Manry; Paul Bastard; Adrian Gervais; Tom Le Voyer; Jérémie Rosain; Quentin Philippot; Eleftherios Michailidis; Hans-Heinrich Hoffmann; Shohei Eto; Marina Garcia-Prat; Lucy Bizien; Alba Parra-Martínez; Rui Yang; Liis Haljasmägi; Mélanie Migaud; Karita Särekannu; Julia Maslovskaja; Nicolas de Prost; Yacine Tandjaoui-Lambiotte; Charles-Edouard Luyt; Blanca Amador-Borrero; Alexandre Gaudet; Julien Poissy; Pascal Morel; Pascale Richard; Fabrice Cognasse; Jesus Troya; Sophie Trouillet-Assant; Alexandre Belot; Kahina Saker; Pierre Garçon; Jacques Rivière; Jean-Christophe Lagier; Stéphanie Gentile; Lindsey Rosen; Elana Shaw; Tomohiro Morio; Junko Tanaka; David Dalmau; Pierre-Louis Tharaux; Damien Sene; Alain Stepanian; Bruno Mégarbane; Vasiliki Triantafyllia; Arnaud Fekkar; James Heath; Jose Franco; Juan-Manuel Anaya; Jordi Solé-Violán; Luisa Imberti; Andrea Biondi; Paolo Bonfanti; Riccardo Castagnoli; Ottavia Delmonte; Yu Zhang; Andrew Snow; Steve Holland; Catherine Biggs; Marcela Moncada-Vélez; Andrés Arias; Lazaro Lorenzo; Soraya Boucherit; Dany Anglicheau; Anna Planas; Filomeen Haerynck; Sotirija Duvlis; Robert Nussbaum; Tayfun Ozcelik; Sevgi Keles; Aziz Bousfiha; Jalila El Bakkouri; Carolina Ramirez-Santana; Stéphane Paul; Qiang Pan-Hammarstrom; Lennart Hammarstrom; Annabelle Dupont; Alina Kurolap; Christine Metz; Alessandro Aiuti; Giorgio Casari; Vito Lampasona; Fabio Ciceri; Lucila Barreiros; Elena Dominguez-Garrido; Mateus Vidigal; Mayana Zatz; Diederik van de Beek; Sabina Sahanic; Ivan Tancevski; Yurii Stepanovskyy; Oksana Boyarchuk; Yoko Nukui; Miyuki Tsumura; Loreto Vidaur; Stuart Tangye; Sonia Burrel; Darragh Duffy; Lluis Quintana-Murci; Adam Klocperk; Nelli Kann; Anna Shcherbina; Yu-Lung Lau; Daniel Leung; Matthieu Coulongeat; Julien Marlet; Rutger Koning; Luis Reyes; Angélique Chauvineau-Grenier; Fabienne Venet; guillaume monneret; Michel Nussenzweig; Romain Arrestier; Idris Boudhabhay; Hagit Baris-Feldman; David Hagin; Joost Wauters; Isabelle Meyts; Adam Dyer; Sean Kennelly; Nollaig Bourke; Rabih Halwani; Fatemeh Sharif-Askari; Karim Dorgham; Jérôme Sallette; Souad Mehlal-Sedkaoui; Suzan AlKhater; Raúl Rigo-Bonnin; Francisco Morandeira; Lucie Roussel; Donald Vinh; Christian Erikstrup; Antonio Condino-Neto; Carolina Prando; Anastasiia Bondarenko; András Spaan; Laurent Gilardin; Jacques Fellay; Stanislas Lyonnet; Kaya Bilguvar; Richard Lifton; Shrikant Mane; Mark Anderson; Bertrand Boisson; Vivien Béziat; Shen-Ying Zhang; Evangelos Andreakos; Olivier Hermine; Aurora Pujol; Pärt Peterson; Trine Hyrup Mogensen; Lee Rowen; James Mond; Stéphanie Debette; Xavier deLamballerie; Charles Burdet; Lila Bouadma; Marie Zins; Pere Soler-Palacin; Roger Colobran; Guy Gorochov; Xavier Solanich; Sophie Susen; Javier Martinez-Picado; Didier Raoult; Marc Vasse; Peter Gregersen; Carlos Rodríguez-Gallego; Lorenzo Piemonti; Luigi Notarangelo; Helen Su; Kai Kisand; Satoshi Okada; Anne Puel; Emmanuelle Jouanguy; Charles Rice; Pierre Tiberghien; Qian Zhang; Jean-Laurent Casanova; Laurent Abel; Aurélie Cobat.
researchsquare; 2022.


SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.

ssrn; 2020.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3658226


Background: Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation and coagulation in the presence of complement activation. Methods: We conducted an explorative phase 2 randomized, open label first part of an adaptive phase 2/3 trial of intravenous IFX-1, a monoclonal antibody selectively blocking the anaphylatoxin C5a, in adults with severe Covid-19. Patients were randomized between IFX-1 plus best supportive care (BSC) or BSC only. Results: 30 patients underwent randomization: 15 assigned to IFX-1 and 15 to BSC. PaO2/FiO2 ratio improvement on day 5, chosen as primary outcome parameter, did not show significant differences between groups. However, IFX-1 treatment was associated with consistent trends of improvement as evidenced by lower mortality rate, reduction in renal impairment, normalization of lymphocyte counts, and lowering of plasma lactate dehydrogenase concentrations. Kaplan-Meier estimates of mortality by 28 days were 13% for IFX-1 and 27% for BSC (HR for death, 0.56; 95%CI 0.09-3.74). Serious adverse events rates were comparable between groups but the rate of pulmonary embolisms was three-fold lower in the IFX-1 group (13%) compared to BSC group (40%). IFX-1 treatment was associated with significant increase of D-dimer levels suggesting a potential pro-fibrinolytic activity of anti-C5a treatment. Conclusion: In this exploratory part of the study, C5a inhibition with IFX-1 was shown to be safe in severe Covid-19. PaO2/FiO2 ratio at day five was comparable between groups, but consistent signals of benefit including a lower 28-day all-cause mortality rate, lower rate in impaired kidney function and a lower rate of pulmonary embolism warrant investigating C5a-inhibition with IFX-1 within a phase 3 trial.Trial Registration: This trial has been registered with the NIH, U.S. National Library of Medicine at (NCT04333420). Funding Statement: The trial is funded by InflaRx GmbH.Declaration of Interests: NR and RG are founders, active officers and executive directors of InflaRx (InflaRx GmbH, InflaRx Pharmaceuticals Inc. and InflaRx N.V.) and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9 and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors have no Conflict of Interest. Ethics Approval Statement: The study protocol was approved by the institutional review board of the Academic Medical Center, part of Amsterdam UMC, Amsterdam, the Netherlands (IRB: 2020_067#B2020179). If direct informed consent of patients was not feasible, patients could be included with a deferred consent procedure. All patients or their legally authorized representatives gave written informed consent for the study.

Coronavirus Infections , Learning Disabilities , COVID-19