Aurelie Guironnet-Paquet ^1,2 Hind Hamzeh-Cognasse ³ Frederic Berard ⁴ Fabrice Cognasse ^3,5 Jean-Christophe Richard ⁶ Hodane Yonis ⁶ Mehdi Mezidi ⁶ Olivier Desebbe ⁷ Bertrand Delannoy ⁸ Sophie Demeret ⁹ Benjamin Rohaut ^10,11 Clemence Marois ^10,11,12 Samir Saheb ¹³ Quoc-Viet Hung ¹⁴ Mathieu Schoeffler ¹⁵ Paul-Simon Pugliesi ¹⁶ Sophie Debord ¹⁷ Paul Bastard ^18,19,20,21 Aurélie Cobat ^18,19,20 Jean-Laurent Casanova ^{18,19,20,21,22} Rémi Pescarmona ²³ Sébastien VIEL ²⁴ Jean-François Nicolas ^1,4 Audrey Nosbaum ^1,4 Marc Vocanson ¹ Olivier Hequet ^1,25*

• ¹ UMR5308 Centre International de Recherche en Infectiologie (CIRI), Lyon, Rhône-Alpes, France
• ² Apheresis unit, EFS Auvergne Rhône-Alpes, Pierre Bénite, France
• ³ INSERM U1059 SAnté INgéniérie BIOlogie, Saint-Etienne, France
• ⁴ Clinical Immunology and Allergology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France
• ⁵ Scientific department, Etablisement Français du Sang Auvergne Rhône-Alpes, St Etienne, France
• ⁶ Intensive Care Unit, Centre Hospitalier Croix-Rousse, Hospices Civils de Lyon, Lyon, France
• ⁷ Department of Anesthesiology and Perioperative Medicine, Sauvegarde Clinic, Lyon, France
• ⁸ Departmemnt of anesthesiology and Perioperative Medicine, Sauvegarde Clinic, Lyon, France
• ⁹ Neuro-intensive care Unit, hôpital de la Pitié-Salpétrière, AP-HP, Paris, France
• ¹⁰ Neuro-intensive care Unit, AP-HP, Hôpital de la Pitié-Sapétrière, Paris, France
• ¹¹ Institut du Cerveau, Faculté de Médecine, Sorbonne Universités, Paris, France
• ¹² Groupe de recherche Clinique en REanimation et Soins intensifs du patient en insuffisance respiratoire aiguE (GRC-rESPIRE), Sorbonne université, Paris, France
• ¹³ Hemobiotherapy unit, Hopital Universitaire Pitié Salpétrière, AP-HP, Paris, France
• ¹⁴ Intensive Care Unit, Lyon Villeurbanne, Lyon, Rhône-Alpes, France
• ¹⁵ Department of Anesthesiology and Intensive Care Unit, Centre Hospitalier de Montélimar, Montélimar, France
• ¹⁶ Intensive Care unit, Centre Hospitalier William Morey, Chalon Sur Saone, France
• ¹⁷ Department of Anesthesiology and Intensive Care Medicine, Hopital Edouard Herriot, Lyon, Rhône-Alpes, France
• ¹⁸ Laboratory of Human Genetics of Infectious disease, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France
• ¹⁹ Paris Cité University, Institute Imagine, Paris, France
• ²⁰ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York City, New York, United States
• ²¹ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick children, AP-HP, Paris, France
• ²² Howards Hugues Medical Institute, New York, United States
• ²³ Immun monitorage laboratory, Centre hospitalier Lyon Sud, Pierre Bénite, France
• ²⁴ Plateforme de Biotherapies et de production de MTI, Hôpital Edouard Herriot, Lyon, Rhône-Alpes, France
• ²⁵ EFS, Lyon, Rhône-Alpes, France

Background: Immunological disturbances (anti-type I IFN auto-antibody production, cytokine storm, lymphopenia, T-cell hyperactivation and exhaustion) are responsible for disease exacerbation during severe COVID-19 infections.In this study, we set up a prospective, randomised clinical trial (ClinicalTrials.gov ID: NCT047551643) and performed therapeutic plasma exchange (TPE) in severe COVID-19 patients in order to decrease excess cytokines and auto-antibodies and to assess whether adding TPE to the standard treatment (ST, including corticosteroids plus high-flow rate oxygen) could help restore immune parameters and limit the progression of acute respiratory distress syndrome (ARDS).Results: As expected, performing TPE decreased the amount of anti-type I IFN autoantibodies and improved the elimination or limited the production of certain inflammatory mediators (IL-18, IL-7, CCL2, CCL3, etc.) circulating in the blood of COVID-19 patients, compared to ST controls. Interestingly, while TPE did not influence changes in ARDS parameters throughout the protocol, it proved more effective than ST in reversing lymphopenia, preventing T-cell hyperactivation and reducing T-cell exhaustion, notably in a fraction of TPE patients who had an early favourable respiratory outcome. TPE also restored appropriate numbers of CD4+ and CD8+ T-cell memory populations and increased the number of circulating virus-specific T cells in these patients.Our results therefore indicate that the addition of TPE sessions to the standard treatment accelerates immune cell recovery and contributes to the development of appropriate antiviral T-cell responses in some patients with severe COVID-19 disease.