Neutrophil Activation and Immune Thrombosis Profiles Persist in Convalescent COVID-19
Authors: Hocini Hakim , Wiedemann Aurélie , Blengio Fabiola , Lefebvre Cécile , Cervantes-Gonzalez Minerva , Foucat Emile , Tisserand Pascaline , Surenaud Mathieu , Coléon Séverin , Prague Mélanie , Guillaumat Lydia , Krief Corinne , Fenwick Craig , Laouénan Cédric , Bouadma Lila , Ghosn Jade , Pantaleo Giuseppe , Thiébaut Rodolphe ,   the French COVID cohort study group, Abel Laurent , Abrous Amal , Andrejak Claire , Angoulvant François , Bachelet Delphine , Bartoli Marie , Behilill Sylvie , Beluze Marine , Bhavsar Krishna , Chair Anissa , Charpentier Charlotte , Chenard Léo , Chirouze Catherine , Couffin-cadiergues Sandrine , Couffignal Camille , Castro Nathalie DE. , Debray Marie-Pierre , Deplanque Dominique , Descamps Diane , Diallo Alpha , Silva Fernanda Dias DA , Dorival Céline , Duval Xavier , Eloy Philippine , Enouf Vincent , Esperou Hélène , Esposito-farese Marina , Etienne Manuel , Florence Aline-Marie , Gaymard Alexandre , Gigante Tristan , Gilg Morgane , Goehringer François , Guedj Jérémie , Houas Ikram , Hoffmann Isabelle , Hulot Jean-Sébastien , Jaafoura Salma , Jamard Simon , Kafif Ouifiya , Khalil Antoine , Lafhej Nadhem , Laribi Samira , Le Minh , Hingrat Quentin LE. , Mestre Soizic LE. , Letrou Sophie , Lina Bruno , Lingas Guillaume , Malvy Denis , Mentré France , Mouquet Hugo , Neant Nadège , Paul Christelle , Papadopoulos Aurélie , Petrov-sanchez Ventzislava , Peytavin Gilles , Piquard Valentine , Picone Olivier , Rosa-calatrava Manuel , Rossignol Bénédicte , Rossignol Patrick , Roy Carine , Schneider Marion , Tardivon Coralie , Timsit Jean-François , Tubiana Sarah , Werf Sylvie VAN. DER. , Visseaux Benoit , Lévy Yves 
Published: March 2023

Abstract
Purpose
Following a severe COVID-19 infection, a proportion of individuals develop prolonged symptoms. We investigated the immunological dysfunction that underlies the persistence of symptoms months after the resolution of acute COVID-19.

Methods
We analyzed cytokines, cell phenotypes, SARS-CoV-2 spike-specific and neutralizing antibodies, and whole blood gene expression profiles in convalescent severe COVID-19 patients 1, 3, and 6 months following hospital discharge.

Results
We observed persistent abnormalities until month 6 marked by (i) high serum levels of monocyte/macrophage and endothelial activation markers, chemotaxis, and hematopoietic cytokines; (ii) a high frequency of central memory CD4+ and effector CD8+ T cells; (iii) a decrease in anti-SARS-CoV-2 spike and neutralizing antibodies; and (iv) an upregulation of genes related to platelet, neutrophil activation, erythrocytes, myeloid cell differentiation, and RUNX1 signaling. We identified a “core gene signature” associated with a history of thrombotic events, with upregulation of a set of genes involved in neutrophil activation, platelet, hematopoiesis, and blood coagulation.

Conclusion
The lack of restoration of gene expression to a normal profile after up to 6 months of follow-up, even in asymptomatic patients who experienced severe COVID-19, signals the need to carefully extend their clinical follow-up and propose preventive measures.