Markers of T cell activation and exhaustion in plasma are associated with persistent symptoms up to 18 months Following Mild SARS-CoV-2 infection

Thor Ueland^1,2,3Rebecca Cox^4,5,6Annika E Michelsen^1,7Elisabeth Berg Fjelltveit^5,6Kari Otterdal^1*Tuva Dahl¹Fan Zhou⁶Rebecca Elyanow⁸Pål Aukrust^1,7,9Bjorn Blomberg^10,4Bente Halvorsen^1,7Nina Langeland^10,4

• ¹Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
• ²University of Oslo, Oslo, Oslo, Norway
• ³Thrombosis Research Center, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Troms, Norway
• ⁴Department of Clinical Science, University of Bergen, Bergen, Norway
• ⁵Department of Microbiology, Haukeland University Hospital, Bergen, Hordaland, Norway
• ⁶Influenza Centre, Bergen, Norway
• ⁷Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
• ⁸Adaptive Biotechnologies (United States), Seattle, Washington, United States
• ⁹Section of Clinical Immunology and Infectious Diseases, Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
• ¹⁰Norwegian National Advisory Unit for Tropical Infectious Diseases, Haukeland University Hospital, Bergen, Hordaland, Norway

Background: Persistent symptoms following SARS-CoV-2 is an increasing problem after COVID-19 disease. The pathogenesis of this persistent post Covid-19 Condition (PCC) is, however, largely unknown. We hypothesized that persistent T cell activation and exhaustion play a role in PCC development. We examined plasma levels of soluble (s) CD25, TIM-3 and LAG-3, all markers of T cell activation/exhaustion, by enzyme immunoassays in 170 home-isolated and 53 hospitalized patients for up to 18 months after COVID-19 in relation to persistent symptomatology. Results: Our major findings were: (i) Cases with persistent dyspnea and fatigue had markedly higher sCD25 at 6-18 months with a more modest increase in sTIM-3. (ii) Cases with memory problems at 12-18 months had increased sLAG-3 iii) sCD25 correlated with SARS-CoV-2 antibody titers and microneutralization titers only in cases with PCC while sTIM-3 correlated with these parameters irrespectively of symptoms. iv) Although hospitalized patients had markedly elevated levels of T cell activation/exhausting markers during follow-up, there was no relation to PCC symptoms. Our study indicates a role for T cell activation/exhaustion in PCC following home isolated COVID-19 infection, with somewhat different patterns of sCD25, sTIM-3 and sLAG-3, but not in hospitalized COVID-19 patients where disease severity may be more important.