Prolonged T-cell activation and long COVID symptoms independently associate with severe disease at 3 months in a UK cohort of hospitalized COVID-19 patients

COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed the extent and nature of immune activation at 3 months post hospital admission in patients with mild, moderate or severe COVID-19 and investigated whether immune activation associates with disease severity and long COVID. Patients with severe disease displayed persistent activation of CD4⁺and CD8⁺T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, but they lacked activation of other immune subsets. Elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α were present in patients with severe compared to mild and/or moderate disease. Plasma from severe patients caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that factors in the plasma of severe patients may increase T-cell responsiveness to IL-15-driven ‘bystander” activation, which may drive persistent T-cell activation after severe COVID-19. Patients with severe disease reported a higher number of long COVID symptoms which correlated with the frequency of two subsets of activated CD4⁺and CD8⁺T cells (CD4⁺T-cell population 2 and CD8⁺T-cell population 4; FDR p<0.05), however these associations were lost after adjusting for age, sex and disease severity. Our data suggests that persistent immune activation and long COVID correlate independently with severe disease.