Most acute viral infections induce proliferation and activation of CD8 T cells detectable by increases in KI67 or co-expression of CD38 and HLA-DR (34, 35). There was a significant increase in KI67+ and also HLA-DR+CD38+ non-naïve CD8 T cells in COVID-19 patients compared to HD or RD (Fig. 2, E and F). In COVID-19 patients, KI67+ CD8 T cells were increased compared to HD and RD across all subsets of non-naïve CD8 T cells, including CM and EM1 (fig. S2B). These data indicate broad T cell activation, potentially driven by bystander activation and/or homeostatic proliferation in addition to antigen-driven activation of virus-specific CD8 T cells. This activation phenotype was confirmed by HLA-DR and CD38 co-expression that was significantly increased for all non-naïve CD8 T cell subsets (Fig. 2F and fig. S2C). However, the magnitude of the KI67+ or CD38+HLA-DR+ CD8 T cells varied widely in this cohort. The frequency of KI67+ CD8 T cells correlated with the frequency of CD38+HLA-DR+ CD8 T cells (fig. S2D). However, the frequency of CD38+HLA-DR+, but not KI67+ CD8 T cells, was elevated in COVID-19 patients who had concomitant infection with another microbe but was not impacted by pre-existing immunosuppression or treatment with steroids (fig. S2E). Moreover, these changes in CD8 T cell subsets in COVID-19 patients did not show clear correlations with individual metrics of clinical disease such as hsCRP or D-dimer (fig. S2E), although the frequency of KI67+ CD8 T cells associated with IL-6 and ferritin levels. Although CD8 T cell activation was common, ~20% of patients had no increase in KI67+ or CD38+HLA-DR+ CD8 T cells above the level found in HD (Fig. 2, E and F). Thus, although robust CD8 T cell activation was a clear characteristic of many hospitalized COVID-19 patients, a substantial fraction of patients had little evidence of CD8 T cell activation in the blood compared to controls.