Contribution of sMAdCAM and IL-6 to COVID-19 associated lymphopenia
To assess the contribution of known soluble inflammatory cytokines and mucosal migration markers to the observed cellular immune signatures we undertook the evaluation of circulating IL-6 and sMAdCAM levels in our cohort. As expected, we observed elevated IL-6 levels, with the highest being observed in hypoxemic individuals, in plasma of all groups compared to seronegative controls (Figure 2A). Additionally, extending our previously reported results (12) obtained with sMAdCAM in mild infection, we observed a progressive decline in these levels across mild as well as hypoxemic patients that seemed converse to the pattern observed for IL-6 (Figure 2B). Indeed, the levels of these 2 markers were significantly negatively correlated (Figure 2C). Further, it was interesting to note that neither in the case of IL-6 or sMAdCAM was it possible to discriminate between AM and SM individuals. Next, correlation analysis was undertaken to delineate putative relationships between the aforementioned soluble markers and cellular subsets described above (Supplementary Figure S4). Intriguingly and reflective of their apparently divergent relationship, both IL-6 and sMAdCAM showed significant opposing correlations with absolute counts of lymphocytes, T cells (CD4+ and CD8+), B cells and NK cells supporting their clear, albeit, opposing roles in COVID-19 associated lymphopenia (Figure 2 D-I). We also noted a unique negative correlation of IL-6 with Treg counts together with a heretofore unreported positive correlation of sMAdCAM levels with CD8+ effector memory T cell counts (Supplementary Figure S5A-B). Elevated LPS levels, associated with microbial translocation and severe COVID-19 disease were observed in hypoxemic individuals (Supplementary Figure S5C). Furthermore, and possibly related to altered monocyte frequencies observed ex vivo (Figure 1G), a negative correlation of sMAdCAM levels occurred with frequencies of intermediate monocytes (Supplementary Figure S5D). Gut pathology associated markers LPS and sMAdCAM were poorly correlated with only the latter exhibiting major correlations to lymphopenia.