Deep immune profiling integrated with computational approach revealed intricate relations of B cell response with clinical parameters at various stages of the COVID-19 disease severity. These cells express proliferation (Ki67+), differentiation (CD27+ CD38+), as well as exhaustion markers (PD-1+). More robust expression of these markers was observed in severe cases compared to mild-moderate, with an overall decrease in memory B cell number (Mathew et al., 2020). Further, 70% of the patients reported have IgG and IgM S protein-specific antibodies, suggesting activation status of the antibody-secreting plasmablasts. Thus, this study shows that B cells, in severe cases, display concomitant activation and exhaustion markers, while mild cases or healthy controls showed a normal response. However, how this activated status of B cells had an impact on disease severity was not studied. By looking at the alleged relationship of activated B cells with disease severity, Woodruff et al. (2020) showed robust activation status of extrafollicular B cells which resembled their behavior in autoimmune condition. The activation status of these cells was found more pronounced in critically ill patients (n = 10) than non-critical (n = 7) and healthy control (n = 17), which correlated with SARS-CoV-2-specific antibody production and disease progression. Further, an increase in antibody-secreting cells (ASCs) was found in critically ill cases compared to non-severe cases along with an increase in S protein-specific antibodies, probably with a non-neutralizing property. This study shows that in some patients with a critical disease condition, robust B cell response and presence of SARS-CoV-2 antigen-specific antibodies may be associated with worsening of the disease condition. The ASCs were identified as the population of cells with CD138+ and CD21low expression. However, no comparison was drawn between various age groups concerning disease severity. While across studies, B cell activation is apparent in severe cases, it is subsequently associated with a sharp decline in their number. Various mechanisms may be responsible for this decline, among which B cell exhaustion is one, but still poorly understood (Yi et al., 2010).