Discussion
All patients with pneumonia caused by SARS-CoV-2 who develop SRF display hyper-inflammatory responses with features of either immune dysregulation or MAS, both of which are characterized by pro-inflammatory cytokines: the immune dysregulation described here, which is driven by IL-6 and not by IL-1β, and MAS, which is driven by IL-1β. There are two key features of this immune dysregulation: over-production of pro-inflammatory cytokines by monocytes and dysregulation of lymphocytes characterized by CD4 lymphopenia and subsequently B cell lymphopenia. In parallel, the absolute natural killer (NK) cell count is depleted, probably as result of the rapidly propagating virus.
It was previously shown that the addition of IL-6 in the growth medium of healthy dendritic cells attenuated HLA-DR membrane expression and decreased the production of IFN-γ by CD4 cells (Ohno et al., 2016). Three findings of our study are compatible with the proposal that IL-6 is one of the drivers of decreased HLA-DR on the CD14 monocytes: (1) IL-6 concentrations in the blood is inversely associated with HLA-DR expression (Figure 5A), (2) the addition of Tocilizumab in the plasma-enriched medium of cells partially restored the expression of HLA-DR on cell membranes (Figures 5E and 5F), and (3) absolute lymphocyte counts of six patients increased after Tocilizumab treatment (Figure 5G). Our findings are indirectly supported by the increase of circulating HLA-DR+ cells during convalescence of one case of COVID-19 of moderate severity (Thevarajan et al., 2020).
In conclusion, we identified a unique signature of immune dysregulation in the patients with SARS-CoV-2, characterized on the one hand by normal or high cytokine production capacity and increased circulating cytokines (especially IL-6) and on the other hand by defects in the lymphoid function associated with IL-6-mediated decrease in HLA-DR expression. These findings support the rationale of launched clinical trials on the efficacy of Anakinra, Sarilumab, Siltuximab, and Tocilizumab (Clinicaltrials.gov NCT04330638, NCT04317092, and NCT04315298 and EudraCT number 2020-001039-29) to elaborate anti-inflammatory responses in these patients.