Tocilizumab-induced unexpected increase of several inflammatory cytokines in critically ill COVID-19 patients

Abstract Early evidence during the COVID-19 pandemic indicated high levels of IL-6 in patients with severe COVID-19. This led to the off-label use of tocilizumab (TCZ) during the first wave of the pandemic.We aimed to monitor IL-6 and several inflammatory cytokines in critically ill COVID-19 patients receiving off-label TCZ. Fifteen critically ill SARS-CoV-2 PCR confirmed cases were enrolled and serum samples were collected during 8 days, before and following administration of a single dose of TCZ. In parallel, a control group consisting of 8 non-treated COVID-19 patients not receiving TCZ was established. Serum profile of 12 cytokines (IL-1β, -2, -4, -6, -8, -10, -12, -13, -17, -18, TNF-α and INF-γ) and of IL-6R were assessed in these two groups. Although the increased IL-6 concentrations after TCZ infusion were expected, we observed an unexpected increase in IL-1β, -2, -4, -10, -12p70, -18 and IL-6R levels in the treated patients with maximal values reached 2 to 4 days after TCZ. In contrast, no change in cytokine levels was observed in the control group. There was no significant difference in cytokine levels between survivors (TCZ/S) or non-survivors (TCZ/D). This observation suggests that some inflammatory pathways escape IL-6R blockade leading to an increase in several pro-inflammatory cytokines. Our findings could highlight an anti-inflammatory role of IL-6 and may explain why TCZ has failed to improve survival in critically ill COVID-19 patients when given alone.