Tocilizumab treatment leads to early resolution of lymphopenia and myeloid dysregulation in patients hospitalized with COVID-19

High interleukin (IL)-6 levels are associated with more severe clinical manifestations in patients hospitalized with COVID-19, but the complex role of IL-6 in antiviral and inflammatory processes has made it difficult to decipher its involvement in the disease. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial that assessed the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab in addition to identifying novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to standard of care and potentially leading to faster recovery in patients hospitalized with COVID-19. One sentence summary Interleukin-6 receptor blockade with tocilizumab accelerated resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19