The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

• Knoll, R.
• Helbig, E. T.
• Dahm, K.
• Bolaji, O.
• Hamm, F.
• Dietrich, O.
• van Uelft, M.
• Müller, S.
• Bonaguro, L.
• Schulte-Schrepping, J.
• Petrov, L.
• Krämer, B.
• Kraut, M.
• Stubbemann, P.
• Thibeault, C.
• Brumhard, S.
• Theis, H.
• Hack, G.
• De Domenico, E.
• Nattermann, J.
• Becker, M.
• Beyer, M. D.
• Hillus, D.
• Georg, P.
• Loers, C.
• Tiedemann, J.
• Tober-Lau, P.
• Lippert, L.
• Millet Pascual-Leone, B.
• Tacke, F.
• Rohde, G.
• Suttorp, N.
• Witzenrath, M.
• Saliba, A. E.
• Ulas, T.
• Polansky, J. K.
• Sawitzki, B.
• Sander, L. E.
• Schultze, J. L.
• Aschenbrenner, A. C.
• Kurth, F.