The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation, 2024, Knoll et al.

The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation
Rainer Knoll; Elisa T. Helbig; Kilian Dahm; Olufemi Bolaji; Frederik Hamm; Oliver Dietrich; Martina van Uelft; Sophie Müller; Lorenzo Bonaguro; Jonas Schulte-Schrepping; Lev Petrov; Benjamin Krämer; Michael Kraut; Paula Stubbemann; Charlotte Thibeault; Sophia Brumhard; Heidi Theis; Gudrun Hack; Elena De Domenico; Jacob Nattermann; Matthias Becker; Marc D. Beyer; David Hillus; Philipp Georg; Constantin Loers; Janina Tiedemann; Pinkus Tober-Lau; Lena Lippert; Belén Millet Pascual-Leone; Frank Tacke; Gernot Rohde; Norbert Suttorp; Martin Witzenrath; Antoine-Emmanuel Saliba; Thomas Ulas; Julia K. Polansky; Birgit Sawitzki; Leif E. Sander; Joachim L. Schultze; Anna C. Aschenbrenner; Florian Kurth

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.


Link | PDF (Cell) [Open Access]