TY  - JOUR
AU  - Knoll, Rainer
AU  - Helbig, Elisa T
AU  - Dahm, Kilian
AU  - Bolaji, Olufemi
AU  - Hamm, Frederik
AU  - Dietrich, Oliver
AU  - van Uelft, Martina
AU  - Müller, Sophie
AU  - Bonaguro, Lorenzo
AU  - Schulte-Schrepping, Jonas
AU  - Petrov, Lev
AU  - Krämer, Benjamin
AU  - Kraut, Michael
AU  - Stubbemann, Paula
AU  - Thibeault, Charlotte
AU  - Brumhard, Sophia
AU  - Theis, Heidi
AU  - Hack, Gudrun
AU  - De Domenico, Elena
AU  - Nattermann, Jacob
AU  - Becker, Matthias
AU  - Beyer, Marc D
AU  - Hillus, David
AU  - Georg, Philipp
AU  - Loers, Constantin
AU  - Tiedemann, Janina
AU  - Tober-Lau, Pinkus
AU  - Lippert, Lena
AU  - Millet Pascual-Leone, Belén
AU  - Tacke, Frank
AU  - Rohde, Gernot
AU  - Suttorp, Norbert
AU  - Witzenrath, Martin
AU  - Saliba, Antoine-Emmanuel
AU  - Ulas, Thomas
AU  - Polansky, Julia K
AU  - Sawitzki, Birgit
AU  - Sander, Leif E
AU  - Schultze, Joachim L
AU  - Aschenbrenner, Anna C
AU  - Kurth, Florian
TI  - The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation.
JO  - Cell
VL  - 187
IS  - 16
SN  - 0092-8674
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2024-01024
SP  - 4318 - 4335.e20
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Dexamethasone: pharmacology
KW  - Dexamethasone: therapeutic use
KW  - Monocytes: metabolism
KW  - Monocytes: drug effects
KW  - COVID-19 Drug Treatment
KW  - COVID-19
KW  - SARS-CoV-2: drug effects
KW  - Male
KW  - Single-Cell Analysis
KW  - Female
KW  - Transcriptome
KW  - Middle Aged
KW  - Aged
KW  - Glucocorticoids: therapeutic use
KW  - Glucocorticoids: pharmacology
KW  - Lung: pathology
KW  - Adult
KW  - COVID-19 (Other)
KW  - companion diagnostics (Other)
KW  - glucocorticoid (Other)
KW  - in vivo target engagement (Other)
KW  - monocytes (Other)
KW  - single-cell analysis (Other)
KW  - transcriptomics (Other)
KW  - treatment response prediction (Other)
KW  - Dexamethasone (NLM Chemicals)
KW  - Glucocorticoids (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38964327
DO  - DOI:10.1016/j.cell.2024.06.014
UR  - https://pub.dzne.de/record/271285
ER  -