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. To assess the possible influence of patient’s DNA-methylation status on responsiveness to dexamethasone treatment, we performed comparative analysis of the included patients from the Pa-COVID-19 study cohort with stable (Responder, n = 10) versus progressive disease (Non_Responder, n = 10) under treatment, i.e. which progressed from moderate to severe disease or death after having received at least 2 days of treatment with a sample collected within the first 4 days of treatment. Control patients without disease progression under treatment were matched for sex, age and available early samples after initiation of dexamethasone treatment. If more than one equivalent match was available, data was reviewed by at least two clinically experienced physicians for pre-existing comorbidities to find the most appropriate match. CAPNETZ Study Group Pa-COVID-19 Study Group