Plasma IL-6 levels following corticosteroid therapy as an indicator of ICU length of stay in critically ill COVID-19 patients

March 26,2021

March 15, 2021

Abstract: Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by “cytokine storms” and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation in some COVID-19 patients with respiratory failure, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.

Samir Awasthi1+Tyler Wagner1+AJ Venkatakrishnan1Arjun Puranik1Matthew Hurchik1Vineet Agarwal1Ian Conrad1Christian Kirkup1Raman Arunachalam2John O'Horo3Walter Kremers3Rahul Kashyap3William Morice, II3,4John Halamka3,5Amy W. Williams3William A. Faubion Jr.3Andrew D. Badley3Gregory J. Gores3, Venky Soundararajan1*
1nference, Cambridge, MA 02142, USA
2nference Labs, Bengaluru, KA 560047, India
3Mayo Clinic, Rochester, MN 55905, USA
4Mayo Clinic Laboratories, Rochester, MN 55905, USA
5Mayo Clinic Platform, Rochester, MN 55905, USA
+Joint First Authors
Correspondence: Venky Soundararajan (


The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.