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Plasma IL-6 Levels following Corticosteroid Therapy as an Indicator of ICU Length of Stay in Critically ill COVID-19 Patients

By Samir Awasthi, Tyler Wagner, AJ Venkatakrishnan, Arjun Puranik, Matthew Hurchik, Vineet Agarwal, Ian Conrad, Christian Kirkup, Raman Arunachalam, John C O'Horo, Walter Kremers, Rahul Kashyap, William Morice, John Halamka, Amy W Williams, William Faubion, Andrew D Badley, Gregory J Gores, Venky Soundararajan

Posted 03 Jul 2020
medRxiv DOI: 10.1101/2020.07.02.20144733

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.

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