COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone

Sarma, Aartik; Christenson, Stephanie; Mick, Eran; Deiss, Thomas; DeVoe, Catherine; Pisco, Angela; Ghale, Rajani; Jauregui, Alejandra; Byrne, Ashley; Moazed, Farzad; Spottiswoode, Natasha; Sinha, Pratik; Zha, Beth; Neff, Norma; Tan, Michelle; Serpa, Paula Hayakawa; Ansel, K. Mark; Wilson, Jennifer; Leligdowicz, Aleksandra; Seigel, Emily; Sirota, Marina; DeRisi, Joseph; Matthay, Michael; Consortium, COMET; Hendrickson, Carolyn; Kangelaris, Kirsten; Krummel, Matthew; Woodruff, Prescott; Erle, David; Calfee, Carolyn; Langelier, Charles

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.