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

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

doi:10.21203/rs.3.rs-141578/v1

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

Res Sq [Preprint]. 2021 Jan 14:rs.3.rs-141578. doi: 10.21203/rs.3.rs-141578/v1.

Authors

Aartik Sarma¹, Stephanie A Christenson¹, Eran Mick^{1

2

3}, Catherine DeVoe², Thomas Deiss², Angela Oliveira Pisco³, Rajani Ghale^{1

2}, Alejandra Jauregui², Ashley Byrne³, Farzad Moazed¹, Natasha Spottiswoode⁴, Pratik Sinha⁵, Beth Shoshana Zha¹, Norma Neff³, Michelle Tan³, Paula Hayakawa Serpa^{2

3}, K Mark Ansel^{6

7}, Jennifer G Wilson⁸, Aleksandra Leligdowicz², Emily R Siegel⁹, Marina Sirota¹⁰, Joseph L DeRisi^{3

11}, Michael A Matthay¹; COMET Consortium; Carolyn M Hendrickson¹, Kirsten N Kangelaris⁴, Matthew F Krummel¹², Prescott G Woodruff^{1

7}, David J Erle^{4

13

14}, Carolyn S Calfee¹, Charles R Langelier^{2

3}

Affiliations

¹ Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, CA, USA.
² Division of Infectious Diseases, University of California, San Francisco, CA, USA.
³ Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁴ Department of Medicine, University of California, San Francisco, CA, USA.
⁵ Department of Anesthesia, Washington University, Saint Louis, Missouri, MO, USA.
⁶ Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.
⁷ Sandler Asthma Basic Research Center, University of California, San Francisco, CA, USA.
⁸ Department of Emergency Medicine, Stanford University, Palo Alto, CA, USA.
⁹ School of Medicine, University of California, San Francisco, CA, USA.
¹⁰ Division of Rheumatology, University of California, San Francisco, CA, USA.
¹¹ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
¹² Department of Pathology, University of California, San Francisco, CA, USA.
¹³ Lung Biology Center, University of California, San Francisco, CA, USA.
¹⁴ UCSF CoLabs, University of California, San Francisco, CA, USA.

Abstract

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.

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Preprint

Abstract

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