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[Preprint]. 2021 Jan 14:rs.3.rs-141578.

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

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.

PMID: 33469573
PMCID: PMC7814832
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

Aartik Sarma et al. Res Sq. 2021.

[Preprint]. 2021 Jan 14:rs.3.rs-141578.

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

Authors

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.

PMID: 33469573
PMCID: PMC7814832
DOI: 10.21203/rs.3.rs-141578/v1

Update in

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.
Sarma A, Christenson SA, Byrne A, Mick E, Pisco AO, DeVoe C, Deiss T, Ghale R, Zha BS, Tsitsiklis A, Jauregui A, Moazed F, Detweiler AM, Spottiswoode N, Sinha P, Neff N, Tan M, Serpa PH, Willmore A, Ansel KM, Wilson JG, Leligdowicz A, Siegel ER, Sirota M, DeRisi JL, Matthay MA; COMET Consortium; Hendrickson CM, Kangelaris KN, Krummel MF, Woodruff PG, Erle DJ, Calfee CS, Langelier CR. Sarma A, et al. Nat Commun. 2021 Aug 26;12(1):5152. doi: 10.1038/s41467-021-25040-5. Nat Commun. 2021. PMID: 34446707 Free PMC article.

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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Figures

**Figure 1.**
Lower respiratory tract transcriptional signature of COVID-19 ARDS. a) Heatmap of the top 50 differentially expressed genes by adjusted p value between patients with COVID-19 related ARDS (COVID-ARDS, red) versus controls with ARDS due to other etiologies (Other-ARDS, violet). Intubated controls with no ARDS were also included in the unsupervised clustering (No-ARDS, grey). b) Ingenuity Pathway Analysis (IPA) based on differential gene expression analyses demonstrating expression of signaling pathways by IPA activation Z-score with respect to a baseline of COVID-ARDS. Values are tabulated in (Supplementary Data 3). c) Differences in plasma inflammatory cytokine concentrations between patients with ARDS due to COVID-19 (COVID-ARDS, red) or other etiologies (Other-ARDS, violet). Lines indicate medians. P values calculated based on Mann-Whitney test. Values tabulated in (Supplementary Data 4). d) Pharmacologic agents predicted to mitigate the dysregulated host response of COVID-19 ARDS with respect to Other-ARDS (violet) or No-ARDS patients (grey) identified by computational matching against the IPA database of drug transcriptional signatures. Values tabulated in (Supplementary Data 5). Pathways with a Z-score absolute value > 2 and overlap P value < 0.05 are significant.

**Figure 2.**
Lower respiratory tract transcriptional signature of ARDS due to COVID-19 versus other viral or bacterial lower respiratory tract infections. a) Heatmap depicting expression and unsupervised clustering of top differentially expressed genes by adjusted P value between patients with COVID-19 related ARDS (COVID-ARDS, red) versus ARDS due to viral LRTI (Viral-ARDS, blue). b) Heatmap depicting expression and unsupervised clustering of the top 50 differentially expressed genes between patients with COVID-19 related ARDS (COVID-ARDS, red) versus ARDS due to bacterial LRTI (Bacterial-ARDS, green). c) Pathway analysis based on differentially expressed genes depicting relative expression of signaling pathways by IPA Z-score with respect to a baseline of gene expression in COVID-ARDS. Values are tabulated in (Supplementary Data 8). d) Predicted activation of upstream interferons in patients with ARDS due to viral or bacterial LRTI compared to those with COVID-ARDS revealed downregulation of type-I/III interferons in COVID-ARDS versus other viral LRTI-related ARDS. Values tabulated in (Supplementary Data 9). e) Scatterplot of the relationship between interferon-stimulated gene (ISG) counts and SARS-CoV-2 viral load (reads per million, rpM), quantified by the regression slope, in nasopharyngeal (NP) samples from patients with mostly mild/early COVID-19 (x-axis) and in tracheal aspirate (TA) samples from patients with severe COVID-19 and ARDS (y-axis). f) *RSAD2* is an ISG whose expression (y-axis) is correlated with SARS-CoV-2 viral load (x-axis) in both early/mild (NP) and severe (TA) disease, while *OASL* is an ISG for which the correlation observed in early/mild COVID-19 is absent in severe COVID-19 patients with ARDS. Values are tabulated in (Supplementary Data 10).

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References

1. Matthay M. A. et al. Acute respiratory distress syndrome. Nature Reviews Disease Primers 5, (2019). - PMC - PubMed
1. Mehta P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet 395, 1033–1034 (2020). - PMC - PubMed
1. Blanco-Melo Daniel. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. doi: 10.1016/j.cell.2020.04.026 - DOI - PMC - PubMed
1. Giamarellos-Bourboulis E. J. et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe 27, 992–1000.e3 (2020). - PMC - PubMed
1. Wilson J. G. et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight 5, (2020). - PMC - PubMed

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This is a preprint.

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

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

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