Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

Samuel Druzak, Elizabeth Iffrig, Blaine R. Roberts, Tiantian Zhang, Kirby S. Fibben, Yumiko Sakurai, Hans P. Verkerke, Christina A. Rostad, Ann Chahroudi, Frank Schneider, Andrew Kam Ho Wong, Anne M. Roberts, Joshua D. Chandler, Susan O. Kim, Mario Mosunjac, Marina Mosunjac, Rachel Geller, Igor Albizua, Sean R. Stowell, Connie M. Arthur, Evan J. Anderson, Anna A. Ivanova, Jun Ahn, Xueyun Liu, Kristal Maner-Smith, Thomas Bowen, Mirko Paiardini, Steve E. Bosinger, John D. Roback, Deanna A. Kulpa, Guido Silvestri, Wilbur A. Lam (), Eric A. Ortlund () and Cheryl L. Maier ()
Additional contact information
Samuel Druzak: Emory University School of Medicine
Elizabeth Iffrig: Emory University School of Medicine
Blaine R. Roberts: Emory University School of Medicine
Tiantian Zhang: Emory University School of Medicine
Kirby S. Fibben: Georgia Institute of Technology and Emory University
Yumiko Sakurai: Georgia Institute of Technology and Emory University
Hans P. Verkerke: Emory University School of Medicine
Christina A. Rostad: Emory University School of Medicine
Ann Chahroudi: Emory University School of Medicine
Frank Schneider: Emory University School of Medicine
Andrew Kam Ho Wong: Emory University School of Medicine
Anne M. Roberts: Emory University School of Medicine
Joshua D. Chandler: Emory University School of Medicine
Susan O. Kim: Emory University School of Medicine
Mario Mosunjac: Emory University School of Medicine
Marina Mosunjac: Emory University School of Medicine
Rachel Geller: Emory University School of Medicine
Igor Albizua: Emory University School of Medicine
Sean R. Stowell: Harvard Medical School
Connie M. Arthur: Harvard Medical School
Evan J. Anderson: Emory University School of Medicine
Anna A. Ivanova: Emory University School of Medicine
Jun Ahn: Emory University School of Medicine
Xueyun Liu: Emory University School of Medicine
Kristal Maner-Smith: Emory University School of Medicine
Thomas Bowen: Emory University School of Medicine
Mirko Paiardini: Emory University School of Medicine
Steve E. Bosinger: Emory University School of Medicine
John D. Roback: Emory University School of Medicine
Deanna A. Kulpa: Emory University School of Medicine
Guido Silvestri: Emory University School of Medicine
Wilbur A. Lam: Georgia Institute of Technology and Emory University
Eric A. Ortlund: Emory University School of Medicine
Cheryl L. Maier: Emory University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Date: 2023
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DOI: 10.1038/s41467-023-37269-3

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