Validating a Proteomic Signature of Severe COVID-19

Author:

Cosgriff Christopher V.1,Miano Todd A.2,Mathew Divij34,Huang Alexander C.3567,Giannini Heather M.8,Kuri-Cervantes Leticia39,Pampena M. Betina39,Ittner Caroline A. G.810,Weisman Ariel R.810,Agyekum Roseline S.810,Dunn Thomas G.810,Oniyide Oluwatosin810,Turner Alexandra P.810,D’Andrea Kurt3,Adamski Sharon11,Greenplate Allison R.3411,Anderson Brian J.810,Harhay Michael O.2,Jones Tiffanie K.2810,Reilly John P.810,Mangalmurti Nilam S.381012,Shashaty Michael G. S.810,Betts Michael R.39,Wherry E. John346,Meyer Nuala J.381012

Affiliation:

1. Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

2. Department of Epidemiology, Biostatistics, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

3. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

4. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

5. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

6. Parker Institute for Cancer Immunotherapy, Philadelphia, PA.

7. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

8. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

9. Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

10. Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

11. Immune Health Project, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

12. Lung Biology Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Abstract

OBJECTIVES: COVID-19 is a heterogenous disease. Biomarker-based approaches may identify patients at risk for severe disease, who may be more likely to benefit from specific therapies. Our objective was to identify and validate a plasma protein signature for severe COVID-19. DESIGN: Prospective observational cohort study. SETTING: Two hospitals in the United States. PATIENTS: One hundred sixty-seven hospitalized adults with COVID-19. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We measured 713 plasma proteins in 167 hospitalized patients with COVID-19 using a high-throughput platform. We classified patients as nonsevere versus severe COVID-19, defined as the need for high-flow nasal cannula, mechanical ventilation, extracorporeal membrane oxygenation, or death, at study entry and in 7-day intervals thereafter. We compared proteins measured at baseline between these two groups by logistic regression adjusting for age, sex, symptom duration, and comorbidities. We used lead proteins from dysregulated pathways as inputs for elastic net logistic regression to identify a parsimonious signature of severe disease and validated this signature in an external COVID-19 dataset. We tested whether the association between corticosteroid use and mortality varied by protein signature. One hundred ninety-four proteins were associated with severe COVID-19 at the time of hospital admission. Pathway analysis identified multiple pathways associated with inflammatory response and tissue repair programs. Elastic net logistic regression yielded a 14-protein signature that discriminated 90-day mortality in an external cohort with an area under the receiver-operator characteristic curve of 0.92 (95% CI, 0.88–0.95). Classifying patients based on the predicted risk from the signature identified a heterogeneous response to treatment with corticosteroids (p = 0.006). CONCLUSIONS: Inpatients with COVID-19 express heterogeneous patterns of plasma proteins. We propose a 14-protein signature of disease severity that may have value in developing precision medicine approaches for COVID-19 pneumonia.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Critical Care and Intensive Care Medicine

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