Erythrocytes Reveal Complement Activation in Patients with COVID-19

LK MetthewLam,Sophia J.Murphy,LeticiaKuri-Cervantes,Ariel R.Weisman,Caroline A. G.Ittner,John P.Reilly,M. BetinaPampena,Michael RBetts,E. JohnWherry,Wen-ChaoSong,John D.Lambris,Douglas B.Cines,Nuala J.Meyer,Nilam S.Mangalmurti

doi: https://doi.org/10.1101/2020.05.20.20104398

LK Metthew Lam

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

2Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

Sophia J. Murphy

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

Leticia Kuri-Cervantes

3Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

Ariel R. Weisman

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

Caroline A. G. Ittner

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

John P. Reilly

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

2Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

M. Betina Pampena

3Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

Michael R Betts

3Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

E. John Wherry

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

5Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

6Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, Pennsylvania 19104,USA

Wen-Chao Song

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

5Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

John D. Lambris

7Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

Douglas B. Cines

2Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

7Department of Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

Nuala J. Meyer

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

2Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

8Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,USA

Nilam S. Mangalmurti

1Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104,USA

2Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

4Penn Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104,USA

8Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,USA

Abstract

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-organ failure characterized by respiratory insufficiency, arrhythmias, thromboembolic complications and shock^1-5. The mortality of patients hospitalized with COVID-19 is unacceptably high and new strategies are urgently needed to rapidly identify and treat patients at risk for organ failure. Clinical epidemiologic studies demonstrate that vulnerability to organ failure is greatest after viral clearance from the upper airway^6-8, which suggests that dysregulation of the host immune response is a critical mediator of clinical deterioration and death. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure^9,10. A potential therapeutic strategy warranting investigation is to inhibit complement, with case reports of successful treatment of COVID-19 with inhibitors of complement^10-13. However, this approach requires careful balance between the host protective and potential injurious effects of complement activation, and biomarkers to identify the optimal timing and candidates for therapy are lacking. Here we report the presence of complement activation products on circulating erythrocytes from hospitalized COVID-19 patients using flow cytometry. These findings suggest that novel erythrocyte-based diagnostics provide a method to identify patients with dysregulated complement activation.

Competing Interest Statement

E.J.W. is a member of the Parker Institute for Cancer Immunotherapy. E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech.J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes and is the inventor of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes some of which are developed by Amyndas. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan).N.J.M has received grant funding to her institution from Athersys, Inc., Biomarck, Inc., and the Marcus Foundation for work unrelated to manuscript under consideration. W.-C.S. is a co-founder, and a consultant to Kira Pharmaceuticals and Aevitas Therapeutics from which he receives research grants.

Funding Statement

The research was supported by grants from the NIH (HL126788 to NSM, HL137006 to NJM).

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