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Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19 - 09/01/21

Doi : 10.1016/j.jaci.2020.08.031 
Jonathan T. Sims, PhD a, , Venkatesh Krishnan, PhD a, , , Ching-Yun Chang, PhD a, Sarah M. Engle, MS a, Giacomo Casalini, MD b, George H. Rodgers, BS a, Nicoletta Bivi, PhD a, Brian J. Nickoloff, MD, PhD a, Robert J. Konrad, MD a, Stephanie de Bono, MD, PhD a, Richard E. Higgs, MS a, Robert J. Benschop, PhD a, Silvia Ottaviani, MD c, Anabela Cardoso, MD, MBA a, Ajay Nirula, MD, PhD a, Mario Corbellino, MD d, Justin Stebbing, MD, PhD c,
a Eli Lilly and Company, Indianapolis, Ind 
b Luigi Sacco Department of Clinical and Biomedical Sciences, University of Milan, Milan, Italy 
c Department of Surgery and Cancer, Imperial College, London, United Kingdom 
d Division of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy 

Corresponding authors: Justin Stebbing, MD, PhD, ICTEM Building, Imperial College, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK.ICTEM BuildingImperial CollegeHammersmith HospitalDu Cane RdLondonW12 0NNUK∗∗Venkatesh Krishnan, PhD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.Eli Lilly and CompanyLilly Corporate CenterIndianapolisIN46285

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Abstract

Background

Physicians treating patients with coronavirus disease 2019 (COVID-19) increasingly believe that the hyperinflammatory acute stage of COVID-19 results in a cytokine storm. The circulating biomarkers seen across the spectrum of COVID-19 have not been characterized compared with healthy controls, but such analyses are likely to yield insights into the pursuit of interventions that adequately reduce the burden of these cytokine storms.

Objective

To identify and characterize the host inflammatory response to severe acute respiratory syndrome coronavirus 2 infection, we assessed levels of proteins related to immune responses and cardiovascular disease in patients stratified as mild, moderate, and severe versus matched healthy controls.

Methods

Blood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with age- and sex-matched healthy controls to provide insights into differential regulation of 185 markers.

Results

Results indicate a dominant hyperinflammatory milieu in the circulation and vascular endothelial damage markers within patients with COVID-19, and strong biomarker association with patient response as measured by Ordinal Scale. As patients progress, we observe statistically significant dysregulation of IFN-γ, IL-1RA, IL-6, IL-10, IL-19, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, CXCL9, CXCL10, CXCL5, ENRAGE, and poly (ADP-ribose) polymerase 1. Furthermore, in a limited series of patients who were sampled frequently, confirming reliability and reproducibility of our assays, we demonstrate that intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine storm.

Conclusions

These wide-ranging circulating biomarkers show an association with increased disease severity and may help stratify patients and selection of therapeutic options. They also provide insights into mechanisms of severe acute respiratory syndrome coronavirus 2 pathogenesis and the host response.

El texto completo de este artículo está disponible en PDF.

Key words : COVID-19, biomarkers, cardiovascular, inflammation, Ordinal Scale, baricitinib

Abbreviations used : COVID-19, GDF-2, HC, MCP, PARP-1, PTX3, SARS-CoV-2


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 Disclosure of potential conflict of interest: J. T. Sims, V. Krishnan, C.-Y. Chang, S. M. Engle, G. H. Rodgers, N. Bivi, B. J. Nickoloff, R. J. Konrad, S. de Bono, R. E. Higgs, R. J. Benschop, A. Cardoso, and A. Nirula are all employees of Eli Lilly and Company. J. Stebbing is editor-in-chief of Oncogene; has sat on several scientific advisory boards, including Benevolent AI; consults with Lansdowne Partners, Vitruvian, and Eli Lilly and Company; and sits on the Board of Directors for BB Biotech Healthcare Trust. The rest of the authors declare that they have no relevant conflicts of interest.


© 2020  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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Vol 147 - N° 1

P. 107-111 - janvier 2021 Regresar al número
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