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Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections
Kenneth E. Remy, … , Lyle L. Moldwawer, Richard S. Hotchkiss
Kenneth E. Remy, … , Lyle L. Moldwawer, Richard S. Hotchkiss
Published July 20, 2020
Citation Information: JCI Insight. 2020;5(17):e140329. https://doi.org/10.1172/jci.insight.140329.
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Research Article COVID-19

Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections

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Abstract

COVID-19–associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-ɣ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%–50% of the IFN-ɣ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-ɣ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.

Authors

Kenneth E. Remy, Monty Mazer, David A. Striker, Ali H. Ellebedy, Andrew H. Walton, Jacqueline Unsinger, Teresa M. Blood, Philip A. Mudd, Daehan J. Yi, Daniel A. Mannion, Dale F. Osborne, R. Scott Martin, Nitin J. Anand, James P. Bosanquet, Jane Blood, Anne M. Drewry, Charles C. Caldwell, Isaiah R. Turnbull, Scott C. Brakenridge, Lyle L. Moldwawer, Richard S. Hotchkiss

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Figure 8

IL-7 restores adaptive immune function in patients with COVID-19.

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IL-7 restores adaptive immune function in patients with COVID-19.
Line p...
Line plot demonstrating change in the number of cytokine-producing cells using ELISpot between control (anti-CD3/anti-CD28 antibody or LPS) samples and stimulation with IL-7 for IFN-ɣ (A) and TNF-α (B). Each dot represents and individual patient. Red lines represent values for patients who died. IL-7 caused a significant increase in the number of IFN-ɣ–producing T cells in COVID-19 patients; ****P < 0.0001. IL-7 did not increase monocyte TNF-α production. (C and D) Representative photomicrographs demonstrating ELISpot change from control sample to IL-7 stimulated for IFN-ɣ and TNF-α. Paired samples were analyzed using a paired Wilcoxon’s rank-sum test. IFN-ɣ n = 25, TNF-α n = 25.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

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