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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 5

Suppressed innate immune TNF-α response in COVID-19.

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Suppressed innate immune TNF-α response in COVID-19.
Representative ELIS...
Representative ELISpot photomicrographs displaying baseline innate immune (monocyte) function with LPS-stimulated TNF-α production in PBMCs. Comparison between different donor types, including (A) healthy control volunteers and (B) CINS, (C) septic, and (D) COVID-19 patients. Number of spots demonstrates the number of cytokine-producing monocytes, and counts are presented as corrected number of spots per thousand monocytes plated as fraction of the 2.5 × 103 PBMCs plated in each well. COVID-19 patients had suppressed TNF-α production when compared with controls. Each photomicrograph was captured with the same magnification, and each image is to scale. ELISpot assays were performed using the PBMC fraction from freshly drawn whole blood. Each condition was run in duplicate for control samples and triplicate for COVID-19 samples.

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

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