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

• Published in: JCI insight 2020-09, Vol.5 (17)
• Main Authors: Remy, Kenneth E, Mazer, Monty, Striker, David A, Ellebedy, Ali H, Walton, Andrew H, Unsinger, Jacqueline, Blood, Teresa M, Mudd, Philip A, Yi, Daehan J, Mannion, Daniel A, Osborne, Dale F, Martin, R Scott, Anand, Nitin J, Bosanquet, James P, Blood, Jane, Drewry, Anne M, Caldwell, Charles C, Turnbull, Isaiah R, Brakenridge, Scott C, Moldwawer, Lyle L, Hotchkiss, Richard S
• Format: Article
• Language: English
• Subjects: Adaptive Immunity - immunology; Adolescent; Adult; Aged; Aged, 80 and over; Betacoronavirus; Case-Control Studies; Coronavirus Infections - immunology; COVID-19; Critical Illness; Cytokine Release Syndrome - immunology; Enzyme-Linked Immunospot Assay; Female; Healthy Volunteers; Humans; Immune Tolerance - immunology; Immunity, Innate - immunology; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-6 - immunology; Male; Middle Aged; Monocytes - immunology; Monocytes - metabolism; Pandemics; Pneumonia, Viral - immunology; SARS-CoV-2; Sepsis - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Young Adult
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.140329

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.