Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology
Open Access
- 20 May 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in Clinical Infectious Diseases
- Vol. 74 (2), 254-262
- https://doi.org/10.1093/cid/ciab376
Abstract
Several inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI and age on disease severity. IL-18, IL-1β, IL-6, and TNF-α were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-γ, IFN-λ1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. These findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.Funding Information
- Johns Hopkins COVID-19 Research Response Program
- Johns Hopkins University Provost Research
- The Bill and Melinda Gates Foundation (134582)
- National Cancer Institute (U54CA260491)
- National Institutes of Health Centers of Excellence in Influenza Research and Surveillance (HHSN272201400007C)
- National Institute of Allergy and Infectious Diseases (U19AI088791, R01AI108403, HHSN272201400007C, HHSN272201400007C)
- US Department of Health
- Human Services Biomedical Advanced Research
- Development Authority (IDSEP160031-01-00, IDSEP160031-01-00)
- Johns Hopkins Center of Excellence in Influenza Research
- National Institutes of Health (R01HG009518, T32 AI007291-27, D18HP29037)
- US Health Resources and Services Administration
- Bureau of Health Workforce
- Health Careers Opportunity Program
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