Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology

Andrew H. Karaba, Weiqiang Zhou, Leon L. Hsieh, Alexis Figueroa, Guido Massaccesi, Richard E. Rothman, Katherine Z.J. Fenstermacher, Lauren Sauer, Kathryn Shaw-Saliba, Paul W. Blair, Matthew L. Robinson, Sherry Leung, Russell Wesson, Nada Alachkar, Ramy El-Diwany, Hongkai Ji, Andrea L. Cox

Research output: Contribution to journalArticlepeer-review


Background: Several inflammatory cytokines are upregulated in severe coronavirus disease 2019 (COVID-19). We compared cytokines in COVID-19 versus influenza 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. Methods: 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 used to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was used to identify cytokines that mediate the effect of BMI and age on disease severity. Results: Interleukin-18 (IL-18), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were significantly increased in COVID-19 versus influenza patients, whereas granulocyte macrophage colony-stimulating factor, interferon-γ(IFN-γ), IFN-λ1, IL-10, IL-15, and monocyte chemoattractant protein 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 in 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. Conclusions: These findings point to activation of fundamentally different innate immune pathways in severe acute respiratory syndrome coronavirus 2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.

Original languageEnglish (US)
Pages (from-to)254-262
Number of pages9
JournalClinical Infectious Diseases
Issue number2
StatePublished - Jan 15 2022


  • COVID-19
  • Cytokines
  • Influenza
  • Obesity
  • SARS-CoV-2

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases


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