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

Abstract

Background 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. 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 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. Results 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. Conclusions 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.

Integrated cell-free DNA and cytokine analysis uncovers distinct tissue injury and immune response patterns in solid organ transplant recipients with COVID-19

“…This was an unexpected finding as IFN-λ1 and type I interferons are thought to be suppressed in SARS-CoV-2 infections 47 . Moreover, IFN-λ1 is actually higher in influenza infection than in SARS-CoV-2 31 .…”

“…An excessive and dysregulated cytokine response is associated with severe COVID-19 disease 31,37 . To determine whether the immunosuppressed SOTRs with COVID-19 display dysregulated circulatory cytokines signatures, admission plasma levels of 36 cytokines and chemokines were measured (see Methods) in SOTRs with COVID-19 (n=44) and compared with matched Non-SOT COVID-19 patients (n=38) and healthy controls (n=30).…”

“…Notably, most of the severe COVID-19 complications that result in multiorgan failure and death are primarily attributed to virus-independent immunopathologic mechanisms 30 . Indeed, high serum levels of inflammatory cytokines such as interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α) are observed in COVID-19 patients and predicted disease severity and poor outcome 31,32 . Additionally, cfDNA is also considered as a trigger of deleterious proinflammatory and prothrombotic pathways in addition to being a biomarker [33][34][35][36] .…”

High-value Laboratory Testing for Hospitalized COVID-19 Patients: A Review

“…A wide range of cytokines and chemokines are involved in the pathophysiology of COVID-19, but several studies reviewed in this section demonstrate that IL-6 is perhaps one of the most useful biomarkers in predicting COVID-19 severity during hospitalization and can also distinguish severe COVID-19 from severe influenza infection [2][3][4]. IL-6 is a pro-inflammatory cytokine primarily released by monocytes, macrophages and dendritic cells in response to pathogens, cellular damage, or signaling from other pro-inflammatory cytokines [5].…”

Interleukin-1- Receptor Kinase 4 Inhibition: Achieving Immunomodulatory Synergy to Mitigate the Impact of COVID-19

“…The CRS phase of SARS-CoV-2 is thought to occur due to an influx of neutrophils and macrophages as well as elevations of inflammatory cytokines, with higher levels of IL-6, IL-1, IL-8, and IL-18 (1,2). In CRS, a variety of pro-inflammatory cytokines, including IL-1, IL-6, IL-8, CXCL-10, interferon (INF)-induced chemokines, and tumor necrosis factor (TNF)-a are secreted by alveolar macrophages that drive the inflammatory response and promote further influx of neutrophils, monocytes, and other inflammatory cells (1,3).…”