Blood Biomarkers May Identify, Distinguish Influenza and COVID-19 Infection

Interleukin (IL)-10 and other IL-10 family cytokines are significantly different between SARS-CoV-2 and influenza virus infection and may thus potentially serve as biomarkers for differentiating between these infections, according to a study in Open Forum Infectious Diseases.

Researchers sought to identify cytokines and other inflammatory blood biomarkers that could be used in statistical and machine learning (ML) models to predict and distinguish SARS-CoV-2 vs influenza infection. Toward that end, the researchers evaluated the levels of 57 cytokines and other inflammatory markers from blood samples of inpatients and outpatients with influenza and COVID-19.

The study authors obtained serum and plasma samples from patients during the 2018 and 2019 influenza seasons (December 2018 to March 2019 and December 2019 to March 2020) or during the 2021 COVID-19 pandemic (November 2020 to May 2021) through the CDC’s Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) and USFlu Vaccine Effectiveness (FluVE) network.

The analysis included 141 patients — 69 from FluVE and 72 from HAIVEN — who were diagnosed with either influenza virus (n=76) or SARS-CoV-2 virus (n=65). Among inpatients included in the study, a greater ratio of females had influenza vs COVID-19. The outpatient cohort had no significant demographic differences.

Ten of the pro-inflammatory cytokines or associated molecules assessed were different between inpatients and outpatients with COVID-19 vs those with influenza. Significant differences were found regarding the expression of cytokines, including interferon (IFN)β (increased for influenza), IFNγ (increased for influenza), and IL-8 (increased in COVID-19).

The 7 IL-10 cytokine family members found to be significantly different in patients with influenza vs those with COVID-19 were: IL-10, IL-19, IL-20, IL-22, IL-26, IL-28A, and IL-29. Among inpatient samples, most of the IL-10 family cytokines (IL-10, IL-19, IL-22, IL-28A, and IL-29) were significantly increased in patients with COVID-19 vs influenza. IL-20 was increased among inpatients and outpatients with influenza vs COVID-19. IL-26 was increased in influenza outpatient samples vs COVID-19 samples, but it was decreased in influenza vs COVID-19 inpatient samples.

Machine learning was then used to identify cytokine combinations that are capable of differentiating between influenza virus and SARS-CoV-2 virus in inpatients and outpatients. The researchers assessed biomarkers that were nonsignificant (false discovery rate >0.01) between influenza and SARS-CoV-2 infection and individually produced an average area under the receiver operating characteristics curve (AUC) score of 0.4 to 0.6 in a support vector machine (SVM) model. For the inpatient group, the SVM model yielded an average AUC score up to 81% across the 5-fold cross-validation; for the outpatient group, the SVM model yielded an average AUC score up to 84%.

This study is limited by: (1) the relatively small sample size, which reduced the power of the analysis; (2) differences in sample collection between the inpatient and outpatient cohorts; (3) the inability to infer the effect of pre-existing immunity on cytokine expression during infection; and (4) the unavailability of participants’ complete electronic medical records.

“After analyzing numerous cytokines and inflammatory markers in the blood, our study has identified several powerful biomarkers that can categorize influenza or COVID-19 infection,” concluded the researchers. “These findings have highlighted potential pathways involved in disease pathogenesis, which serve as potential therapeutic targets for the reduction of disease burden.”