Circulating Type I Interferon Levels and COVID-19 Severity: A Systematic Review and Meta-Analysis

Abstract

IntroductionCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, resulting in a range of clinical manifestations and outcomes. Laboratory and immunological alterations have been considered as potential markers of disease severity and clinical evolution. Type I interferons (IFN-I), mainly represented by IFN-α and β, are a group of cytokines with an important function in antiviral responses and have played a complex role in COVID-19. Some studies have demonstrated that IFN-I levels and interferon response is elevated in mild cases, while other studies have noted this in severe cases. The involvement of IFN-I on the pathogenesis and outcomes of SARS-CoV-2 infection remains unclear. In this study, we summarize the available evidence of the association of plasma protein levels of type I IFN with the severity of COVID-19.MethodsThe PRISMA checklist guided the reporting of the data. A systematic search of the MEDLINE (PubMed), EMBASE, and Web of Science databases was performed up to March of 2021, looking for articles that evaluated plasma protein levels of IFN-I in mild, severe, or critical COVID-19 patients. Comparative meta-analyses with random effects were performed to compare the standardized mean differences in plasma protein levels of IFN-I of mild versus severe and mild versus critical patients. Meta-regressions were performed to test the moderating role of age, sex, time that the IFN-I was measured, and limit of detection of the assay used in the difference between the means.ResultsThere was no significant difference in plasma levels of IFN-α when comparing between mild and severe patients (SMD = -0.236, 95% CI -0.645 to 0.173, p = 0.258, I2 = 82.11), nor when comparing between patients mild and critical (SMD = 0.203, 95% CI -0.363 to 0.770, p = 0.481, I2 = 64.06). However, there was a significant difference between healthy individuals and patients with mild disease (SMD = 0.447, 95% CI 0.085 to 0.810, p = 0.016, I2 = 62.89).ConclusionsPeripheral IFN-α cannot be used as a severity marker as it does not determine the clinical status presented by COVID-19 patients.

Hematological Abnormalities in COVID-19 Disease: Association With Type I Interferon Pathway Activation and Disease Outcomes

“…Though inborn genetic errors in type I IFN pathway and neutralizing antibodies against type I IFNs leading to impaired type I IFN responses have been associated with adverse outcomes in the setting of SARS-CoV-2 infection ( 43 – 45 ), in the present study we did not detect a direct association between type I IFN peripheral blood score and adverse outcomes such as intubation risk or death. This observation is in accord with a recent meta-analysis by da Silva et al reporting that plasma protein levels of type I IFN cannot be used as a severity marker for COVID-19 ( 46 ). Besides, activation of type I IFN pathway has been previously shown to upregulate the expression of angiotensin converting enzyme-2 receptors in a loop-back mechanism, resulting in further augmentation in intracellular viral load in COVID-19 disease ( 47 ).…”

Circulating Type I Interferon Levels in the Early Phase of COVID-19 Are Associated With the Development of Respiratory Failure

“…However, a recent meta-analysis by Silva et al. ( 24 ), which included 15 studies examining the plasma protein levels of IFN-I (α and β), could not confirm a significant association between plasma IFN- I levels and COVID-19 disease severity. In the included studies, IFN-α was measured over 7 days after the onset of symptoms ( 25 – 32 ), and IFN-α levels at the early phase of SARS-CoV-2 infection (within 5 days after the onset of symptoms) were assessed only in one study ( 30 ).…”

Low Serum Levels of Interferon Alpha in COVID-19 Patients Are Associated with Older Age

“…However, despite the likely protective role of IFN, data are still conflicting regarding the association between IFN levels and the outcome of SARS-CoV-2 infection. A recent meta-analysis on circulating IFNα in COVID-19 patients concluded that peripheral IFNα cannot be used as a severity marker [16]. In fact, the outcome relies not only on IFNα levels but also on other factors such as the timing of production.…”