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

Abstract

Background: The role of type I interferons (IFNs) in the early phase of COVID-19 remains unclear.

Objectives: To evaluate the relationship between IFN-I levels in patients with COVID-19 and clinical presentation, SARS-CoV-2 viral load, and other major pro-inflammatory cytokines.

Methods: This prospective observational study recruited patients hospitalized with COVID-19. The levels of interferon-alpha (IFN-α), interferon-beta (IFN-β), interleukin-6 (IL-6), and C-X-C motif chemokine ligand (CXCL10) within 5 days after symptom onset were measured using an ELISA, in serum from blood collected within 5 days after the onset of symptoms. The SARS-CoV-2 viral load was determined via qPCR using nasal-swab specimens and serum.

Results: The study enrolled 50 patients with COVID-19. IFN-α levels were significantly higher in patients who presented with pneumonia or developed hypoxemic respiratory failure (p < 0.001). Furthermore, IFN-α levels were associated with viral load in nasal-swab specimens and RNAemia (p < 0.05). In contrast, there was no significant association between IFN-β levels and the presence of pneumonia or RNAemia, despite showing a stronger association with nasal-swab viral load (p < 0.001). Correlation analysis showed that the serum levels of IFN-α significantly correlated with those of IFN-β, IL-6, and CXCL10, while the levels of IFN-β did not correlate with those of IL-6 or CXCL10.

Conclusions: Serum IFN-I levels in the early phase of SARS-CoV-2 infection were higher in patients who developed hypoxemic respiratory failure. The association between IFN-α, IL-6, and CXCL10 may reflect the systemic immune response against SARS-CoV-2 invasion into pulmonary circulation, which might be an early predictor of respiratory failure due to COVID-19.

Keywords: COVID-19; CXCL10; hypoxemia; interleukin-6; pneumonia; type I interferon.

Figure 1

The serum type I Interferon (IFN) levels in patients with COVID-19 and their association with pneumonia and hypoxemic respiratory failure: (A) IFN-α levels, (B) IFN-β levels. (C) CRP levels, and (D) Neutrophils-to-lymphocytes ratio in patients with COVID-19. Each level was measured at the time of admission (within 5 days after the onset of symptoms), without hypoxemic respiratory failure at the time. Data are presented as Tukey boxplots and individual values. Nonparametric Mann-Whitney test was used to compare values between groups: ^*p < 0.05. ^**p < 0.001.

Figure 2

Correlations between serum type I Interferon (IFN-I) levels and SARS-CoV-2 viral load in nasal swab specimens from patients with COVID-19: (A) IFN-α levels and (B) IFN-β levels. Spearman correlation test was used, and Spearman correlation coefficient is shown. Corresponding logarithmic trendlines are shown. Serum IFN-I levels in patients with COVID-19 and the association with RNAemia, (C) IFN-α levels, (D) IFN-β levels. Each level was measured at the time of admission (within 5 days after the onset of symptoms). Data are presented as Tukey boxplots and individual values. Nonparametric Mann-Whitney test was used to compare values between groups: ^*p < 0.05.

Figure 3

Serum cytokine and chemokine levels in patients with COVID-19 and the associations with pneumonia and hypoxemic respiratory failure: (A) CXCL10 levels, (B) IL-6 levels, and (C) IL-10 levels. Each level was measured at the time of admission (within 5 days after the onset of symptoms), without hypoxemic respiratory failure. One value was excluded from the analyses of IL-6 and IL-10 as an outlier (IL-6 with 476 pg/mL, and IL-10 with 1640 pg/mL). Data are presented as Tukey boxplots and individual values. Nonparametric Mann-Whitney test was used to compare values between groups: ^*p < 0.05. ^**p < 0.001.

Figure 4

The association observed between serum cytokine levels and SARS-CoV-2 viral load in nasal swab specimens from patients with COVID-19 at admission (within 5 days after the onset of symptoms): (A) CXCL10 levels, (B) IL-6 levels, and (C) IL-10 levels. Spearman correlation test was used, and Spearman correlation coefficient is shown. Corresponding logarithmic trendlines are shown. The association between serum cytokine levels in patients with COVID-19 and RNAemia: (D) CXCL10 levels, (E) IL-6 levels, and (F) IL-10 levels. One value was excluded from the analyses of IL-6 and IL-10 as an outlier (IL-6 with 476 pg/mL, and IL-10 with 1640 pg/mL). Data are presented as Tukey boxplots and individual values. Nonparametric Mann-Whitney test was used to compare values between groups: ^*p < 0.05.

Figure 5

Correlation matrix of immune parameters in patients with COVID-19 at admission (within 5 days after the onset of symptoms). (A) Results are presented as a correlation matrix. Spearman correlation coefficients are plotted. Cells were colored according to the strength and trend of correlations (shades of red = positive correlations; shades of blue = negative correlations). ^*p < 0.05. ^**p < 0.001. Significant correlations between serum IFN-α levels and IFN/cytokines; (B) IFN-β levels, (C) CXCL10 levels, and (D) IL-6 levels. Spearman correlation test was used, and Spearman correlation coefficient is shown. Corresponding logarithmic trendlines are shown.

Figure 6

The landscape of IFN-I and predominant cytokines (CXCL10, IL-6) during the early phase of a SARS-CoV-2 infection. A SARS-CoV-2 infection in the nasopharynx induces IFN-β expression rather than IFN-α. IFN-α, IL-6, and CXCL10 expression is induced when the infection reaches the lungs, rather than IFN-β; and the expression of IFN-α and CXCL10 is induced by the presence of SARS-CoV-2 infection in circulation. An increase of IL-6 and CXCL10 in pulmonary circulation subsequently trigger a cytokine storm.