Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia

Abstract

Hyper-inflammatory responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major cause of disease severity and death. Predictive prognosis biomarkers to guide therapeutics are critically lacking. Several studies have indicated a "cytokine storm" with the release of interleukin-1 (IL-1), IL-6, and IL-8, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. Here, we proposed to assess the relationship between IL-6 and outcomes of patients with coronavirus disease 2019 (COVID-19). Our cohort consisted of 46 adult patients with PCR-proven SARS-CoV-2 infection admitted in a COVID-19 ward of the Hospital de Braga (HB) from April 7 to May 7, 2020, whose IL-6 levels were followed over time. We found that IL-6 levels were significantly different between the disease stages. Also, we found a significant negative correlation between IL-6 levels during stages IIb and III, peripheral oxygen saturation (SpO₂), and partial pressure of oxygen in arterial blood (PaO₂), showing that IL-6 correlates with respiratory failure. Compared to the inflammatory markers available in the clinic routine, we found a positive correlation between IL-6 and C-reactive protein (CRP). However, when we assessed the predictive value of these two markers, IL-6 behaves as a better predictor of disease progression. In a binary logistic regression, IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome.

Keywords: COVID-19; IL-6; SARS-CoV-2; biomarker; fatal pneumonia.

Figure 1

Plasma IL-6 and CRP profile in COVID-19 patients. (A) The levels of IL-6 and CRP were quantified on the plasma of COVID-19 patients segregated by disease stages. (B) Correlation between the plasma IL-6 and CRP levels in all patients. (C) IL-6 and CRP plasma concentration in patients at stage IIb that move to stage IIa or III. (D) ROC curves of IL-6 and CRP. In (A,B), we have included multiple data from each patient (n = 46). Data are shown as mean ± SD ^*p < 0.05, ^**p < 0.01, ^***p < 0.001.

Figure 2

IL-6 correlation with respiratory parameters in COVID-19 patients. Correlation of plasma IL-6 levels with (A) oxygen saturation (SpO₂) and (B) oxygen partial pressure (PaO₂). We have included multiple data from each patient (n = 46).

Figure 3

IL-6 as a mortality predictor in COVID-19 Patients. (A) Kinetic analysis of plasma IL-6 concentrations in COVID-19 patients assembled by days after the onset of symptomatology and after hospitalization. Data are represented as the median of plasma IL-6 levels in the non-survivors' group (red n = 5) and two distinguished groups of survivors (blue n = 15 and black n = 10). (B) Plasma levels of IL-6 and CRP. Data depict the number of patients as shown in Table 2, where each dot represents the highest IL-6 level for each patient during hospitalization. (C) Distribution among the disease staging at patient admission assigned to the three groups of non-survivors and survivors. Data are shown as mean ± SD ^*p < 0.05, ^**p < 0.01. †patient's death.