Elevated Interleukin-6 (IL-6) Levels with Ig (G & M) Antibodies in the Recovery Phase of Patients with COVID-19: Indication of Cytokine Storm and Re-infection

Abstract

The innate immune response to coronavirus disease (COVID-19) by inflammatory cytokines, such as interleukin 6 (IL-6), has been described as an early response, followed by an adaptive immune response with the production of antibodies. IL-6 is produced in response to viral infections and is crucial for the activation of T cells and the differentiation of B cells, which produce antibodies. Immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies are produced during the initial acute period of infection and the recovery period from the period of onset of symptoms. There has been some relationship between the innate response of the cytokine and the adaptive response of the antibodies in patients with COVID-19 infection. There has been a positive correlation between IL-6 levels and the presence of COVID-19 antibodies, suggesting that higher IL-6 levels may be associated with a stronger immune response and studies have confirmed that patients with higher IL-6 levels have a higher antibody response. High IL-6 levels on admission observed within 2 weeks after onset of symptoms were positively correlated with high concentrations of IgG seen 5 weeks after onset of symptoms. We have previously described elevated IL-6 levels in the sera of 68% of COVID-19 convalescent patients (40–93 days) post-onset of symptoms (recovery phase). In this study we decided to investigate whether there was some relationship between the IL-6 levels in patients 40–93 days post-onset of symptom in the recovery phase and their antibody response using a wide range of antibody assays (iCHROMA IgG, GOLD IgG & IgM, Abbott SARS-CoV-2 IgG II Quant-test (Abbott S IgG), Diasorin Liaison SARS-CoV-2 S1/2 (Diasorin S1/2 IgG). The patients were divided into two groups, those with normal IL-6 levels (<7 pg/ml) and those with elevated IL-6 levels (>7 pg/ml). All patients (100%) had positive IgG antibodies, only 8 out the 28 patients (29%) were positive for IgM antibodies. The mean antibodies concentrations of the patients (n = 9) with normal IL-6 levels (<7 pg/ml) for iCHROMA IgG (20.0 Units), GOLD IgG (34.4 AU/mL), Abbott IgG (4175 AU/mL), Diasorin Liaison IgG (75.8 AU/mL) and GOLD IgM (4.7 AU/mL), respectively. The mean antibodies concentrations of the patients (n = 19) with elevated IL-6 levels (>7 pg/ml) for iCHROMA IgG (20.9 Units), GOLD IgG, (34.9 AU/mL), Abbott IgG (2287 AU/mL), Diasorin Liaison IgG (121.7 AU/mL) and GOLD IgM (11.2 AU/mL), respectively. The antibodies of the patients with the elevated IL-6 levels were significantly higher for Diasorin Liaison IgG (p = 0.02) and GOLD IgM (p = 0.003) but lower for Abbott IgG (p = 0.02). In conclusion, this study using a panel of antibody assays highlights that increased levels of IL-6 in the convalescent phase (recovery phase) indicate an active immune response leading to higher concentrations of antibodies especially IgM, suggesting that cytokine storms and re-infection occur in the recovery phase.