Effect of IL-6R blockade on plasma lipids and clinical outcomes among hospitalized patients with COVID-19 infection

Abstract

Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.

Keywords: COVID-19; CRP; HDL; LDL; SARS-CoV-2; inflammation; interleukin 6; lipids; lipoproteins; monoclonal antibody; triglycerides.

Fig. 1

Baseline viral load by (A) COVID-19 severity and (B) quartiles of baseline lipid parameters. MSOD, multisystem organ dysfunction.

Fig. 2

Median change from baseline to day 7 in (A) CRP and (B) IL-6 levels. Of the 476 samples, 393 and 273 patients had day 1 and day 7 measurements for CRP and IL-6, respectively. ∗∗∗∗P < 0.0001. CRP, C-reactive protein; IL-6, interleukin-6.

Fig. 3

Baseline lipid levels by (A) COVID-19 severity and (B) sex and COVID-19 severity. COVID-19, coronavirus disease 2019; MSOD, multisystem organ dysfunction.

Fig. 4

Change in lipid levels from baseline to day 7 by treatment group. ∗∗∗∗P < 0.0001 and ∗∗∗P < 0.001. ns, not significant; TG, triglyceride.

Fig. 5

Subgroup analysis for (A) mortality, (B) oxygenation improvement, and (C) clinical improvement by day 60 in change from baseline lipid quartiles. HR, hazard ratio; TG, triglyceride.