Levels of the TNF-Related Cytokine LIGHT Increase in Hospitalized COVID-19 Patients with Cytokine Release Syndrome and ARDS

Abstract

Many coronavirus disease 2019 (COVID-19) patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but levels of tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) have not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients compared to healthy age- and gender-matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (P = 0.0209) in those who died than in survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients, with significantly (P = 0.0076) higher levels observed in patients who died than in survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited success in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses. The findings presented here demonstrate that LIGHT is a cytokine which may play an important role in COVID-19 patients presenting with acute respiratory distress syndrome (ARDS) and CRS and suggest that LIGHT neutralization may be beneficial to COVID-19 patients.

Trial registration: ClinicalTrials.gov NCT04412057.

Keywords: ARDS; COVID-19; IL-6; LIGHT; MAb; TNFSF14; cytokine storm.

FIG 1

IL-6 and free LIGHT levels in serum of COVID-19 patients. (A) Free LIGHT serum levels in ventilated (n = 27) and nonventilated (n = 20) COVID-19 patients compared to healthy controls (n = 30). (B) Free LIGHT serum levels in COVID-19 patients who were 60 years of age or older, grouped by clinical outcome (recovered versus deceased). (C) IL-6 serum levels in ventilated (n = 27) and nonventilated (n =20) COVID-19 patients compared to healthy controls (n = 30). (D) IL-6 serum levels in COVID-19 patients who were 60 years of age or older, grouped by clinical outcome (recovered versus deceased). IL-6 levels were measured using a validated immunoassay and a Luminex platform. Free LIGHT levels were measured using a validated immunoassay and a Quanterix ultra-high-sensitivity SIMOA platform. P values were calculated using the Kruskal-Wallis test.