Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID-19 patients’

Smieszek, Sandra P.; Przychodzen, Bartlomiej P.; Polymeropoulos, Vasilios; Polymeropoulos, Christos; Polymeropoulos, Mihael H.

Background Elevated Interleukin-6 (IL-6) may play an important role in the pathophysiology of COVID-19 yet attenuated response is not seen across all severe patients. We aimed to determine the effect of IL-6 baseline levels and other clinical variables on mortality and outcomes in hospitalized COVID-19 patients as well as to explore genetic variants associated with attenuated IL-6 response. Methods Baseline IL-6 cytokine levels were measured in hospitalized patients participating in ongoing ODYSSEY phase 3 randomized study of tradipitant and placebo in hospitalized patients with severe COVID-19 who are receiving supplemental oxygen support. Furthermore blood samples for whole genome sequencing analysis were collected from 150 participants. Results We report significantly elevated IL-6 in COVID-19 infected hospitalized patients, n=100 (p-value<0.0001) when compared to controls n=324. We also report a significantly increased level of IL-6 (p-value<0.01) between the severe and mild COVID-19 patients with severity defined on a WHO scale. Excessive IL-6 plasma levels correlate with higher mortality (p-value 0.001). Additionally based on our classification analysis, combination of IL-6 elevation and high levels of serum glucose can identify highest risk-group of COVID19 patients. Furthermore we explore the role of genetic regulatory variants affecting baseline IL-6 levels specifically in COVID-19 patients. We have directly tested the association between variants in the IL6 and IL6R gene region and IL6 plasma levels. We provide results of common IL-6 variant previously associated with pneumonia, rs1800795, and rs2228145 that was previously shown to affect IL-6 plasma levels, as well as report on novel variants associated with IL-6 plasma levels detected in our study patients. Conclusions While it is unlikely that “cytokine storm” is the norm in severe COVID19, baseline elevations above 150pg/ml may be associated with worst outcomes and as such may warrant treatment considerations. So far no clinical studies used IL-6 baseline assessment to stratify patient population participating in clinical studies. We believe that careful examination and interpretation of the IL-6 levels and genetic variants can help to determine patient population with potentially most robust clinical response to IL-6 inhibition. Trial Registration: Clinicaltrials.gov: NCT04326426