Activation of the MAPK network provides a survival advantage during the course of COVID-19-induced sepsis: a real-world evidence analysis of a multicenter COVID-19 Sepsis Cohort

Abstract

Purpose: There is evidence that lower activity of the RAF/MEK/ERK network is associated with positive outcomes in mild and moderate courses of COVID-19. The effect of this cascade in COVID-19 sepsis is still undetermined. Therefore, we tested the hypothesis that activity of the RAF/MEK/ERK network in COVID-19-induced sepsis is associated with an impact on 30-day survival.

Methods: We used biomaterial from 81 prospectively recruited patients from the multicentric CovidDataNet.NRW-study cohort (German clinical trial registry: DRKS00026184) with their collected medical history, vital signs, laboratory parameters, microbiological findings and patient outcome. ERK activity was measured by evaluating ERK phosphorylation using a Proximity Ligation Assay.

Results: An increased ERK activity at 4 days after diagnosis of COVID-19-induced sepsis was associated with a more than threefold increased chance of survival in an adjusted Cox regression model. ERK activity was independent of other confounders such as Charlson Comorbidity Index or SOFA score (HR 0.28, 95% CI 0.10-0.84, p = 0.02).

Conclusion: High activity of the RAF/MEK/ERK network during the course of COVID-19 sepsis is a protective factor and may indicate recovery of the immune system. Further studies are needed to confirm these results.

Keywords: COVID-19; ERK; MAPK; MEK; PLA; RAF; Sepsis.

Fig. 1

81 patients with confirmed Covid-19 induced sepsis in the intensive care unit were prospectively enrolled. 3 patients died within the first 3 days, 8 patients were discharged and one patient could not be followed up. 65 patients were included in the final analysis of ERK activity on day 4

Fig. 2

The Kaplan–Meier curve of 30-day survival as a function of ERK activity is plotted. Patients with increased ERK activity have a significantly lower mortality rate (p = 0.011). In the following Cox regression, the ERK activity was adjusted for CCI, gender and the SOFA score at the time of inclusion. Increased ERK activity was identified as the only significant, protective factor

Fig. 3

The trajectories of ERK activity in the survivors and non-survivors are presented. While there is no significant difference between the two groups on day 1 of sepsis, significantly higher ERK activity is observed in the survivor group on day 4 (p = 0.011)