IFIH1 rs1990760 variants, systemic inflammation and outcome in critically-ill COVID-19 patients

Amado-Rodriguez, L.; Salgado del Riego, E.; Gomez de Ona, J.; Lopez-Alonso, I.; Gil-Pena, H.; Lopez-Martinez, C.; Martin-Vicente, P.; Lopez-Vazquez, A.; Gonzalez Lopez, A.; Cuesta-Llavona, E.; Rodriguez-Garcia, R.; Boga, J. A.; alvarez-Arguelles, M. E.; Mayordomo-Colunga, J.; Vidal-Castineira, J. R.; Crespo, I.; Fernandez, M.; Criado, L.; Salvadores, V.; Jimeno-Demuth, F. J.; Blanch, L.; Prieto, B.; Fernandez-Fernandez, A.; Lopez-Larrea, C.; Coto, E.; Albaiceta, G. M.

Rationale: Outcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by virus clearance and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. Objective: To characterize the impact of IFIH1 rs199076 variants on host response and outcomes after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Measurements and Main Results: 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to a MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids (N=14) survived their ICU stay (HR 2.49, 95% confidence interval 1.29-4.79). Patients with a TT variant treated with dexamethasone (N=50) showed an increased hospital mortality (HR 2.19, 95% confidence interval 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.