Transcriptomic clustering of critically ill COVID-19 patients (preprint)

Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit (ICU), to identify two transcriptomic clusters characterized by expression of either interferon-related or immune checkpoint genes, respectively. These profiles have different ICU outcome, in spite of no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding similar results. These findings reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19, aimed to ultimately personalize their therapies.

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

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.