Interferon-induced protein 35 (IFI35) is associated with COVID-19 severity and clinical outcomes.

Excessive activation of the immune system by damage-associated molecular patterns (DAMPs) contributes to COVID-19 severity. Interferon-induced protein 35 (IFI35) is a DAMP-related interferon-stimulated gene recently proposed as a biomarker of hyperinflammation. We investigated the association between IFI35 serum levels, gene expression, and COVID-19 severity in 430 hospitalized patients (214 critical and 216 severe) and 112 convalescent controls. Serum IFI35 levels were quantified using ELISA, and IFI35 mRNA expression in PBMCs was assessed using quantitative PCR (qPCR). IFI35 levels were significantly higher in critically ill patients (median 1,003.6 pg/mL) than in severe cases (867.6 pg/mL; p = 0.001) and controls (798.3 pg/mL; p < 0.0001). Gene expression analysis showed a similar pattern (p = 0.014). Higher IFI35 levels were also associated with adverse clinical outcomes, including mortality, invasive mechanical ventilation, acute kidney injury, and cardiac arrest (all p < 0.05). In receiver operating characteristic analysis, adding IFI35 to a model including C-reactive protein and D-dimer improved discriminative performance for mortality. In survival analysis, IFI35 > 1,475 pg/mL was associated with reduced survival in this cohort (p = 0.0062). These findings identify IFI35 as a promising prognostic biomarker associated with COVID-19 severity and adverse outcomes.