Prospective observational study of cell-free DNA as a prognostic biomarker in COVID-19 and bacterial sepsis: COVSEP-study

Hyperinflammation and extensive cell damage characterize both COVID-19-sepsis and bacterial sepsis, contributing to poor clinical outcomes. Cell-free DNA (cfDNA), a damage-associated molecular pattern (DAMP), reflects ongoing tissue injury and may predict mortality. We aimed to evaluate cfDNA as a prognostic biomarker for 30-day mortality in ICU patients with COVID-19- vs. bacterial sepsis, and its association with inflammatory markers and disease progression. In a prospective observational study (ethics approval: 2020-15,535; DRKS-ID: DRKS00025222), cfDNA was quantified in 64 ICU patients (COVID-19-sepsis n = 27, bacterial sepsis n = 37) at four time points using quantitative PCR targeting 90 bp and 222 bp fragments of LINE-1 elements. An Integrity Index (222/90 bp) was calculated to infer the predominant mode of cell death. Nineteen healthy individuals served as controls. Associations with mortality and clinical parameters were analyzed using adjusted Cox regression, time-dependent models, and correlation analyses. Higher cfDNA levels (90 bp) within the first 24 h were strongly associated with 30-day (p = 0.003) and 180-day mortality (p = 0.003) in COVID-19-sepsis, but not in bacterial sepsis. COVID-19 patients showed significantly higher cfDNA levels (p < 0.01), which correlated with CRP, PCT, LDH, and lactate. The Integrity Index increased over time in bacterial sepsis and remained stable in COVID-19-sepsis, but was not predictive of survival. Elevated cfDNA levels were associated with ECMO therapy but not with renal replacement therapy. cfDNA is a valuable early prognostic biomarker in COVID-19-sepsis. Its rapid dynamics and strong correlation with clinical outcomes highlight its potential for real-time monitoring and risk stratification in viral sepsis.