What question did this study set out to answer?

This study aims to explore the role of serum cell-free nucleic acids as biomarkers for predicting COVID-19 severity and outcomes.

April 16, 2026Open Access

Cell-free nucleic acids as a non-invasive biomarker for predicting COVID-19 disease severity and outcome: a retrospective cohort study

Key Points

This study aims to explore the role of serum cell-free nucleic acids as biomarkers for predicting COVID-19 severity and outcomes.
Conducted a retrospective cohort study involving COVID-19 patients and healthy controls.
Collected serum samples upon hospital admission and retrieved health information from a biobank.
Measured cfDNA concentration via capillary electrophoresis and detected cfRNA using quantitative real-time PCR.
cfDNA concentrations were significantly higher in COVID-19 patients compared to healthy controls.
cfDNA levels correlated with disease severity, increasing from mild to critical cases.
cfDNA exhibited high predictive values for ICU admission, ARS, and mortality, outperforming other biomarkers.

Abstract

Background The COVID-19 pandemic highlighted the need for novel biomarkers to identify patients at risk of developing severe disease. Circulating cell-free nucleic acids (cfNAs) are released from injured host cells or can be derived from pathogens. As cfNA is suggested to be a useful biomarker in oncologic, autoimmune, and other diseases, the aim of our study was to investigate the role of serum cfNA in predicting the course and outcome of COVID-19 disease. Methods We conducted a retrospective cohort study at Vilnius University Hospital Santaros Klinikos, utilizing serum samples collected upon admission and accompanying health information obtained from the Vilnius Santaros Klinikos Biobank. A total of 108 adult COVID-19 patients hospitalized between November 24, 2020, and November 10, 2021, and 24 healthy controls were enrolled. cfDNA concentration was measured using capillary electrophoresis. cfRNA was detected using quantitative real-time PCR. Results cfDNA concentration was higher in COVID-19 patients compared with controls (4.28 vs. 0.51 ng/µL, p < 0.001) and increased with disease severity: from 1.06 ng/µL in mild to 2.65 ng/µL in severe, and 6.68 ng/µL in critical disease. cfDNA levels were higher in intensive care unit (ICU) patients (6.68 vs. 2.30 ng/µL, p < 0.001), patients requiring advanced respiratory support (ARS) (7.11 vs. 2.74 ng/µL, p < 0.001), and non-survivors (16.68 vs. 3.44 ng/µL, p < 0.001). cfDNA showed high predictive values for ICU admission (AUC 0.79), ARS (AUC 0.77), and lethal outcome (AUC 0.81), outperforming other routine biomarkers. In logistic regression analysis, cfDNA remained an independent predictor for ICU admission (OR 1.21, 95%CI 1.08–1.36), ARS requirement (OR 1.15, 95%CI 1.03–1.28), and in-hospital mortality (OR 1.08, 95%CI 1.02–1.14), while serum SARS-CoV-2 RNAemia remained an independent predictor of ARS requirement (OR 4.18, 95%CI 1.15–15.20). Conclusions Higher serum cfDNA concentrations were independently associated with greater COVID-19 disease severity, increased likelihood of requiring intensive care, ARS, and in-hospital mortality. cfDNA demonstrated superior prognostic performance, surpassing established biomarkers. Serum SARS-CoV-2 RNAemia was associated with the need for ARS. This indicates that cfNAs may serve as clinically valuable biomarkers for early risk stratification and outcome prediction in COVID-19 patients. Further validation in independent cohorts is required to confirm generalizability. Clinical trial number Not applicable.

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