Evidence for the utility of cfDNA plasma concentrations to predict disease severity in COVID-19

  1. Katharina Hoeter
  2. Elmo Neuberger
  3. Susanne Fischer
  4. Manuel Herbst
  5. Ema Juškevičiūtė
  6. Heidi Rossmann
  7. Martin F. Sprinzl
  8. Perikles Simon
  9. Marc Bodenstein
  10. Michael K.E. Schäfer

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Abstract

COVID-19 is a pandemic caused by the highly infective SARS-CoV-2. There is a need for biomarkers not only for overall prognosis but also for predicting the response to treatments and thus for improvements in the clinical management of patients with COVID-19. Circulating cell-free DNA (cfDNA) has emerged as a promising biomarker in the assessment of various disease conditions. The aim of this retrospective and observational pilot study was to examine the potential value of cfDNA plasma concentrations as a correlative biomarker in hospitalized COVID-19 patients. Lithium-Heparin plasma samples were obtained from twenty-one COVID-19 patients during hospitalization in the University Medical Center of Mainz, Germany, and the cfDNA concentrations were determined by quantitative PCR yielding amplicons of long interspersed nuclear elements (LINE-1). cfDNA plasma concentrations of COVID-19 patients ranged between 247.5 and 6346.25 ng/ml and the mean concentrations were 1831 ± 1388 ng/ml (± standard deviation). Correlations were found between cfDNA levels and the occurrence of acute respiratory distress symptom (ARDS), acute kidney injury (AKI), myositis, neurological complications, bacterial superinfection and disease severity as defined by sepsis-related organ failure assessment score (SOFA) score. D-Dimer and C-reactive-protein (CRP), determined by clinical laboratory analysis, showed the highest correlations with cfDNA levels. The results of this observational study suggest that cfDNA plasma concentrations may serve as a predictive biomarker of disease severity in COVID-19. Prospective studies enrolling larger patient cohorts are ongoing to test this hypothesis.

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    SciScore for 10.1101/2021.04.29.21256291: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The study was approved by German law [Landeskrankenhausgesetz §36 and §37] in accordance with the Declaration of Helsinki and by the local Ethics Committee of “Landesärztekammer Rheinland-Pfalz” (reference numbers 2020-15116-retrospective).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations of the present study are the small cohort size showing a broad spectrum of COVID-19 severity and that we analysed a single plasma sample from each patient at individually different phases of their hospitalization. Therefore, a generalization of the results to all patients suffering from COVID-19 is not possible and we cannot discuss data on dynamic alterations of cfDNA over time. The results provide evidence that cfDNA is a liquid biopsy marker potentially predicting disease severity of COVID-19. Our findings are in agreement with recently reported data on the predictive value of circulating (mitochondrial) cfDNA for COVID-19 outcome (20, 21). Significant correlations were further reported between total cfDNA and LDH (preprint medRxiv, https://www.medrxiv.org/content/10.1101/2020.07.27.20163188v1), a biomarker of cell damage, similar to circulating cfDNA. LDH is commonly elevated in severe COVID-19 and is increased in non-survivors (23). As the relative range of cfDNA concentrations determined in COVID-19 patients in our study was broader than the range of LDH, cfDNA may be utilized to discriminate different grades of COVID-19 severity more accurately than LDH. Testing this hypothesis will be the subject of future studies. It should be noted that cfDNA is not only a biomarker for upstream pathophysiological mechanisms but has been also proposed to trigger specific downstream effects. For instance, cfDNA was shown to be an immune system regulator (24) with distinct...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.04.29.21256291 on medRxiv