Level of cell-free DNA in plasma as an early marker of hospital course of covid-19 in patients with type 2 diabetes and obesity
E.I. Dubrovskyi, T.I. Drevytska, D.O. Pashevin, L.V. Tumanovska, D.O. Stroy, V.E. Dosenko
Bogomoletz Institute of Physiology, National Academy of Science, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz69.04.074
Abstract
The progression of COVID-19 varies significantly among individuals; the severity and mortality rate are
correlated with obesity, pre-existing type 2 diabetes and hypertension. However, not all patients from highrisk groups are characterized by severe passing of disease. Finding precise and rapid prognostic indicators
is one of the main aims of our study. The study used plasma samples from 103 patients and volunteers. A
retrospective analysis was performed on 93 COVID-19 patients classified by the severity of the disease as
mild (n = 14), moderate (n = 42), and severe (n = 37). The distribution into groups was conducted after
the completion of treatment in patients. The severity of COVID-19 was retrospectively assessed at the
time of hospital discharge. Upon admission, all patients presented with similar symptoms of the disease.
Glucocorticosteroids were not administered during the pre-hospital treatment phase. Demographic data
and parametric indicators were registered. Clinical analysis and quantification of extracellular DNA
(cfDNA) were performed and the levels of NETosis, the concentration of human myeloperoxidase (MPO)
and human neutrophil elastase in blood plasma were measured. Statistical analyses were provided in the
R environment (www.R-project.org, V.4.0). Our data illustrates that the severity of coronavirus disease
among subjects largely correlates with the initial cell-free DNA in plasma and NETs formation activity.
The plasma cfDNA levels in the early period of the disease were statistically significantly different in the
subsequent course of the disease in patients with diabetes. The cfDNA value of 4297 ng/ml and higher
corresponded to a more severe passing of disease in patients with COVID-19 from a high-risk group with
82% sensitivity and 72% specificity (AUC0.856, 95% CI 0.778-0.935, P < 0.001). The level of elastase in
the blood plasma of patients with severe COVID-19 shows a statistically significant difference from the
level of mild and moderate patients (P < 0.001), as well as compared with the level of elastase in healthy
donors. In addition, the data demonstrate statistically significant differences in MPO levels between all
groups of patients with COVID-19. We found an association between circulating NET formation markers
at the disease’s initial stage and clinical outcome. This demonstrates the potential importance of assessing
plasma levels of cfDNA for clinical decision-making in the early stages of the disease.
Keywords:
cfDNA; neutrophils; COVID-19; NETosis; diabetes; predictors
References
- Shah C, Grando DJ, Rainess RA, Ayad L, Gobran E, Benson P, Neblett MT, Nookala V. Factors associated with increased mortality in hospitalized COVID-19 patients. Ann Med Surg (Lond). 2020;60:308-13.
CrossRef
PubMed PubMedCentral
- Masuda S, Nakazawa D, Shida H, Miyoshi A, Kusunoki Y, Tomaru U, Ishizu A. NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 2016;459:89-93.
CrossRef
PubMed
- Foy BH, Carlson JCT, Reinertsen E, Padros I Valls R, Pallares Lopez R, Palanques-Tost E, Mow C, Westover MB, Aguirre AD, Higgins JM. Association of red blood cell distribution width with mortality risk in hospitalized adults with SARS-CoV-2 infection. JAMA Netw Open. 2020;3(9):e2022058.
CrossRef
PubMed PubMedCentral
- Ruetzler K, Szarpak Ł, Ładny JR, Gąsecka A, GilisMalinowska N, Pruc M, Smereka J, Nowak B, Filipiak KJ, Jaguszewski MJ. D-dimer levels predict COVID-19 severity and mortality. Kardiol Pol. 2021 Feb 25;79(2):217-8.
CrossRef
PubMed
- Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood. 2020 Sep 3;136(10):1169-79.
CrossRef
PubMed PubMedCentral
- Radermecker C, Detrembleur N, Guiot J, Cavalier E, Henket M, d'Emal C, Vanwinge C, Cataldo D, Oury C, Delvenne P, Marichal T. Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19. J Exp Med. 2020;217(12):e20201012.
CrossRef
PubMed PubMedCentral
- Radermecker C, Sabatel C, Vanwinge C, Ruscitti C, Maréchal P, Perin F, et al. Locally instructed CXCR4hi neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps. Nat Immunol. 2019;20(11):1444-55.
CrossRef
PubMed PubMedCentral
- Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, Liew AA, Phoon MC, van Rooijen N, Chow VT. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011;179(1):199-210.
CrossRef
PubMed PubMedCentral
- Saand AR, Flores M, Kewan T, Alqaisi S, Alwakeel M, Griffiths L, Wang X, Han X, Burton R, Al-Jaghbeer MJ, Abi Fadel F. Does inpatient hyperglycemia predict a worse outcome in COVID-19 intensive care unit patients? J Diabetes. 2021;13(3):253-60.
CrossRef
PubMed PubMedCentral
- Azevedo RB, Botelho BG, Hollanda JVG, Ferreira LVL, Junqueira de Andrade LZ, Oei SSML, Mello TS, Muxfeldt ES. Covid-19 and the cardiovascular system: a comprehensive review. J Hum Hypertens. 2021;35(1):4-11.
CrossRef
PubMed PubMedCentral
- Rashedi J, Mahdavi Poor B, Asgharzadeh V, Pourostadi M, Samadi Kafil H, Vegari A, Tayebi-Khosroshahi H, Asgharzadeh M. Risk Factors for COVID-19. Infez Med. 2020;28(4):469-474. PMID: 33257620.
- Song C, Li H, Li Y, Dai M, Zhang L, Liu S, et al. NETs promote ALI/ARDS inflammation by regulating alveolar macrophage polarization. Exp Cell Res. 2019;382(2):111486.
CrossRef
PubMed
- Mikacenic C, Moore R, Dmyterko V, West TE, Altemeier WA, Liles WC, Lood C. Neutrophil extracellular traps (NETs) are increased in the alveolar spaces of patients with ventilator-associated pneumonia. Crit Care. 2018;22(1):358.
CrossRef
PubMed PubMedCentral
- Ebrahimi F, Giaglis S, Hahn S, Blum CA, Baumgartner C, Kutz A, van Breda SV, Mueller B, Schuetz P, Christ-Crain M, Hasler P. Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomized controlled trial. Eur Respir J. 2018;51(4):1701389.
CrossRef
PubMed
- Li H, Zhou X, Tan H, Hu Y, Zhang L, Liu S, et al. Neutrophil extracellular traps contribute to the pathogenesis of acid-aspiration-induced ALI/ARDS. Oncotarget 2017;9:1772-84.
CrossRef
PubMed PubMedCentral
- Lefrançais E, Mallavia B, Zhuo H, Calfee CS, Looney MR. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 2018;3.
CrossRef
PubMed PubMedCentral
- Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA. 2010;107(36):15880-5.
CrossRef
PubMed PubMedCentral
- Ackermann M, Anders HJ, Bilyy R, Bowlin GL, Daniel C. Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death Differ. 2021; 24:1-15.
CrossRef
PubMed PubMedCentral
- Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Egeblad M, Woods RJ, Kanthi Y, Knight JS. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999.
CrossRef
- Hammad R, Eldosoky MAER, Fouad SH, Elgendy A, Tawfeik AM, Alboraie M, Abdelmaksoud MF. Circulating cell-free DNA, peripheral lymphocyte subsets alterations and neutrophil-lymphocyte ratio in the assessment of COVID-19 severity. Innate Immun. 2021;27(3):240-50.
CrossRef
PubMed PubMedCentral
- Ng H, Havervall S, Rosell A, Aguilera K, Parv K, von Meijenfeldt FA, Lisman T, Mackman N, Thålin C, Phillipson M. Circulating Markers of Neutrophil. Extracellular traps are of prognostic value in patients with COVID-19. Arterioscler Thromb Vasc Biol. 2021;41(2):988-94.
CrossRef
PubMed PubMedCentral
- Sørensen OE, Borregaard N. Neutrophil extracellular traps - the dark side of neutrophils. J Clin Invest. 2016;126(5):1612-20.
CrossRef
PubMed PubMedCentral
- Zuo Y, Zuo M, Yalavarthi S, Gockman K, Madison JA, Shi H, Woodard W, Lezak SP, Lugogo NL, Knight JS, Kanthi Y. Neutrophil extracellular traps and thrombosis in COVID-19. MedRxiv. 2020.04.30.20086736.
CrossRef
- Kostyuk S, Smirnova T, Kameneva L, Porokhovnik L, Speranskij A, Ershova E, Stukalov S, Izevskaya V, Veiko N. GC-Rich extracellular DNA induces oxidative stress, double-strand DNA breaks, and DNA damage response in human adipose-derived mesenchymal stem cells. Oxid Med Cell Long. 2015;2015:782123.
CrossRef
PubMed PubMedCentral
- Kostjuk S, Loseva P, Chvartatskaya O, Ershova E, Smirnova T, Malinovskaya E, Roginko O, Kuzmin V, Izhevskaia Received 17.04.2023 V, Baranova A, Ginter E, Veiko N. Extracellular GC-rich DNA activates TLR9- and NF-kB-dependent signaling pathways in human adipose-derived mesenchymal stem cells (haMSCs). Expert Opin Biol Ther. 2012:S99-111.
CrossRef
PubMed
- Liu B. Free DNA, a reason for severe COVID-19 infection? Med Hypothes. 2020 Sep;142:109812.
CrossRef
PubMed PubMedCentral
- Apel F, Andreeva L, Knackstedt LS, Streeck R, Frese CK, Goosmann C, Hopfner KP, Zychlinsky A. The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps. Sci Signal. 2021;14(673).
CrossRef
PubMed
|