Neutrophil extracellular traps: diagnostic and prognostic value in COVID-19

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Rationale: An important element of antiviral defense in the pathophysiology of COVID-19 is the innate cell immunity including polymorphonuclear neutrophils prone to netotic transformation. Neutrophils can be not only a marker of acute infection, but, being a source of neutrophil extracellular traps (NET), can play a key role in the development of thrombotic complications leading to acute respiratory insufficiency in COVID-19.

Aim: To determine the diagnostic and prognostic value of NET levels in patients with COVID-19.

Materials and methods: We monitored NET levels in peripheral blood of 34 patients with COVID-19 (mean age, 67 ± 15.8 years), admitted to MONIKI hospital. The control group consisted of 54 healthy volunteers (mean age, 52 ± 11.5 years). Whole blood samples of 2 pL each were used for the preparation of monolayer smears (Giemsa stain) and calculation of at least 200 cell structures including native intact and transformed neutrophils (MECOS-C2 microscope, Medical computer systems).

Results: Patients with COVID-19 had higher NET levels, compared to those in healthy controls: 14.5% (2.9-28.6%) vs. 5.0% (1.8-11.9%, p < 0.0001). The patients who were on non-invasive respiratory support (23.5%) had a NET level of 12% (8.122.3%), whereas those on invasive mechanical ventilation (17.6%) had a 1.5-fold higher NET level of 17.9% (12.3-28.2%) (p < 0.05). In the patients who died (11.8% of the cases), the NET level amounted to 19% (16.5-26%, p < 0.05). Monitoring of blood NET levels was performed in 9 patients from the day of admittance to the day of their transfer to the intensive care unit / discharge / death. It was shown that a decrease of NET levels mirrors an improvement of the patient's clinical condition and efficacy of his/hers treatment. On the opposite, an increase of NET levels can indicate a deterioration and risk of unfavorable course.

Conclusion: We have identified some pathophysiological mechanisms in COVID-19, related to the neutrophil compartment. Patients with coronavirus infection are characterized by high NET levels which is at least 3-fold higher than that in healthy volunteers. This indicates an abnormality in immune host defense and development of an inadequate inflammatory response. An increase of NET in whole blood smears of more than 16% can be a criterion of an unfavorable prognosis of the disease course and the risk of death.

About the authors

D. V. Kassina

Moscow Regional Research and Clinical Institute (MONIKI);

ORCID iD: 0000-0002-6759-9121

Darya V. Kassina - Research Fellow, Scientific and Research Laboratory.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

I. A. Vasilenko

Moscow Regional Research and Clinical Institute (MONIKI); The Kosygin State University of Russia

Author for correspondence.
ORCID iD: 0000-0002-6374-9786

Irina A.Vasilenko - MD, PhD, Professor, Leading Research Fellow, Scientific and Research Laboratory MONIKI; Professor, Chair of Applied Mathematics and Programming KSUR.

33/1 Sadovnicheskaya ul., Moscow, 115035, Tel.: +7 (495) 951 54 97

Russian Federation

A. S. Gur’ev

Moscow Regional Research and Clinical Institute (MONIKI); Medtechnopark

ORCID iD: 0000-0001-8823-7819

Alexander S. Gur'ev - PhD, Senior Research Fellow, Scientific and Research Laboratory.

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

A. Yu. Volkov


ORCID iD: 0000-0001-5110-553X

Alexey Yu. Volkov - PhD (in Phys. and Math.), General Director.

8-2-383 Profsoyuznaya ul., Moscow, 117292

Russian Federation

V. B. Metelin

Moscow Regional Research and Clinical Institute (MONIKI); The Kosygin State University of Russia

ORCID iD: 0000-0003-0600-5729

Vladislav B. Metelin - PhD (in Biol.), Leading Research Fellow, Scientific and Research Laboratory MONIKI; Associate Professor, Chair of Philosophy, Manusology and Theology KSUR.

61/2 Shchepkina ul., Moscow, 129110; 33/1 Sadovnicheskaya ul., Moscow, 115035

Russian Federation


  1. Li H, Liu Z, Ge J. Scientific research progress of COVID-19 / SARS-CoV-2 in the first five months. J Cell Mol Med. 2020;24(12):6558-70. doi: 10.1111/jcmm.15364.
  2. Heffernan DS, Evans HL, Huston JM, Clar-idge JA, Blake DP, May AK, Beilman GS, Barie PS, Kaplan LJ. Surgical Infection Society Guidance for Operative and Peri-Operative Care of Adult Patients Infected by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Surg Infect (Larchmt). 2020;21(4):301-8. doi: 10.1089/sur.2020.101.
  3. Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020;46(6):1105-8. doi: 10.1007/s00134-020-06059-6.
  4. Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, Zhi L, Wei H, Zhang Z, Qiu Y, Wang J, Wang A. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38-42. doi: 10.1016/j.cytog-fr.2020.04.002.
  5. Vlachakis PK, Tentolouris A, Tousoulis D, Tentolouris N. Current data on the cardiovascular effects of COVID-19. Hellenic J Cardiol. 2020;61(1):46-8. doi: 10.1016/j.hjc.2020.04.001.
  6. Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019;133(9): 906-18. doi: 10.1182/blood-2018-11-882993.
  7. Twaddell SH, Baines KJ, Grainge C, Gibson PG. The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease. Chest. 2019;156(4): 774-82. doi: 10.1016/j.chest.2019.06.012.
  8. Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, DaBler-Plenker J, Guerci P, Huynh C, Knight JS, Loda M, Looney MR, McAllister F, Rayes R, Re-naud S, Rousseau S, Salvatore S, Schwartz RE, Spicer JD, Yost CC, Weber A, Zuo Y, Egeblad M. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020;217(6):e20200652. doi: 10.1084/jem.20200652.
  9. 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. doi: 10.1016/j.cca.2016.05.029.
  10. Gur'ev A, Mosalskaia D, Lopatin A, Volkov A. Prognostic value of cellular markers in sepsis: extracellular DNA traps and platelet count relation. Intensive Care Med Exp. 2019;7 Suppl 3:55. doi: 10.1186/s40635-019-0265-y.
  11. Волков АЮ, Мосальская ДВ, Гурьев АС, авторы; ООО «Медтехнопарк», патентообладатель. Способ определения относительного количества этотически трансформированных фагоцитов. Пат. 2712179 Рос. Федерация. Опубл. 24.01.2020.
  12. Богданова ВД, Андрюков БГ, Ляпун ИН, Бынина МП. Фенотипические субпопуляции нейтрофилов: новые диагностические и иммуномодулирующие стратегии. Здоровье. Медицинская экология. Наука. 2019;(1):5-10. doi: 10.5281/zenodo.2562122. [Bogdanova VD, Andryukov BG, Lyapun IN, Bynina MP.
  13. Плескова СН, Горшкова ЕН, Боряков АВ, Крюков РН. Морфологические особенности быстрого и классического нетоза. Цитология. 2019;61(9):704-12. doi: 10.1134/S0041377119090098.
  14. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-47. doi: 10.1038/nri.2017.105.
  15. Андрюков БГ, Сомова ЛМ, Дробот ЕИ, Матосова ЕВ. Защитные стратегии нейтрофиль-ных гранулоцитов от патогенных бактерий. Здоровье. Медицинская экология. Наука. 2017;(1):4-18. doi: 10.5281/zenodo.345606.
  16. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Ege-blad M, Woods RJ, Kanthi Y, Knight JS. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999. doi: 10.1172/jci.insight.138999.
  17. Tomar B, Anders HJ, Desai J, Mulay SR. Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19. Cells. 2020;9(6):1383. doi: 10.3390/cells9061383.
  18. Yaqinuddin A, Kashir J. Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1 p/neutrophil extracellular traps feedback loop. Med Hypotheses. 2020;143:109906. Epub ahead of print. doi: 10.1016/j.mehy.2020.109906.
  19. Lv D, Xu Y, Cheng H, Ke Y, Zhang X, Ying K. A novel cell-based assay for dynamically detecting neutrophil extracellular traps-induced lung epithelial injuries. Exp Cell Res. 2020;394(2): 112101. Epub ahead of print. doi: 10.1016/j.yex-cr.2020.112101.
  20. Weber AG, Chau AS, Egeblad M, Barnes BJ, Janowitz T. Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series. Preprint. medRxiv. doi: 10.1101/2020.05.13.20087734.
  21. Gupta S, Sahni V. The intriguing commonality of NETosis between COVID-19 & Periodontal disease. Med Hypotheses. 2020;144:109968. Epub ahead of print. doi: 10.1016/j.mehy.2020.109968.
  22. Seif S, Ayuna A, Kumar A, Macdonald J. Massive coronary thrombosis caused primary percutaneous coronary intervention to fail in a COVID-19 patient with ST-elevation myocardial infarction. Catheter Cardiovasc Interv. 2020:10.1002/ccd.29050. Epub ahead of print. doi: 10.1002/ccd.29050.
  23. Thierry AR, Roch B. SARS-CoV2 may evade innate immune response, causing uncontrolled neutrophil extracellular traps formation and multi-organ failure. Clin Sci (Lond). 2020;134(12): 1295-300. doi: 10.1042/CS20200531.

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Copyright (c) 2020 Kassina D.V., Vasilenko I.A., Gur’ev A.S., Volkov A.Y., Metelin V.B.

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