Neutrophil Markers as Predictors of COVID-19 Severity at Hospital Admission: A Cross-sectional Study
-
Maedeh Vahabi
,
Abdolrahman Rostamian
,
Ensie Sadat Mirsharif
,
keyvan latifi
,
Sara Iranparast
,
Tooba Ghazanfari
Abstract
COVID-19 is capable of undermining self-tolerance in a host's immune system and triggering autoimmunity by hyper-activating the innate and adaptive immune systems, which has not investigated in Iranian society until now. In the innate immune system neutrophils are the predominant immune cells that protect the human body against invaders.
Here, we sought to explore 2 important variables related to neutrophil: DNA complexes with myeloperoxidase (MPO-DNA) as a reliable indicator of neutrophil extracellular traps (NETs) by MPO-DNA complex evaluation using a sandwich ELISA and the underlying role of IL-8 in (NETs) formation during COVID-19 infection.
According to our results, in COVID-19 patients, neutrophil-to-lymphocyte ratio (NLR) was significantly higher in ICU patients (14.62±11.81) compared to non-ICU patients (3.16±3.33). Elevated IL-8 levels were observed in COVID-19 patients, particularly in ICU patients. MPO-DNA levels, indicating NETosis, were significantly higher in COVID-19 patients and strongly correlated with neutrophil counts (r=0.472).
Thus, our studies suggest that neutrophils count, IL-8, and MPO-DNA can be used as powerful biomarkers in diagnosing COVID-19 severity. patients with severe COVID-19 infection are prone to heart disease because most of them develop excessive NET formation. Additionally, In COVID-19 patients, a higher MPO-DNA level may increase the risk of developing heart disease too.
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8. Cicco S, Cicco G, Racanelli V, Vacca A. Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment. Med Inflamm. 2020;2020:7527953.
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10. Lee KH, Kronbichler A, Park DD-Y, Park Y. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160-73.
11. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-75.
12. Kraft R, Herndon DN, Finnerty CC, Cox RA, Song J, Jeschke MG. Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study. Shock. 2015;43(3):222-7.
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14. Teijeira A, Garasa S, Ochoa MC, Villalba M, Olivera I, Cirella A, et al. IL8, Neutrophils, and NETs in a Collusion against Cancer Immunity and Immunotherapy. Clin Cancer Res. 2021;27(9):2383-93.
15. Lee KH, Kronbichler A, Park DD-Y, Park Y. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160-73.
16. Kumar S, Payal N, Srivastava VK, Kaushik S, Saxena J, Jyoti A. Neutrophil extracellular traps and organ dysfunction in sepsis. Clin Chim Acta. 2021;523:152-62.
17. Dinse GE, Parks CG, Meier HCS, Co CA, Chan EKL, Jusko TA, et al. Prescription medication use and antinuclear antibodies in the United States, 1999-2004. J Autoimmun. 2018;92:93-103.
18. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus. 2009;18(11):935-19.
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20. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146-53.
21. Melero I, Villalba-Esparza M, Recalde-Zamacona B, Jiménez-Sánchez D, Teijeira Á, Argueta A, et al. Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19. Chest. 2022;162(5):1006-16.22.
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24. de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016;16(6):378-91.
25. Teijeira A, Garasa S, Ochoa MDC, Cirella A, Olivera I, Glez-Vaz J, et al. Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils. Europ J Immunol. 2021;51(9):2274-80.26.
26. Itelman E, Wasserstrum Y, Segev A, Avaky C, Negru L, Cohen D, et al. Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center. Isr Med Assoc J. 2020;22(5):271-4.
27. Ardestani SK, Salehi MR, Attaran B, Hashemi SM, Sadeghi S, Ghaffarpour S, et al. Neutrophil to Lymphocyte Ratio (NLR) and Derived NLR Combination: A Cost-effective Predictor of Moderate to Severe COVID-19 Progression. Iran J Allergy Asthma Immunol. 2022;21(3):241-53.
28. Zhang B, Zhou X, Zhu C, Song Y, Feng F, Qiu Y, et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci. 2020;7:157.
29. Ye W, Chen G, Li X, Lan X, Ji C, Hou M, et al. Dynamic changes of D-dimer and neutrophil-lymphocyte count ratio as prognostic biomarkers in COVID-19. Resp Res. 2020;21(1):169.
30. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3.
31. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-43.
32. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, et al. Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19. 2020;5(11):e138999.
33. Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, Lima Md, Nascimento DC, et al. SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology. 2020;217(12).
34. Xue G, Gan X, Wu Z, Xie D, Xiong Y, Hua L, et al. Novel serological biomarkers for inflammation in predicting disease severity in patients with COVID-19. Int Immunopharmacol. 2020;89(Pt A):107065.
35. McCarthy CG, Saha P, Golonka RM, Wenceslau CF, Joe B, Vijay-Kumar M. Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Compr Physiol. 2021;11(1):1575-89.
2. Vahabi M, Ghazanfari T, Sepehrnia S. Molecular mimicry, hyperactive immune system, and SARS-COV-2 are three prerequisites of the autoimmune disease triangle following COVID-19 infection. Int Immunopharmacol. 2022;112:109183.
3. Dotan A, Muller S, Kandu D, David P, Halpert G, Shoenfelda Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun Rev. 2021;20(4102792.).
4. Kanduc D, Shoenfeld Y. Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine. Immunologic Res. 2020;68(5):310-3.
5. Soehnlein O, Steffens S, Hidalgo A, Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nature reviews Immunology. 2017;17(4):248-61.
6. Tomar B, Anders HJ, Desai J, Mulay SR. Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19. Cells. 2020;9(6).
7. Jayaprakash K, Demirel I, Khalaf H, Bengtsson T. The role of phagocytosis, oxidative burst and neutrophil extracellular traps in the interaction between neutrophils and the periodontal pathogen Porphyromonas gingivalis. Mol Oral Microbiol. 2015;30(5):361-75.
8. Cicco S, Cicco G, Racanelli V, Vacca A. Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment. Med Inflamm. 2020;2020:7527953.
9. Singh K, Mittal S, Gollapudi S, Butzmann A, Kumar J, Ohgami RS. A meta-analysis of SARS-CoV-2 patients identifies the combinatorial significance of D-dimer, C-reactive protein, lymphocyte, and neutrophil values as a predictor of disease severity. Int J lab Hematol. 2021;43(2):324-8.
10. Lee KH, Kronbichler A, Park DD-Y, Park Y. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160-73.
11. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-75.
12. Kraft R, Herndon DN, Finnerty CC, Cox RA, Song J, Jeschke MG. Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study. Shock. 2015;43(3):222-7.
13. Kaiser R, Leunig A, Pekayvaz K, Popp O, Joppich M, Polewka V, et al. Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. JCI Insight. 2021;6(18).
14. Teijeira A, Garasa S, Ochoa MC, Villalba M, Olivera I, Cirella A, et al. IL8, Neutrophils, and NETs in a Collusion against Cancer Immunity and Immunotherapy. Clin Cancer Res. 2021;27(9):2383-93.
15. Lee KH, Kronbichler A, Park DD-Y, Park Y. Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. Autoimmun Rev. 2017;16(11):1160-73.
16. Kumar S, Payal N, Srivastava VK, Kaushik S, Saxena J, Jyoti A. Neutrophil extracellular traps and organ dysfunction in sepsis. Clin Chim Acta. 2021;523:152-62.
17. Dinse GE, Parks CG, Meier HCS, Co CA, Chan EKL, Jusko TA, et al. Prescription medication use and antinuclear antibodies in the United States, 1999-2004. J Autoimmun. 2018;92:93-103.
18. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus. 2009;18(11):935-19.
Mumoli N, Dentali F, Conte G, Colombo A, Capra R, Porta C, et al. Upper extremity deep vein thrombosis in COVID-19: Incidence and correlated risk factors in a cohort of non-ICU patients. PloS one. 2022;17(1):e0262522.
20. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146-53.
21. Melero I, Villalba-Esparza M, Recalde-Zamacona B, Jiménez-Sánchez D, Teijeira Á, Argueta A, et al. Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19. Chest. 2022;162(5):1006-16.22.
Caso F, Costa L, Ruscitti P, Navarini L, Puente AD, Giacomelli R, et al. Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects? Autoimmun Rev. 2020;19(5):102524.
23. Chang R, Chen TY-T, Wang S-I, Hung Y-M, Chen H-Y, Wei C-CJ. Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study. Clin Medi. 2023;56:101783.
24. de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016;16(6):378-91.
25. Teijeira A, Garasa S, Ochoa MDC, Cirella A, Olivera I, Glez-Vaz J, et al. Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils. Europ J Immunol. 2021;51(9):2274-80.26.
26. Itelman E, Wasserstrum Y, Segev A, Avaky C, Negru L, Cohen D, et al. Clinical Characterization of 162 COVID-19 patients in Israel: Preliminary Report from a Large Tertiary Center. Isr Med Assoc J. 2020;22(5):271-4.
27. Ardestani SK, Salehi MR, Attaran B, Hashemi SM, Sadeghi S, Ghaffarpour S, et al. Neutrophil to Lymphocyte Ratio (NLR) and Derived NLR Combination: A Cost-effective Predictor of Moderate to Severe COVID-19 Progression. Iran J Allergy Asthma Immunol. 2022;21(3):241-53.
28. Zhang B, Zhou X, Zhu C, Song Y, Feng F, Qiu Y, et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci. 2020;7:157.
29. Ye W, Chen G, Li X, Lan X, Ji C, Hou M, et al. Dynamic changes of D-dimer and neutrophil-lymphocyte count ratio as prognostic biomarkers in COVID-19. Resp Res. 2020;21(1):169.
30. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3.
31. Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-43.
32. Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, et al. Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19. 2020;5(11):e138999.
33. Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, Lima Md, Nascimento DC, et al. SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology. 2020;217(12).
34. Xue G, Gan X, Wu Z, Xie D, Xiong Y, Hua L, et al. Novel serological biomarkers for inflammation in predicting disease severity in patients with COVID-19. Int Immunopharmacol. 2020;89(Pt A):107065.
35. McCarthy CG, Saha P, Golonka RM, Wenceslau CF, Joe B, Vijay-Kumar M. Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Compr Physiol. 2021;11(1):1575-89.
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| Autoimmunity COVID-19 IL-8 Neutrophil extracellular traps Neutrophil | ||
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How to Cite
1.
Vahabi M, Rostamian A, Mirsharif ES, latifi keyvan, Iranparast S, Ghazanfari T. Neutrophil Markers as Predictors of COVID-19 Severity at Hospital Admission: A Cross-sectional Study. Iran J Allergy Asthma Immunol. 2024;:1-10.
