Erythrocytes in COVID-19: Effects on Morphology, Function, and Potential Role in Disease Pathogenesis
Main Article Content
Abstract
Since the SARS CoV-2 virus was first identified in December 2019, huge scientific endeavor has occurred in order to characterize the pathogenesis of this virus and how best to treat it. Early observations noted marked cytokine release, coagulopathy and a prothrombotic phenotype associated with severe disease. The potential contribution of red blood cells to these findings remains an area of ongoing investigation.
While there is no evidence of direct infection of red blood cells by the SARS CoV-2 RNA virus, anaemia and increased variability in shape and size of red cells have been shown to be associated with adverse outcomes in COVID-19 infection. This is likely related to the impact of inflammatory cytokine-induced oxidative stress on erythrocytes, where decreased levels of reducing agents have been shown to correlate with disease severity. The consequences of increased oxidative stress on red cells include membrane damage leading to the morphological abnormalities seen in patients, and increased rates of programmed red cell death with resultant anaemia. Production of nitric oxide by red cells is altered, possibly as a means to alleviate tissue hypoxia in these patients, and red cells may also demonstrate enhanced lactate influx, possibly reducing circulating levels at a time of increased glycolysis.
In this review we discuss the currently available evidence describing the impact of SARS CoV-2 infection on erythrocytes and the possible roles they play in patients with COVID-19 infection.
Article Details
How to Cite
SWAN, D et al.
Erythrocytes in COVID-19: Effects on Morphology, Function, and Potential Role in Disease Pathogenesis.
Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3257>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i10.3257.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. website W. https://covid19.who.ie. accessed 6th sept 2022;
2. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. May 1 2020;130(5):2620-2629. doi:10.1172/jci137244
3. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. European Heart Journal. 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623
4. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147. doi:10.1016/j.thromres.2020.04.013
5. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. May 2020;18(5):1094-1099. doi:10.1111/jth.14817
6. Foy BH, Carlson JCT, Reinertsen E, et al. Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection. JAMA Netw Open. Sep 1 2020;3(9):e2022058. doi:10.1001/jamanetworkopen.2020.22058
7. Lippi G, Henry BM, Sanchis-Gomar F. Red Blood Cell Distribution Is a Significant Predictor of Severe Illness in Coronavirus Disease 2019. Acta Haematol. 2021;144(4):360-364. doi:10.1159/000510914
8. Marchi G, Bozzini C, Bertolone L, et al. Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19. Front Physiol. 2022;13:932013. doi:10.3389/fphys.2022.932013
9. Andersson MI, Arancibia-Carcamo CV, Auckland K, et al. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus. Wellcome Open Res. 2020;5:181. doi:10.12688/wellcomeopenres.16002.2
10. Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia. Jul 2020;34(7):1726-1729. doi:10.1038/s41375-020-0887-9
11. Cameron K, Rozano L, Falasca M, Mancera RL. Does the SARS-CoV-2 Spike Protein Receptor Binding Domain Interact Effectively with the DPP4 (CD26) Receptor? A Molecular Docking Study. Int J Mol Sci. Jun 29 2021;22(13) doi:10.3390/ijms22137001
12. Shilts J, Crozier TWM, Greenwood EJD, Lehner PJ, Wright GJ. No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep. Jan 11 2021;11(1):413. doi:10.1038/s41598-020-80464-1
13. Cosic I, Cosic D, Loncarevic I. RRM Prediction of Erythrocyte Band3 Protein as Alternative Receptor for SARS-CoV-2 Virus. Applied Sciences. 2020;10(11):4053.
14. Berzuini A, Bianco C, Migliorini AC, Maggioni M, Valenti L, Prati D. Red blood cell morphology in patients with COVID-19-related anaemia. Blood Transfus. Jan 2021;19(1):34-36. doi:10.2450/2020.0242-20
15. Gérard D, Ben Brahim S, Lesesve JF, Perrin J. Are mushroom-shaped erythrocytes an indicator of COVID-19? British Journal of Haematology. 2021;192(2):230-230. doi:https://doi.org/10.1111/bjh.17127
16. Ortiz-Prado E, Simbaña-Rivera K, Gómez-Barreno L, et al. Clinical, molecular, and epidemiological characterization of the SARS-CoV-2 virus and the Coronavirus Disease 2019 (COVID-19), a comprehensive literature review. Diagn Microbiol Infect Dis. Sep 2020;98(1):115094. doi:10.1016/j.diagmicrobio.2020.115094
17. wenzhong l, Hualan L. COVID-19:Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. 2020.
18. Read R. Flawed methods in “COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism”. 2020.
19. San Juan I, Bruzzone C, Bizkarguenaga M, et al. Abnormal concentration of porphyrins in serum from COVID-19 patients. Br J Haematol. Sep 2020;190(5):e265-e267. doi:10.1111/bjh.17060
20. Daniel Y, Hunt BJ, Retter A, et al. Haemoglobin oxygen affinity in patients with severe COVID-19 infection. British Journal of Haematology. 2020;190(3):e126-e127. doi:https://doi.org/10.1111/bjh.16888
21. DeMartino AW, Rose JJ, Amdahl MB, et al. No evidence of hemoglobin damage by SARS-CoV-2 infection. Haematologica. 09/10 2020;105(12):2769-2773. doi:10.3324/haematol.2020.264267
22. Goel R, Bloch EM, Pirenne F, et al. ABO blood group and COVID-19: a review on behalf of the ISBT COVID-19 Working Group. Vox Sang. Sep 2021;116(8):849-861. doi:10.1111/vox.13076
23. Yamamoto F-i, Clausen H, White T, Marken J, Hakomori S-i. Molecular genetic basis of the histo-blood group ABO system. Nature. 1990/05/01 1990;345(6272):229-233. doi:10.1038/345229a0
24. Wu Y, Feng Z, Li P, Yu Q. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clin Chim Acta. Oct 2020;509:220-223. doi:10.1016/j.cca.2020.06.026
25. Li J, Wang X, Chen J, Cai Y, Deng A, Yang M. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br J Haematol. Jul 2020;190(1):24-27. doi:10.1111/bjh.16797
26. Leaf RK, Al-Samkari H, Brenner SK, Gupta S, Leaf DE. ABO phenotype and death in critically ill patients with COVID-19. Br J Haematol. Aug 2020;190(4):e204-e208. doi:10.1111/bjh.16984
27. Göker H, Aladağ Karakulak E, Demiroğlu H, et al. The effects of blood group types on the risk of COVID-19 infection and its clinical outcome. Turk J Med Sci. Jun 23 2020;50(4):679-683. doi:10.3906/sag-2005-395
28. Abdollahi A, Mahmoudi-Aliabadi M, Mehrtash V, Jafarzadeh B, Salehi M. The Novel Coronavirus SARS-CoV-2 Vulnerability Association with ABO/Rh Blood Types. Iran J Pathol. Summer 2020;15(3):156-160. doi:10.30699/ijp.2020.125135.2367
29. Hoiland RL, Fergusson NA, Mitra AR, et al. The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19. Blood Adv. Oct 27 2020;4(20):4981-4989. doi:10.1182/bloodadvances.2020002623
30. Guillon P, Clément M, Sébille V, et al. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology. Dec 2008;18(12):1085-93. doi:10.1093/glycob/cwn093
31. Deleers M, Breiman A, Daubie V, et al. Covid-19 and blood groups: ABO antibody levels may also matter. Int J Infect Dis. Mar 2021;104:242-249. doi:10.1016/j.ijid.2020.12.025
32. Bhattacharjee S, Banerjee M, Pal R. ABO blood groups and severe outcomes in COVID-19: A meta-analysis. Postgrad Med J. Mar 2022;98(e2):e136-e137. doi:10.1136/postgradmedj-2020-139248
33. Mantovani A, Sozzani S, Introna M. Endothelial Activation by Cytokinesa. https://doi.org/10.1111/j.1749-6632.1997.tb46240.x. Annals of the New York Academy of Sciences. 1997/12/01 1997;832(1):93-116. doi:https://doi.org/10.1111/j.1749-6632.1997.tb46240.x
34. Napoleone E, Di Santo A, Lorenzet R. Monocytes upregulate endothelial cell expression of tissue factor: a role for cell-cell contact and cross-talk. Blood. Jan 15 1997;89(2):541-9.
35. Canzano P, Brambilla M, Porro B, et al. Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients. JACC Basic Transl Sci. Feb 24 2021;doi:10.1016/j.jacbts.2020.12.009
36. Lüscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986/04/01 1986;8(4):344-348. doi:10.1161/01.HYP.8.4.344
37. Busch MH, Timmermans S, Nagy M, et al. Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19. Circulation. Nov 3 2020;142(18):1787-1790. doi:10.1161/circulationaha.120.050656
38. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. Sep 7 2010;107(36):15880-5. doi:10.1073/pnas.1005743107
39. Camini FC, da Silva Caetano CC, Almeida LT, de Brito Magalhães CL. Implications of oxidative stress on viral pathogenesis. Arch Virol. Apr 2017;162(4):907-917. doi:10.1007/s00705-016-3187-y
40. Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol. Jun 2013;32(3):249-70. doi:10.3109/08830185.2012.755176
41. Veenith T, Martin H, Le Breuilly M, et al. High generation of reactive oxygen species from neutrophils in patients with severe COVID-19. Scientific Reports. 2022/06/21 2022;12(1):10484. doi:10.1038/s41598-022-13825-7
42. Fu J, Kong J, Wang W, et al. The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: A retrospective study in Suzhou China. Thromb Res. 2020/08/01/ 2020;192:3-8. doi:https://doi.org/10.1016/j.thromres.2020.05.006
43. Violi F, Oliva A, Cangemi R, et al. Nox2 activation in Covid-19. Redox Biol. Sep 2020;36:101655. doi:10.1016/j.redox.2020.101655
44. Arcanjo A, Logullo J, Menezes CCB, et al. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19). Sci Rep. Nov 12 2020;10(1):19630. doi:10.1038/s41598-020-76781-0
45. Griendling KK, Lassègue B, Murphy TJ, Alexander RW. Angiotensin II receptor pharmacology. Adv Pharmacol. 1994;28:269-306. doi:10.1016/s1054-3589(08)60498-6
46. Wysocki J, Ortiz-Melo DI, Mattocks NK, et al. ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. Physiol Rep. 2014;2(3):e00264. doi:10.1002/phy2.264
47. Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. Feb-Apr 2009;30(1-2):42-59. doi:10.1016/j.mam.2008.05.005
48. Suhail S, Zajac J, Fossum C, et al. Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review. Protein J. Dec 2020;39(6):644-656. doi:10.1007/s10930-020-09935-8
49. Fraternale A, Paoletti MF, Casabianca A, et al. Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem. 2006;13(15):1749-55. doi:10.2174/092986706777452542
50. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. Jul 10 2020;6(7):1558-1562. doi:10.1021/acsinfecdis.0c00288
51. Kumar P, Osahon O, Vides DB, Hanania N, Minard CG, Sekhar RV. Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID-19: Implications for GlyNAC (Glycine and N-Acetylcysteine) Supplementation. Antioxidants (Basel). Dec 27 2021;11(1)doi:10.3390/antiox11010050
52. Thomas T, Stefanoni D, Dzieciatkowska M, et al. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients. J Proteome Res. Nov 6 2020;19(11):4455-4469. doi:10.1021/acs.jproteome.0c00606
53. Kawatani Y, Suzuki T, Shimizu R, Kelly VP, Yamamoto M. Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia. Blood. Jan 20 2011;117(3):986-96. doi:10.1182/blood-2010-05-285817
54. Olagnier D, Farahani E, Thyrsted J, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. Oct 2 2020;11(1):4938. doi:10.1038/s41467-020-18764-3
55. Diederich L, Suvorava T, Sansone R, et al. On the Effects of Reactive Oxygen Species and Nitric Oxide on Red Blood Cell Deformability. Front Physiol. 2018;9:332. doi:10.3389/fphys.2018.00332
56. Grau M, Ibershoff L, Zacher J, et al. Even patients with mild COVID-19 symptoms after SARS-CoV-2 infection show prolonged altered red blood cell morphology and rheological parameters. J Cell Mol Med. May 2022;26(10):3022-3030. doi:10.1111/jcmm.17320
57. Piagnerelli M, Vanderelst J, Rousseau A, et al. Red Blood Cell Shape and Deformability in Patients With COVID-19 Acute Respiratory Distress Syndrome. Front Physiol. 2022;13:849910. doi:10.3389/fphys.2022.849910
58. Mahdi A, Collado A, Tengbom J, et al. Erythrocytes Induce Vascular Dysfunction in COVID-19. JACC Basic Transl Sci. Mar 2022;7(3):193-204. doi:10.1016/j.jacbts.2021.12.003
59. Mullen E BS, Healy G, Quinn J, Glavey S, Murphy PT. Red blood cells from COVID-19 patients suffer from increased oxidative stress and may have increased lactate influx. Blood Res (in press). 2022;
60. Amer J, Goldfarb A, Fibach E. Flow cytometric analysis of the oxidative status of normal and thalassemic red blood cells. Cytometry A. Jul 2004;60(1):73-80. doi:10.1002/cyto.a.20017
61. Sadeghi-Haddad-Zavareh M, Bayani M, Shokri M, et al. C-Reactive Protein as a Prognostic Indicator in COVID-19 Patients. Interdiscip Perspect Infect Dis. 2021;2021:5557582. doi:10.1155/2021/5557582
62. Villoteau A, Asfar M, Otekpo M, Loison J, Gautier J, Annweiler C. Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS One. 2021;16(9):e0256931. doi:10.1371/journal.pone.0256931
63. Basina B, Bielosludtseva K, Pertseva T, Kirieieva T, Krykhtina M, Kravchenko N. C-reactive protein (CRP) at admission: is it really usefull in COVID-19 pneumonia? European Respiratory Journal. 2021;58(suppl 65):PA654. doi:10.1183/13993003.congress-2021.PA654
64. Bissinger R, Bhuyan AAM, Qadri SM, Lang F. Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases. Febs j. Mar 2019;286(5):826-854. doi:10.1111/febs.14606
65. Duranton C, Huber SM, Lang F. Oxidation induces a Cl(-)-dependent cation conductance in human red blood cells. J Physiol. Mar 15 2002;539(Pt 3):847-55. doi:10.1113/jphysiol.2001.013040
66. Mandal D, Baudin-Creuza V, Bhattacharyya A, et al. Caspase 3-mediated proteolysis of the N-terminal cytoplasmic domain of the human erythroid anion exchanger 1 (band 3). J Biol Chem. Dec 26 2003;278(52):52551-8. doi:10.1074/jbc.M306914200
67. Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol. Mar 2015;39:35-42. doi:10.1016/j.semcdb.2015.01.009
68. Lang KS, Myssina S, Brand V, et al. Involvement of ceramide in hyperosmotic shock-induced death of erythrocytes. Cell Death Differ. Feb 2004;11(2):231-43. doi:10.1038/sj.cdd.4401311
69. Walker B, Towhid ST, Schmid E, et al. Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors. Am J Physiol Cell Physiol. Feb 1 2014;306(3):C291-7. doi:10.1152/ajpcell.00318.2013
70. Setty BN, Kulkarni S, Stuart MJ. Role of erythrocyte phosphatidylserine in sickle red cell-endothelial adhesion. Blood. Mar 1 2002;99(5):1564-71. doi:10.1182/blood.v99.5.1564
71. Faverio P, Rebora P, Rossi E, et al. Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study. ERJ Open Res. Jan 2022;8(1) doi:10.1183/23120541.00542-2021
72. Izquierdo JL, Soriano JB, González Y, et al. Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci Prog. Jan-Mar 2022;105(1):368504221074574. doi:10.1177/00368504221074574
73. Sharma JN, Al-Omran A, Parvathy SS. Role of nitric oxide in inflammatory diseases. Inflammopharmacology. Dec 2007;15(6):252-9. doi:10.1007/s10787-007-0013-x
74. Förstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. Jun 1994;23(6 Pt 2):1121-31. doi:10.1161/01.hyp.23.6.1121
75. Han H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. Dec 2020;9(1):1123-1130. doi:10.1080/22221751.2020.1770129
76. Zhang Y, Wang X, Li X, et al. Potential contribution of increased soluble IL-2R to lymphopenia in COVID-19 patients. Cell Mol Immunol. Aug 2020;17(8):878-880. doi:10.1038/s41423-020-0484-x
77. Grivennikov SI, Tumanov AV, Liepinsh DJ, et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/ neutrophils: protective and deleterious effects. Immunity. Jan 2005;22(1):93-104. doi:10.1016/j.immuni.2004.11.016
78. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. Jun 2020;20(6):363-374. doi:10.1038/s41577-020-0311-8
79. Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). Jul 2010;49(7):1215-28. doi:10.1093/rheumatology/keq031
80. Dogan D, Deveci HA, Nur G. Manifestations of oxidative stress and liver injury in clothianidin exposed Oncorhynchus mykiss. Toxicol Res (Camb). May 2021;10(3):501-510. doi:10.1093/toxres/tfab027
81. Renoux C, Fort R, Nader E, et al. Impact of COVID-19 on red blood cell rheology. Br J Haematol. Feb 2021;192(4):e108-e111. doi:10.1111/bjh.17306
82. Ozdemir B, Yazici A. Could the decrease in the endothelial nitric oxide (NO) production and NO bioavailability be the crucial cause of COVID-19 related deaths? Med Hypotheses. Nov 2020;144:109970. doi:10.1016/j.mehy.2020.109970
83. Gille T, Sesé L, Aubourg E, et al. The Affinity of Hemoglobin for Oxygen Is Not Altered During COVID-19. Front Physiol. 2021;12:578708. doi:10.3389/fphys.2021.578708
84. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. Jun 2020;215:108427. doi:10.1016/j.clim.2020.108427
85. Chen W, Gong P, Guo J, et al. Glycolysis regulates pollen tube polarity via Rho GTPase signaling. PLoS Genet. Apr 2018;14(4):e1007373. doi:10.1371/journal.pgen.1007373
86. Dunn J-O, Mythen M, Grocott M. Physiology of oxygen transport. BJA Education. 2016;16(10):341-348. doi:10.1093/bjaed/mkw012
87. Brooks GA. The Science and Translation of Lactate Shuttle Theory. Cell Metabolism. 2018/04/03/ 2018;27(4):757-785. doi:https://doi.org/10.1016/j.cmet.2018.03.008
88. Codo AC, Davanzo GG, Monteiro LB, et al. Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis. Cell Metab. Sep 1 2020;32(3):437-446.e5. doi:10.1016/j.cmet.2020.07.007
89. Alfano G, Fontana F, Mori G, et al. Acid base disorders in patients with COVID-19. Int Urol Nephrol. Feb 2022;54(2):405-410. doi:10.1007/s11255-021-02855-1
90. Halestrap AP, Wilson MC. The monocarboxylate transporter family--role and regulation. IUBMB Life. Feb 2012;64(2):109-19. doi:10.1002/iub.572
91. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. Oct 15 1999;343 Pt 2(Pt 2):281-99.
92. Walters DK, Arendt BK, Jelinek DF. CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells. Cell Cycle. 2013;12(19):3175-3183. doi:10.4161/cc.26193
93. Köpnick A-L, Jansen A, Geistlinger K, Epalle NH, Beitz E. Basigin drives intracellular accumulation of l-lactate by harvesting protons and substrate anions. PloS one. 2021;16(3):e0249110-e0249110. doi:10.1371/journal.pone.0249110
94. Gupta M, Manek G, Datta D. Admission Serum Lactate as a Predictor of Mortality in COVID-19 Pneumonia with Acute Respiratory Failure. TP92 TP092 CLINICAL ADVANCES IN SARS-COV-2 AND COVID-19. A3855-A3855.
95. Abani O, Abbas A, Abbas F, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0
96. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. New England Journal of Medicine. 2020;384(1):20-30. doi:10.1056/NEJMoa2030340
2. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. May 1 2020;130(5):2620-2629. doi:10.1172/jci137244
3. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. European Heart Journal. 2020;41(32):3038-3044. doi:10.1093/eurheartj/ehaa623
4. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147. doi:10.1016/j.thromres.2020.04.013
5. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. May 2020;18(5):1094-1099. doi:10.1111/jth.14817
6. Foy BH, Carlson JCT, Reinertsen E, et al. Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection. JAMA Netw Open. Sep 1 2020;3(9):e2022058. doi:10.1001/jamanetworkopen.2020.22058
7. Lippi G, Henry BM, Sanchis-Gomar F. Red Blood Cell Distribution Is a Significant Predictor of Severe Illness in Coronavirus Disease 2019. Acta Haematol. 2021;144(4):360-364. doi:10.1159/000510914
8. Marchi G, Bozzini C, Bertolone L, et al. Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19. Front Physiol. 2022;13:932013. doi:10.3389/fphys.2022.932013
9. Andersson MI, Arancibia-Carcamo CV, Auckland K, et al. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus. Wellcome Open Res. 2020;5:181. doi:10.12688/wellcomeopenres.16002.2
10. Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells. Leukemia. Jul 2020;34(7):1726-1729. doi:10.1038/s41375-020-0887-9
11. Cameron K, Rozano L, Falasca M, Mancera RL. Does the SARS-CoV-2 Spike Protein Receptor Binding Domain Interact Effectively with the DPP4 (CD26) Receptor? A Molecular Docking Study. Int J Mol Sci. Jun 29 2021;22(13) doi:10.3390/ijms22137001
12. Shilts J, Crozier TWM, Greenwood EJD, Lehner PJ, Wright GJ. No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep. Jan 11 2021;11(1):413. doi:10.1038/s41598-020-80464-1
13. Cosic I, Cosic D, Loncarevic I. RRM Prediction of Erythrocyte Band3 Protein as Alternative Receptor for SARS-CoV-2 Virus. Applied Sciences. 2020;10(11):4053.
14. Berzuini A, Bianco C, Migliorini AC, Maggioni M, Valenti L, Prati D. Red blood cell morphology in patients with COVID-19-related anaemia. Blood Transfus. Jan 2021;19(1):34-36. doi:10.2450/2020.0242-20
15. Gérard D, Ben Brahim S, Lesesve JF, Perrin J. Are mushroom-shaped erythrocytes an indicator of COVID-19? British Journal of Haematology. 2021;192(2):230-230. doi:https://doi.org/10.1111/bjh.17127
16. Ortiz-Prado E, Simbaña-Rivera K, Gómez-Barreno L, et al. Clinical, molecular, and epidemiological characterization of the SARS-CoV-2 virus and the Coronavirus Disease 2019 (COVID-19), a comprehensive literature review. Diagn Microbiol Infect Dis. Sep 2020;98(1):115094. doi:10.1016/j.diagmicrobio.2020.115094
17. wenzhong l, Hualan L. COVID-19:Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. 2020.
18. Read R. Flawed methods in “COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism”. 2020.
19. San Juan I, Bruzzone C, Bizkarguenaga M, et al. Abnormal concentration of porphyrins in serum from COVID-19 patients. Br J Haematol. Sep 2020;190(5):e265-e267. doi:10.1111/bjh.17060
20. Daniel Y, Hunt BJ, Retter A, et al. Haemoglobin oxygen affinity in patients with severe COVID-19 infection. British Journal of Haematology. 2020;190(3):e126-e127. doi:https://doi.org/10.1111/bjh.16888
21. DeMartino AW, Rose JJ, Amdahl MB, et al. No evidence of hemoglobin damage by SARS-CoV-2 infection. Haematologica. 09/10 2020;105(12):2769-2773. doi:10.3324/haematol.2020.264267
22. Goel R, Bloch EM, Pirenne F, et al. ABO blood group and COVID-19: a review on behalf of the ISBT COVID-19 Working Group. Vox Sang. Sep 2021;116(8):849-861. doi:10.1111/vox.13076
23. Yamamoto F-i, Clausen H, White T, Marken J, Hakomori S-i. Molecular genetic basis of the histo-blood group ABO system. Nature. 1990/05/01 1990;345(6272):229-233. doi:10.1038/345229a0
24. Wu Y, Feng Z, Li P, Yu Q. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clin Chim Acta. Oct 2020;509:220-223. doi:10.1016/j.cca.2020.06.026
25. Li J, Wang X, Chen J, Cai Y, Deng A, Yang M. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br J Haematol. Jul 2020;190(1):24-27. doi:10.1111/bjh.16797
26. Leaf RK, Al-Samkari H, Brenner SK, Gupta S, Leaf DE. ABO phenotype and death in critically ill patients with COVID-19. Br J Haematol. Aug 2020;190(4):e204-e208. doi:10.1111/bjh.16984
27. Göker H, Aladağ Karakulak E, Demiroğlu H, et al. The effects of blood group types on the risk of COVID-19 infection and its clinical outcome. Turk J Med Sci. Jun 23 2020;50(4):679-683. doi:10.3906/sag-2005-395
28. Abdollahi A, Mahmoudi-Aliabadi M, Mehrtash V, Jafarzadeh B, Salehi M. The Novel Coronavirus SARS-CoV-2 Vulnerability Association with ABO/Rh Blood Types. Iran J Pathol. Summer 2020;15(3):156-160. doi:10.30699/ijp.2020.125135.2367
29. Hoiland RL, Fergusson NA, Mitra AR, et al. The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19. Blood Adv. Oct 27 2020;4(20):4981-4989. doi:10.1182/bloodadvances.2020002623
30. Guillon P, Clément M, Sébille V, et al. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology. Dec 2008;18(12):1085-93. doi:10.1093/glycob/cwn093
31. Deleers M, Breiman A, Daubie V, et al. Covid-19 and blood groups: ABO antibody levels may also matter. Int J Infect Dis. Mar 2021;104:242-249. doi:10.1016/j.ijid.2020.12.025
32. Bhattacharjee S, Banerjee M, Pal R. ABO blood groups and severe outcomes in COVID-19: A meta-analysis. Postgrad Med J. Mar 2022;98(e2):e136-e137. doi:10.1136/postgradmedj-2020-139248
33. Mantovani A, Sozzani S, Introna M. Endothelial Activation by Cytokinesa. https://doi.org/10.1111/j.1749-6632.1997.tb46240.x. Annals of the New York Academy of Sciences. 1997/12/01 1997;832(1):93-116. doi:https://doi.org/10.1111/j.1749-6632.1997.tb46240.x
34. Napoleone E, Di Santo A, Lorenzet R. Monocytes upregulate endothelial cell expression of tissue factor: a role for cell-cell contact and cross-talk. Blood. Jan 15 1997;89(2):541-9.
35. Canzano P, Brambilla M, Porro B, et al. Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients. JACC Basic Transl Sci. Feb 24 2021;doi:10.1016/j.jacbts.2020.12.009
36. Lüscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension. 1986/04/01 1986;8(4):344-348. doi:10.1161/01.HYP.8.4.344
37. Busch MH, Timmermans S, Nagy M, et al. Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19. Circulation. Nov 3 2020;142(18):1787-1790. doi:10.1161/circulationaha.120.050656
38. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. Sep 7 2010;107(36):15880-5. doi:10.1073/pnas.1005743107
39. Camini FC, da Silva Caetano CC, Almeida LT, de Brito Magalhães CL. Implications of oxidative stress on viral pathogenesis. Arch Virol. Apr 2017;162(4):907-917. doi:10.1007/s00705-016-3187-y
40. Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol. Jun 2013;32(3):249-70. doi:10.3109/08830185.2012.755176
41. Veenith T, Martin H, Le Breuilly M, et al. High generation of reactive oxygen species from neutrophils in patients with severe COVID-19. Scientific Reports. 2022/06/21 2022;12(1):10484. doi:10.1038/s41598-022-13825-7
42. Fu J, Kong J, Wang W, et al. The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: A retrospective study in Suzhou China. Thromb Res. 2020/08/01/ 2020;192:3-8. doi:https://doi.org/10.1016/j.thromres.2020.05.006
43. Violi F, Oliva A, Cangemi R, et al. Nox2 activation in Covid-19. Redox Biol. Sep 2020;36:101655. doi:10.1016/j.redox.2020.101655
44. Arcanjo A, Logullo J, Menezes CCB, et al. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19). Sci Rep. Nov 12 2020;10(1):19630. doi:10.1038/s41598-020-76781-0
45. Griendling KK, Lassègue B, Murphy TJ, Alexander RW. Angiotensin II receptor pharmacology. Adv Pharmacol. 1994;28:269-306. doi:10.1016/s1054-3589(08)60498-6
46. Wysocki J, Ortiz-Melo DI, Mattocks NK, et al. ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. Physiol Rep. 2014;2(3):e00264. doi:10.1002/phy2.264
47. Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. Feb-Apr 2009;30(1-2):42-59. doi:10.1016/j.mam.2008.05.005
48. Suhail S, Zajac J, Fossum C, et al. Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review. Protein J. Dec 2020;39(6):644-656. doi:10.1007/s10930-020-09935-8
49. Fraternale A, Paoletti MF, Casabianca A, et al. Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem. 2006;13(15):1749-55. doi:10.2174/092986706777452542
50. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. Jul 10 2020;6(7):1558-1562. doi:10.1021/acsinfecdis.0c00288
51. Kumar P, Osahon O, Vides DB, Hanania N, Minard CG, Sekhar RV. Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID-19: Implications for GlyNAC (Glycine and N-Acetylcysteine) Supplementation. Antioxidants (Basel). Dec 27 2021;11(1)doi:10.3390/antiox11010050
52. Thomas T, Stefanoni D, Dzieciatkowska M, et al. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients. J Proteome Res. Nov 6 2020;19(11):4455-4469. doi:10.1021/acs.jproteome.0c00606
53. Kawatani Y, Suzuki T, Shimizu R, Kelly VP, Yamamoto M. Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia. Blood. Jan 20 2011;117(3):986-96. doi:10.1182/blood-2010-05-285817
54. Olagnier D, Farahani E, Thyrsted J, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. Oct 2 2020;11(1):4938. doi:10.1038/s41467-020-18764-3
55. Diederich L, Suvorava T, Sansone R, et al. On the Effects of Reactive Oxygen Species and Nitric Oxide on Red Blood Cell Deformability. Front Physiol. 2018;9:332. doi:10.3389/fphys.2018.00332
56. Grau M, Ibershoff L, Zacher J, et al. Even patients with mild COVID-19 symptoms after SARS-CoV-2 infection show prolonged altered red blood cell morphology and rheological parameters. J Cell Mol Med. May 2022;26(10):3022-3030. doi:10.1111/jcmm.17320
57. Piagnerelli M, Vanderelst J, Rousseau A, et al. Red Blood Cell Shape and Deformability in Patients With COVID-19 Acute Respiratory Distress Syndrome. Front Physiol. 2022;13:849910. doi:10.3389/fphys.2022.849910
58. Mahdi A, Collado A, Tengbom J, et al. Erythrocytes Induce Vascular Dysfunction in COVID-19. JACC Basic Transl Sci. Mar 2022;7(3):193-204. doi:10.1016/j.jacbts.2021.12.003
59. Mullen E BS, Healy G, Quinn J, Glavey S, Murphy PT. Red blood cells from COVID-19 patients suffer from increased oxidative stress and may have increased lactate influx. Blood Res (in press). 2022;
60. Amer J, Goldfarb A, Fibach E. Flow cytometric analysis of the oxidative status of normal and thalassemic red blood cells. Cytometry A. Jul 2004;60(1):73-80. doi:10.1002/cyto.a.20017
61. Sadeghi-Haddad-Zavareh M, Bayani M, Shokri M, et al. C-Reactive Protein as a Prognostic Indicator in COVID-19 Patients. Interdiscip Perspect Infect Dis. 2021;2021:5557582. doi:10.1155/2021/5557582
62. Villoteau A, Asfar M, Otekpo M, Loison J, Gautier J, Annweiler C. Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS One. 2021;16(9):e0256931. doi:10.1371/journal.pone.0256931
63. Basina B, Bielosludtseva K, Pertseva T, Kirieieva T, Krykhtina M, Kravchenko N. C-reactive protein (CRP) at admission: is it really usefull in COVID-19 pneumonia? European Respiratory Journal. 2021;58(suppl 65):PA654. doi:10.1183/13993003.congress-2021.PA654
64. Bissinger R, Bhuyan AAM, Qadri SM, Lang F. Oxidative stress, eryptosis and anemia: a pivotal mechanistic nexus in systemic diseases. Febs j. Mar 2019;286(5):826-854. doi:10.1111/febs.14606
65. Duranton C, Huber SM, Lang F. Oxidation induces a Cl(-)-dependent cation conductance in human red blood cells. J Physiol. Mar 15 2002;539(Pt 3):847-55. doi:10.1113/jphysiol.2001.013040
66. Mandal D, Baudin-Creuza V, Bhattacharyya A, et al. Caspase 3-mediated proteolysis of the N-terminal cytoplasmic domain of the human erythroid anion exchanger 1 (band 3). J Biol Chem. Dec 26 2003;278(52):52551-8. doi:10.1074/jbc.M306914200
67. Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol. Mar 2015;39:35-42. doi:10.1016/j.semcdb.2015.01.009
68. Lang KS, Myssina S, Brand V, et al. Involvement of ceramide in hyperosmotic shock-induced death of erythrocytes. Cell Death Differ. Feb 2004;11(2):231-43. doi:10.1038/sj.cdd.4401311
69. Walker B, Towhid ST, Schmid E, et al. Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors. Am J Physiol Cell Physiol. Feb 1 2014;306(3):C291-7. doi:10.1152/ajpcell.00318.2013
70. Setty BN, Kulkarni S, Stuart MJ. Role of erythrocyte phosphatidylserine in sickle red cell-endothelial adhesion. Blood. Mar 1 2002;99(5):1564-71. doi:10.1182/blood.v99.5.1564
71. Faverio P, Rebora P, Rossi E, et al. Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study. ERJ Open Res. Jan 2022;8(1) doi:10.1183/23120541.00542-2021
72. Izquierdo JL, Soriano JB, González Y, et al. Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci Prog. Jan-Mar 2022;105(1):368504221074574. doi:10.1177/00368504221074574
73. Sharma JN, Al-Omran A, Parvathy SS. Role of nitric oxide in inflammatory diseases. Inflammopharmacology. Dec 2007;15(6):252-9. doi:10.1007/s10787-007-0013-x
74. Förstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. Jun 1994;23(6 Pt 2):1121-31. doi:10.1161/01.hyp.23.6.1121
75. Han H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. Dec 2020;9(1):1123-1130. doi:10.1080/22221751.2020.1770129
76. Zhang Y, Wang X, Li X, et al. Potential contribution of increased soluble IL-2R to lymphopenia in COVID-19 patients. Cell Mol Immunol. Aug 2020;17(8):878-880. doi:10.1038/s41423-020-0484-x
77. Grivennikov SI, Tumanov AV, Liepinsh DJ, et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/ neutrophils: protective and deleterious effects. Immunity. Jan 2005;22(1):93-104. doi:10.1016/j.immuni.2004.11.016
78. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. Jun 2020;20(6):363-374. doi:10.1038/s41577-020-0311-8
79. Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). Jul 2010;49(7):1215-28. doi:10.1093/rheumatology/keq031
80. Dogan D, Deveci HA, Nur G. Manifestations of oxidative stress and liver injury in clothianidin exposed Oncorhynchus mykiss. Toxicol Res (Camb). May 2021;10(3):501-510. doi:10.1093/toxres/tfab027
81. Renoux C, Fort R, Nader E, et al. Impact of COVID-19 on red blood cell rheology. Br J Haematol. Feb 2021;192(4):e108-e111. doi:10.1111/bjh.17306
82. Ozdemir B, Yazici A. Could the decrease in the endothelial nitric oxide (NO) production and NO bioavailability be the crucial cause of COVID-19 related deaths? Med Hypotheses. Nov 2020;144:109970. doi:10.1016/j.mehy.2020.109970
83. Gille T, Sesé L, Aubourg E, et al. The Affinity of Hemoglobin for Oxygen Is Not Altered During COVID-19. Front Physiol. 2021;12:578708. doi:10.3389/fphys.2021.578708
84. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. Jun 2020;215:108427. doi:10.1016/j.clim.2020.108427
85. Chen W, Gong P, Guo J, et al. Glycolysis regulates pollen tube polarity via Rho GTPase signaling. PLoS Genet. Apr 2018;14(4):e1007373. doi:10.1371/journal.pgen.1007373
86. Dunn J-O, Mythen M, Grocott M. Physiology of oxygen transport. BJA Education. 2016;16(10):341-348. doi:10.1093/bjaed/mkw012
87. Brooks GA. The Science and Translation of Lactate Shuttle Theory. Cell Metabolism. 2018/04/03/ 2018;27(4):757-785. doi:https://doi.org/10.1016/j.cmet.2018.03.008
88. Codo AC, Davanzo GG, Monteiro LB, et al. Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis. Cell Metab. Sep 1 2020;32(3):437-446.e5. doi:10.1016/j.cmet.2020.07.007
89. Alfano G, Fontana F, Mori G, et al. Acid base disorders in patients with COVID-19. Int Urol Nephrol. Feb 2022;54(2):405-410. doi:10.1007/s11255-021-02855-1
90. Halestrap AP, Wilson MC. The monocarboxylate transporter family--role and regulation. IUBMB Life. Feb 2012;64(2):109-19. doi:10.1002/iub.572
91. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. Oct 15 1999;343 Pt 2(Pt 2):281-99.
92. Walters DK, Arendt BK, Jelinek DF. CD147 regulates the expression of MCT1 and lactate export in multiple myeloma cells. Cell Cycle. 2013;12(19):3175-3183. doi:10.4161/cc.26193
93. Köpnick A-L, Jansen A, Geistlinger K, Epalle NH, Beitz E. Basigin drives intracellular accumulation of l-lactate by harvesting protons and substrate anions. PloS one. 2021;16(3):e0249110-e0249110. doi:10.1371/journal.pone.0249110
94. Gupta M, Manek G, Datta D. Admission Serum Lactate as a Predictor of Mortality in COVID-19 Pneumonia with Acute Respiratory Failure. TP92 TP092 CLINICAL ADVANCES IN SARS-COV-2 AND COVID-19. A3855-A3855.
95. Abani O, Abbas A, Abbas F, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0
96. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. New England Journal of Medicine. 2020;384(1):20-30. doi:10.1056/NEJMoa2030340