The Key role of Annexin A2 and Plasmin in COVID -19 pathophysiology clinical presentation and outcomes - A Review
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Published:
Oct 30, 2022
Updated:
2022-10-30
Versions:
2022-10-30 (2)
Keywords:
coronavirus, COVID-19, viral proteins, trombosi Annexin A2, Plasmin, viral proteins, Thrombosis, genetic polymorphisms, blood coagulation disorders
Main Article Content
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic has become a defining global health crisis with an exceptionally high rate of transmission causing significant morbidity and mortality.
Recent studies have reported patients presenting with coagulation disorders and thrombo-embolic disease later testing positive for the coronavirus.
In this article, we have discussed the recent trend in symptomatology of COVID-19 including microvascular thrombosis and the potential key role of proteins such as Annexin A2, plasmin, ACE-2 receptors and ENaC channels in the disease pathophysiology.
The interactions between these molecules and the viral proteins might play a role in thrombo-embolic presentation of the disease and explain the selective morbidity in patients with co-morbid conditions.
A diagrammatic working model has also been proposed that shall assist readers in understanding these key bio-molecular interactions influencing the probable pathophysiology at the cellular-receptor level.
This article shall also shed some light on the genetic polymorphisms in ACE-2 receptors and Annexin A2 suggesting a possibility of extensive diversity in clinical presentation and disease severity across the globe.
Evidence-based studies might guide in identifying potential therapies and treatment options for COVID-19.
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[1]
Kamber Zaidi, A., Dawoodi, S., Pirro, M., Monti, M. and Dehgani-Mobaraki, P. 2022. The Key role of Annexin A2 and Plasmin in COVID -19 pathophysiology: clinical presentation and outcomes - A Review. Italian Journal of Prevention, Diagnostic and Therapeutic Medicine. 3, 4 (Oct. 2022), 16-25. DOI:https://doi.org/10.30459/2020-24.
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Review
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
References
1. Ji HL, Zhao R, Matalon S, Matthay MA. Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility. Physiol Rev. 2020;100(3):1065 1075. doi:10.1152/physrev.00013.2020
2. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-n CoV spike in the prefusion conformation. Science 367: 1260–1263, 2020. doi:10.1126/science.abb2507.
3. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly
E. The spike glycoprotein of the new coronavirus 2019-n CoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 176: 104742, 2020. Doi :10.1016/j. antiviral.2020.104742.
4. Kam Y W, Okumura Y, Kido H, Ng L F , Bruzzone R , Altmeyer R . Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells invitro. PLoSOne4:e7870,2009. doi:10.1371/journal.pone. 0007870
5. Hoffmann M, Kleine Weber H, Schroeder S, Krüger N, Herrler T , Erichsen S , Schiergens T S, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 1–10, 2020. doi:10.1016/j.cell.2020.02.052.
6. ZhangH,PenningerJM,LiY,ZhongN,SlutskyAS.Angiotensin- convertingenzyme2 (ACE2) as a SARS-CoV-2 receptor : molecular mechanisms and potential therapeutic target. Intensive Care Med 46: 586–590, 2020. doi:10.1007/s00134-020-05985-9.
7. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020; doi: 10.1093/eurheartj/ehaa254.
8. Chen J, Wang X, Zhang S, Liu B, Wu X, Wang Y, Wang X, Yang M, Sun J, Xie Y. Findings of acute pulmonary embolism in COVID-19 patients.
9. Bonow RO, Fonarow GC, O’Gara PT, Yancy CW. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020; doi: 10.1001/jamacardio.2020.1105.
10. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li T, Zhang F, Zhao Y, Li Y, Zhang S. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020; doi: 10.1056/NEJMc2007575.
11. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, Tao Q, Sun Z, Xia L. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology 2020;200642. doi: 10.1148/radiol.2020200642.
12. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020; doi: 10.1016/j.trsl.2020.04.007.
13. Zhang T, Sun L, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He Hu Xi Za Zhi 2020;43:E040. doi: 10.3760/cma.j.cn112147-20200311-00312.
14. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-1062. doi: 10.1016/S0140-6736(20)30566-3.
15. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; doi: 10.1056/NEJMoa2002032.
16. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus
pneumonia. J Thromb Haemost 2020;18:844-847. doi:10.1111/jth.14768.
17. Li Y, Wang M, Zhou Y, et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. March 13, 2020 (preprint).
18. Flanagan JM, Frohlich DM, Howard TA, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011;117(24):6681 6684. doi:10.1182/blood-2011-01-332205
19. S. E. Moss and R. O. Morgan, “The annexins,” Genome Biology, vol. 5, no. 4, article 219, 2004.
20. V. Gerke, C. E. Creutz, and S. E. Moss, “Annexins: linking Ca2+ signalling to membrane dynamics,” Nature Reviews Molecular Cell Biology, vol. 6, no. 6, pp. 449–461, 2005.
21. V. Gerke and S. E. Moss, “Annexins: from structure to function,”
Physiological Reviews, vol. 82, no. 2, pp. 331–371, 2002.
22. F. Spano, G. Raugei, E. Palla, C. Colella, and M. Melli, “Characterization of the human lipocortin-2-encoding multigene family: its structure suggests the existence of a short amino acid unit undergoing duplication,” Gene, vol. 95, no. 2, pp. 243–251, 1990.
23. D. M. Waisman, “Annexin II tetramer: structure and function,”
Molecular and Cellular Biochemistry, vol. 149-150, pp. 301–322, 1995.
24. U. Rescher and V. Gerke, “S100A10/p11: family, friends and functions,” Pflugers Archiv European Journal of Physiology, vol. 455, no. 4, pp. 575–582, 2008.
25. Kim J, Hajjar KA. Annexin II: a plasminogen—plasminogen activator co-receptor. Front Biosci. 2002;7:d341–d348.
26. Hajjar KA, Menell JS. Annexin II: a novel mediator of cell surface plasmin generation. Ann N Y Acad Sci. 1997;811:337–349.
27. Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, competence in replication and innate immune responses of the SARS-CoV-2 coronavirus in the human respiratory tract and conjunctiva: an analysis in ex-vivo and in vitro cultures [published online before printing, May 7, 2020]. Lancet Respir Med. 2020; S2213-2600 (20) 30.193-4.
28. Li W, Zhang C, Sui J, Kuhn JH, et al. Receptor and viral determinants of SARScoronavirus adaptation to human ACE2. EMBO J. 2005; 24(8):1634-43.
29. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020; 6:11. doi: 10.1038/s41421-0200147-1
30. Q. Ling, A. T. Jacovina, A. Deora et al., “Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo,” The Journal of Clinical Investigation, vol. 113, no. 1, pp. 38–48, 2004.
31. A. P. Surette, P. A. Madureira, K. D. Phipps, V. A. Miller, P. Svenningsson, and D. M. Waisman, “Regulation of fibrinolysis by S100A10 in vivo,” Blood, vol. 118, no. 11, pp. 3172–3181, 2011.
32. A. T. Jacovina, A. B. Deora, Q. Ling et al., “Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2- dependent fibrinolysis,” The Journal of Clinical Investigation, vol. 119, no. 11, pp. 3384–3394, 2009.
33. L. L. Humphrey, R. Fu, K. Rogers, M. Freeman, and M. Helfand, “Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis,” Mayo Clinic Proceedings, vol. 83, no. 11, pp. 1203–1212, 2008.
34. Kwak H, Park MW, Jeong S. Annexin A2 binds RNA and reduces the frameshifting efficiency of infectious bronchitis virus. PLoS One. 2011;6(8):e24067. doi:10.1371/journal.pone.0024067
35. Xydakis MS, Dehgani-Mobaraki P et al. Smell and taste dysfunction in patients with COVID-19. THE LANCET Infectious diseases. 2020. https://doi.org/10.1016/S1473-3099(20)30293-0
36. Hélène Débat, Corinne Eloit, Florence Blon, Benoît Sarazin, Céline Henry, Jean-Claude Huet, Didier Trotier, and Jean-Claude Pernollet. Identification of Human Olfactory Cleft Mucus Proteins Using Proteomic Analysis. Journal of Proteome Research 2007 6 (5), 1985-1996. DOI: 10.1021/pr0606575
37. McNeil PL & Steinhardt RA (2003) Plasma membrane disruption: repair, prevention, adaptation. Annu Rev Cell Dev Biol 19, 697–731.
38. Miwa N, Uebi T, Kawamura S. S100-annexin complexes--biology of conditional association. FEBS J. 2008;275(20):4945 4955. doi:10.1111/j.1742-4658.2008.06653.x
39. Uebi T, Miwa N & Kawamura S (2007) Comprehensive interaction of dicalcin with annexins in frog olfactory and respiratory cilia. FEBS J 274, 4863–4876.
40.Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H, Murakami S. Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope. 2007; 117(2):272-7.
41. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008; 82(15):7264-75. doi: 10.1128/JVI.00737-08.
42. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol.
43. Tobias Herold, Vindi Jurinovic, Chiara Arnreich, Johannes C Hellmuth et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. medRxiv 2020.04.01.20047381; doi:https://doi.org/10.1101/2020.04.01.20047381
44. Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F,Balleyguier C, Besse B, Marabelle A, Netzer F, Merad M, Robert C, Barlesi F, Gachot B, Stoclin A,Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report, Annals of Oncology (2020), doi: https://doi.org/10.1016/j.annonc.2020.03.300.
45. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu HJ. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019. J Clin Invest. 2020; doi: 10.1172/JCI137244.
46. Mehta P, Mcauley D, Brown M, Sanchez E, Tattersall R, Manson JHLH Across Speciality Collaboration, UK. Correspondence COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-1034. doi: 10.1016/S0140-6736(20)30628-0.
2. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-n CoV spike in the prefusion conformation. Science 367: 1260–1263, 2020. doi:10.1126/science.abb2507.
3. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly
E. The spike glycoprotein of the new coronavirus 2019-n CoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 176: 104742, 2020. Doi :10.1016/j. antiviral.2020.104742.
4. Kam Y W, Okumura Y, Kido H, Ng L F , Bruzzone R , Altmeyer R . Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells invitro. PLoSOne4:e7870,2009. doi:10.1371/journal.pone. 0007870
5. Hoffmann M, Kleine Weber H, Schroeder S, Krüger N, Herrler T , Erichsen S , Schiergens T S, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 1–10, 2020. doi:10.1016/j.cell.2020.02.052.
6. ZhangH,PenningerJM,LiY,ZhongN,SlutskyAS.Angiotensin- convertingenzyme2 (ACE2) as a SARS-CoV-2 receptor : molecular mechanisms and potential therapeutic target. Intensive Care Med 46: 586–590, 2020. doi:10.1007/s00134-020-05985-9.
7. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020; doi: 10.1093/eurheartj/ehaa254.
8. Chen J, Wang X, Zhang S, Liu B, Wu X, Wang Y, Wang X, Yang M, Sun J, Xie Y. Findings of acute pulmonary embolism in COVID-19 patients.
9. Bonow RO, Fonarow GC, O’Gara PT, Yancy CW. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020; doi: 10.1001/jamacardio.2020.1105.
10. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li T, Zhang F, Zhao Y, Li Y, Zhang S. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020; doi: 10.1056/NEJMc2007575.
11. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, Tao Q, Sun Z, Xia L. Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology 2020;200642. doi: 10.1148/radiol.2020200642.
12. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res 2020; doi: 10.1016/j.trsl.2020.04.007.
13. Zhang T, Sun L, Feng RE. Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019. Zhonghua Jie He Hu Xi Za Zhi 2020;43:E040. doi: 10.3760/cma.j.cn112147-20200311-00312.
14. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-1062. doi: 10.1016/S0140-6736(20)30566-3.
15. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; doi: 10.1056/NEJMoa2002032.
16. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus
pneumonia. J Thromb Haemost 2020;18:844-847. doi:10.1111/jth.14768.
17. Li Y, Wang M, Zhou Y, et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. March 13, 2020 (preprint).
18. Flanagan JM, Frohlich DM, Howard TA, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011;117(24):6681 6684. doi:10.1182/blood-2011-01-332205
19. S. E. Moss and R. O. Morgan, “The annexins,” Genome Biology, vol. 5, no. 4, article 219, 2004.
20. V. Gerke, C. E. Creutz, and S. E. Moss, “Annexins: linking Ca2+ signalling to membrane dynamics,” Nature Reviews Molecular Cell Biology, vol. 6, no. 6, pp. 449–461, 2005.
21. V. Gerke and S. E. Moss, “Annexins: from structure to function,”
Physiological Reviews, vol. 82, no. 2, pp. 331–371, 2002.
22. F. Spano, G. Raugei, E. Palla, C. Colella, and M. Melli, “Characterization of the human lipocortin-2-encoding multigene family: its structure suggests the existence of a short amino acid unit undergoing duplication,” Gene, vol. 95, no. 2, pp. 243–251, 1990.
23. D. M. Waisman, “Annexin II tetramer: structure and function,”
Molecular and Cellular Biochemistry, vol. 149-150, pp. 301–322, 1995.
24. U. Rescher and V. Gerke, “S100A10/p11: family, friends and functions,” Pflugers Archiv European Journal of Physiology, vol. 455, no. 4, pp. 575–582, 2008.
25. Kim J, Hajjar KA. Annexin II: a plasminogen—plasminogen activator co-receptor. Front Biosci. 2002;7:d341–d348.
26. Hajjar KA, Menell JS. Annexin II: a novel mediator of cell surface plasmin generation. Ann N Y Acad Sci. 1997;811:337–349.
27. Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, competence in replication and innate immune responses of the SARS-CoV-2 coronavirus in the human respiratory tract and conjunctiva: an analysis in ex-vivo and in vitro cultures [published online before printing, May 7, 2020]. Lancet Respir Med. 2020; S2213-2600 (20) 30.193-4.
28. Li W, Zhang C, Sui J, Kuhn JH, et al. Receptor and viral determinants of SARScoronavirus adaptation to human ACE2. EMBO J. 2005; 24(8):1634-43.
29. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020; 6:11. doi: 10.1038/s41421-0200147-1
30. Q. Ling, A. T. Jacovina, A. Deora et al., “Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo,” The Journal of Clinical Investigation, vol. 113, no. 1, pp. 38–48, 2004.
31. A. P. Surette, P. A. Madureira, K. D. Phipps, V. A. Miller, P. Svenningsson, and D. M. Waisman, “Regulation of fibrinolysis by S100A10 in vivo,” Blood, vol. 118, no. 11, pp. 3172–3181, 2011.
32. A. T. Jacovina, A. B. Deora, Q. Ling et al., “Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2- dependent fibrinolysis,” The Journal of Clinical Investigation, vol. 119, no. 11, pp. 3384–3394, 2009.
33. L. L. Humphrey, R. Fu, K. Rogers, M. Freeman, and M. Helfand, “Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis,” Mayo Clinic Proceedings, vol. 83, no. 11, pp. 1203–1212, 2008.
34. Kwak H, Park MW, Jeong S. Annexin A2 binds RNA and reduces the frameshifting efficiency of infectious bronchitis virus. PLoS One. 2011;6(8):e24067. doi:10.1371/journal.pone.0024067
35. Xydakis MS, Dehgani-Mobaraki P et al. Smell and taste dysfunction in patients with COVID-19. THE LANCET Infectious diseases. 2020. https://doi.org/10.1016/S1473-3099(20)30293-0
36. Hélène Débat, Corinne Eloit, Florence Blon, Benoît Sarazin, Céline Henry, Jean-Claude Huet, Didier Trotier, and Jean-Claude Pernollet. Identification of Human Olfactory Cleft Mucus Proteins Using Proteomic Analysis. Journal of Proteome Research 2007 6 (5), 1985-1996. DOI: 10.1021/pr0606575
37. McNeil PL & Steinhardt RA (2003) Plasma membrane disruption: repair, prevention, adaptation. Annu Rev Cell Dev Biol 19, 697–731.
38. Miwa N, Uebi T, Kawamura S. S100-annexin complexes--biology of conditional association. FEBS J. 2008;275(20):4945 4955. doi:10.1111/j.1742-4658.2008.06653.x
39. Uebi T, Miwa N & Kawamura S (2007) Comprehensive interaction of dicalcin with annexins in frog olfactory and respiratory cilia. FEBS J 274, 4863–4876.
40.Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H, Murakami S. Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope. 2007; 117(2):272-7.
41. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008; 82(15):7264-75. doi: 10.1128/JVI.00737-08.
42. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol.
43. Tobias Herold, Vindi Jurinovic, Chiara Arnreich, Johannes C Hellmuth et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. medRxiv 2020.04.01.20047381; doi:https://doi.org/10.1101/2020.04.01.20047381
44. Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F,Balleyguier C, Besse B, Marabelle A, Netzer F, Merad M, Robert C, Barlesi F, Gachot B, Stoclin A,Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report, Annals of Oncology (2020), doi: https://doi.org/10.1016/j.annonc.2020.03.300.
45. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu HJ. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019. J Clin Invest. 2020; doi: 10.1172/JCI137244.
46. Mehta P, Mcauley D, Brown M, Sanchez E, Tattersall R, Manson JHLH Across Speciality Collaboration, UK. Correspondence COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-1034. doi: 10.1016/S0140-6736(20)30628-0.