COVID-19 - a set of symptoms or a systemic pathology? Clinical lecture. Part 1. Details of multiple organ damage

Abstract

Clinical practice shows that in addition to the life-threatening condition caused by lung damage during infection with SARS-CoV-2, the virus provokes multiple organ damage and systemic endothelial inflammation, leading to serious, often fatal consequences. The review article describes possible pathogenetic ways of SARS-CoV-2 manifestation, details of the body's immune system response under conditions of infection with a virus, proposed clinical solutions for systemic multifactorial therapy, including the earlier initiation of the use of targeted antiviral drugs, blockers of interleukins -1 and -6, as well as drugs that block systemic endothelial inflammation, in particular, slowing down the activation of the inflammasome pathway, anticoagulants and drugs that slow down tissue edema and inhibit the effectiveness of binding of the virus to target cells. One of the drugs of antiviral therapy that receives special focus of our review is Areplivir (favipiravir), which prevents the replication of viral RNA and allows the reduction of the viral load and prevention of the development of complications of the disease.

Keywords:COVID-19, SARS-CoV-2, cytokine storm, immunologic response, antiviral therapy, favipiravir

Funding. The research was carried out at the initiative of the Promomed RUS company. The sponsor had no influence on the analysis and interpretation of the results.

Conflict of interests. The authors declare that there is no conflict of interest.

Contribution. Choice and processing of material - Granovskaya M.V., Zaslavskaya K.Ya.; writing text - Granovskaya M.V., Zaslavskaya K.Ya.; editing - Granovskaya M.V.

For citation: Granovskaya M.V., Zaslavskaya K.Ya. COVID-19 - a set of symptoms or a systemic pathology? Clinical lecture. Part 1. Details of multiple organ damage. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2020; 9 (3). Supplement. 3-9. DOI: https://doi.org/10.33029/2305-3496-2020-9-3S-3-9 (in Russian)

References

1. Li W., Moore M., Vasilieva N.. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003, 426: 450-4. DOI: https://doi.org/10.1038/nature02145

2. Lan J., Ge J., Yu J., et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020, 581: 215-20. DOI: https://doi.org/10.1038/s41586-020-2180-5

3. Walls A.C., et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020: 181: 281-92.e286. DOI: https://doi.org/10.1016/j.cell.2020.02.058

4. Li F., Li W., Farzan M., Harrison S.C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005, 309: 1864-8. DOI: https://doi.org/10.1126/science.1116480

5. Wang Q., Zhang Y., Wu L., Niu S., et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020,181 (4): 894-904.e9. DOI: https://doi.org/10.1016/j.cell.2020.03.045

6. Lei C., Qian K., Li T., Zhang S., et al. Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat Commun. 2020, 11 (1): 2070. DOI: https://doi.org/10.1038/s41467-020-16048-4

7. Bakowitz M., Bruns B., McCunn M. Acute lung injury and the acute respiratory distress syndrome in the injured patient. Scand J Trauma Resusc Emerg Med. 2012, 20: 54. DOI: https://doi.org/10.1186/1757-7241-20-54

8. Zhou P, Yang X L., Wang X.G., Hu B., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020, 579 (7798): 270-3. DOI: https://doi.org/10.1038/s41586-020-2012-7

9. Li H., Liu L., Zhang D., Xu J., et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020, 395 (10235): 1517-20. DOI: https://doi.org/10.1016/S0140-6736(20)30920X

10. Gupta A., Madhavan M.V., Sehgal K., Nair N., et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020, 26 (7): 1017-32. DOI: https://doi.org/10.1038/s41591-020-0968-3

11. Guan W.J., Ni Z.Y., Hu Y., et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020, 382: 1708-20. DOI: https://doi.org/10.1056/NEJMoa2002032

12. Holmes K.V. SARS coronavirus: a new challenge for prevention and therapy. J Clin Invest. 2003: 111: 1605-9. DOI: https://doi.org/doi:10.1172/JCI18819

13. https://science.sciencemag.org/

14. Siu KL., Yuen K.S., Castano-Rodriguez C., Ye Z.W., et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J. 2019, 33 (8): 8865-77. DOI: https://doi.org/10.1096/fj.201802418R

15. Xu J., Li Y., Gan F, Du Y., Yao Y. Salivary glands: potential reservoirs for COVID-19 asymptomatic infection. J Dent Res. 2020, 99 (8): 989. DOI: https://doi.org/10.1177/0022034520918518

16. Sims A.C., Baric R.S., Yount B., Burkett S.E., et al. Severe acute respiratory syndrome coronavirus infection of human ciliated airnay epithelia: role of ciliated cells in viral spread in the conducting airnays of the lungs. J Virol. 2005, 79 (24): 15511-24. DOI: https://doi.org/10.1128/JVI.79.24.15511-15524.2005

17. Puelles VG., Lutgehetmann M., Lindenmeyer M.T., Sperhake J.P, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020, 383 (6): 590-92. DOI: https://doi.org/10.1056/NEJMc2011400

18. Su H., Yang M., Wan C., Yi LX., et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020, 98 (1): 219-27. DOI: https://doi.org/10.1016/jkint.2020.04.003

19. Tavazzi G., Pellegrini C., Maurelli M., Belliato M., et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020, 22 (5): 911-5. DOI: https://doi.org/10.1002/ejhf.1828

20. Xiao F., Tang M., Zheng X., Liu Y., et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020, 158 (6):1831-3.e3. DOI: https://doi.org/10.1053/j.gastro.2020.02.055

21. Qi F., Qian S., Zhang S., Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 2020, 526 (1): 135-40. DOI: https://doi.org/10.1016/j.bbrc.2020.03.04

22. Pan X.W., Xu D., Zhang H., Zhou W., et al. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med. 2020, 46 (6): 1114-6. DOI: https://doi.org/10.1007/s00134-020-06026-1

23. Ziegler C.G.K., Allon S.J., Nyquist S.K., Mbano I.M., et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airnay epithelial cells and Is detected in specific cell subsets across tissues. Cell. 2020, 181 (5): 1016-35.e19. DOI: https://doi.org/10.1016/j.cell.2020.04.035

24. Ackermann M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N. Engl. J. Med. 2020, 383: 120-8. DOI: https://doi.org/10.1056/NEJMoa2015432

25. Teuwen L.A., Geldhof V., Pasut A., Carmeliet P COVID-19: the vasculature unleashed. Nat Rev Immunol. 2020, 383: 120-8. DOI: https://doi.org/10.1038/s41577-020-0343-0

26. Varga Z., Flammer AJ., Steiger P, Haberecker M., et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020, 395 (10234): 1417-8. DOI: https://doi.org/10.1016/S0140-6736(20)30937-5

27. Jackson S.P., Darbousset R., Schoenwaelder S.M. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019, 133: 906-18.

28. Bikdeli B., Madhavan M.V., Gupta A., Jimenez D., et al. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost. 2020, 120 (7): 1004-24. DOI: https://doi.org/10.1055/s-0040-1713152

29. Engelmann B., Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013, 13 (1): 34-45. DOI: https://doi.org/10.1038/nri3345

30. Levi M., van der Poll T. Coagulation and sepsis. Thromb Res. 2017, 149: 38-44. DOI: 10.1016/j. thromres.2016.11.007

31. Jackson S.P., Darbousset R., Schoenwaelder S.M. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood. 2019, 133 (9): 906-18. DOI: https://doi.org/10.1182/blood-2018-11-882993

32. Koupenova M., Corkrey H.A., Vitseva O., et al. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019, 10: 1780. DOI: https://doi.org/httpsy/doi.org/10.1038/s41467-019-09607-x

33. Yeaman MR. Platelets in defense against bacterial pathogens. Cell Mol Life Sci. 2010, 67: 525-44. DOI: https://doi.org/10.1007/s00018-009-0210-4

34. Semple J.W., ItalianoJ.E.Jr., Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011, 11: 264-74. DOI: https://doi.org/10.1038/nri2956.

35. Merad M., Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020, 20: 355-62. DOI: https://doi.org/10.1038/s41577-020-0331-4

36. Zuo Y., Yalavarthi S., Shi H., Gockman K., et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020, 5 (11): e138999. DOI: https://doi.org/10.1172/jci.insight.138999

37 Gupta N., Zhao YY., Evans C.E. The stimulation of thrombosis by hypoxia. Thromb Res. 2019, 181: 77-83. DOI: https://doi.org/10.1016/j.thromres.2019.07.013

38. Giannis D., Ziogas I.A., Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. 2020, 127: 104362. DOI: https://doi.org/10.1016/j.jcv.2020.104362

39. Deshpande C. Thromboembolic findings in COVID-19 autopsies: pulmonary thrombosis or embolism? Ann Intern Med. 2020, 173 (5): 394-5. DOI: https://doi.org/10.7326/M20-3255

40. Iba T., Levy J.H. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost. 2018, 16 (2): 231-41. DOI: https://doi.org/10.1111/jth.13911

41. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020, 191: 145-7 DOI: https://doi.org/10.1016/j.thromres.2020.04.013

42. Bangalore S., Sharma A., Slotwiner A., Yatskar L., et al. ST-segment elevation in patients with Covid-19 - a case series. N Engl J Med. 2020, 382 (25): 2478-80. DOI: https://doi.org/10.1056/NEJMc2009020

43. Helms J., Kremer S., Merdji H., Clere-Jehl R., et al. Neurologic features in severe SARS-CoV-2 Infection. N Engl J Med. 2020, 382 (23): 2268-70. DOI: https://doi.org/10.1056/NEJMc2008597

44. Helms J., Tacquard C., Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020, 46 (6): 1089-98. DOI: https://doi.org/10.1007/s00134-020-06062-x

45. Oxley T.J., Mocco J., Majidi S., Kellner C.P., et ak. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020, 382 (20): e60. DOI: https://doi.org/10.1056/NEJMc2009787

46. Llitjos J.F, Leclerc M., Chochois C., Monsallier J.M., et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020, 18 (7): 1743-6. DOI: https://doi.org/10.1111/jth.14869

47. Kim K.D., Zhao J., Auh S., Yang X., et al. Adaptive immune cells temper initial innate responses. Nat Med. 2007, 13 (10): 1248-52. DOI: https://doi.org/10.1038/nm1633

48. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017, 39 (5): 529-39. DOI: https://doi.org/10.1007/s00281-017-0629-x

49. Huang K.J., Su I.J., Theron M., et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005, 75 (2): 185-94. DOI: https://doi.org/10.1002/jmv.20255

50. Petrilli C M., Jones S.A., Yang J., Rajagopalan H., et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020, 369: m1966. DOI: https://doi.org/10.1136/bmj.m1966

51. Mehta P, McAuley D.F, Brown M., Sanchez E., et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020, 395 (10229): 1033-4. DOI: https://doi.org/10.1016/S0140-6736(20)30628-0

52. Terpos E., Ntanasis-Stathopoulos I., Elalamy I., Kastritis E., et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020, 95 (7): 834-47. DOI: https://doi.org/10.1002/ajh.25829

53. Huang C., Wang Y., Li X., Ren L., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020, 395 (10223): 497-506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5

54. Qin C., Zhou L., Hu Z., et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020, 71 (15): 762-8. DOI: https://doi.org/10.1093/cid/ciaa248

55. Fan B E., Chong V.C.L., Chan S.S.W., Lim G.H., et al. Hematologic parameters in patients with COVID-19 infection. Am J Hematol. 2020, 95 (6): E131-4. DOI: https://doi.org/10.1002/ajh.25774

56. Gu J., Gong E., Zhang B., et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005, 202 (3): 415-24. DOI: https://doi.org/10.1084/jem.20050828

57. Xu H., Zhong L., Deng J., et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020, 12: 8. DOI: https://doi.org/10.1038/s41368-020-0074-x

58. Hotchkiss R.S., Opal S.M. Activating immunity to fight a foe - a new path. N Engl J Med. 2020, 382 (13): 1270-2. DOI: https://doi.org/10.1056/NEJMcibr1917242

59. Chu H., Zhou J., Wong B.H., Li C., et al. Middle East Respiratory Syndrome Coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis. 2016, 213 (6): 904-14. DOI: https://doi.org/10.1093/infdis/jiv380

60. Park M.D. Macrophages: a Trojan horse in COVID-19?. Nat Rev Immunol. 2020, 20 (6): 351. DOI: https://doi.org/10.1038/s41577-020-0317-2

61. Lax S.F, Skok K., Zechner P, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center clinicopathologic case series. Ann Intern Med. 2020,173 (5): 350-61. DOI:https://doi.org/10.7326/m20-2566

62. Carter-Timofte ME., Jorgensen S.E., Freytag MR., et al. Deciphering the role of host genetics in susceptibility to severe COVID-19. Front Immunol. 2020, 11: 1606. DOI: https://doi.org/10.3389/fimmu.2020.01606

63. Fagone P, Ciurleo R., Lombardo S.D., Iacobello C., et al. Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies. Autoimmun Rev. 2020, 19 (7): 102571. DOI: https://doi.org/10.1016/jautrev.2020.102571

64. Mehta P, McAuley D.F, Brown M., Sanchez E., et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020, 395 (10229): 1033-4. DOI: https//doi.org/10.1016/S0140-6736(20)30628-0

65. 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 (4): 844-7 DOI: https://doi.org/10.1016/S0140-6736(20)30628-0

66. Vaduganathan M., Vardeny O., Michel T., McMurray J.J.V., et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020, 382 (17): 1653-9. DOI: https://doi.org/10.1056/NEJMsr2005760

67. Banegas I., Prieto I., Segarra AB., Martfnez-Canamero M., et al. Angiotensin II, dopamine and nitric oxide. An asymmetrical neurovisceral interaction between brain and plasma to regulate blood pressure. AIMS Neurosci. 2019, 6 (3): 116-27. DOI: https://doi.org/10.3934/Neuroscience.2019.3116

68. Kuba K., Imai Y., Ohto-Nakanishi T., Penninger J.M. Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor and a partner for amino acid transporters. Pharmacol Ther. 2010: 128 (1): 119-28. DOI: https://doi.org/10.1016/jpharmthera.2010.06.003

69. Strawn W.B., Ferrario C M., Tallant E.A. Angiotensin-(1-7) reduces smooth muscle growth after vascular injury Hypertension. 1999, 33: 207-11 DOI: https://doi.org/10.116V01.hyp.33.L207

70. van de Veerdonk F, Netea M.G., van Deuren M., et al. Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints 2020. 2020040023. DOI: https://doi.org/10.20944/preprints202004.0023.v1

71. Chen D., Li X., Song Q., et al. Hypokalemia and clinical implications in patients with Coronavirus disease 2019 (COVID-19). medRxiv. 2020.02.2720028530. DOI: https://doi.org/10.1101/2020.02.27.20028530

72. Ullah W., Saeed R., Samar U., Patel R., Fischman D.L. COVID-19 complicated by acute pulmonary embolism and right-sided heart failure. JACC Case Rep. 2020, 2 (9): 1379-82. DOI: https://doi.org/10.1016/jjaccas.2020.04.008

73. Clerkin KJ., Fried J.A., Raikhelkar J., Sayer G., et al. COVID-19 and cardiovascular disease. Circulation. 2020, 141 (20): 1648-55. DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.046941

74. Guo T., Fan Y., Chen M., Wu X., et al. Cardiovascular implications of fatal outcomes of patients with Coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020, 5 (7): 811-8. DOI: https://doi.org/10.1001/jamacardio.2020.1017

75. Gallagher P.E., Ferrario CM., Tallant E.A. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol. 2008, 295 (6): H2373-9. DOI: https://doi.org/10.1152/ajpheart.00426.2008

76. Sala S., Peretto G., Gramegna M., Palmisano A., et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 2020, 41 (19): 1861-1862. DOI: https://doi.org/10.1093/eurheartj/ehaa286

77. Cheng Y., Luo R., Wang K., Zhang M., et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020, 97 (5): 829-38. DOI: https://doi.org/10.1016/jkint.2020.03.005

78. Su H., Yang M., Wan C., Yi LX., et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020, 98 (1): 219-27. DOI: https://doi.org/https://doi.org/10.1016/j.kint.2020.04.003

79. Iwasaki A., Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol. 2014, 14 (5): 315-28. DOI: https://doi.org/10.1038/nri3665

80. Mao R., Qiu Y., He J.S., Tan J.Y., et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020, 5 (7): 667-78. DOI: https://doi.org/10.1016/S2468-1253(20)30126-6

81. Zhang C., Shi L., Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol. 2020, 5 (5): 428-30. DOI: https://doi.org/10.1016/S2468-1253(20)30057-1

82. Pilotto A., Odolini S., Masciocchi S., Comelli A., et al. Steroid-responsive encephalitis in Coronavirus disease 2019. Ann Neurol. 2020: 10.1002/ana.25783. DOI: https://doi.org/10.1002/ana.25783

83. Zhao H., Shen D., Zhou H., Liu J., Chen S. Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol. 2020, 19 (5): 383-4. DOI: https://doi.org/10.1016/S1474-4422(20)30109-5

84. AHA/ASA Stroke Council Leadership. Temporary emergency guidance to US stroke centers during the coronavirus disease 2019 (COVID-19) pandemic: On Behalf of the American Heart Association/American Stroke Association Stroke Council Leadership. Stroke. 2020, 51 (6): 1910-2. DOI: https://doi.org/10.116VSTROKEAHA.120.030023

85. Hartung H., Aktas, O. COVID-19 and management of neuroimmunological disorders. Nat Rev Neurol. 2020, 16: 347-8. DOI: https://doi.org/10.1038/s41582-020-0368-9

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CHIEF EDITOR
Aleksandr V. Gorelov
Academician of the Russian Academy of Sciences, MD, Head of Infection Diseases and Epidemiology Department of the Scientific and Educational Institute of Clinical Medicine named after N.A. Semashko ofRussian University of Medicine, Ministry of Health of the Russian Federation, Professor of the Department of Childhood Diseases, Clinical Institute of Children's Health named after N.F. Filatov, Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Deputy Director for Research, Central Research Institute of Epidemiology, Rospotrebnadzor (Moscow, Russian Federation)

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