Novel coronavirus disease (COVID-19) and cytokine storms. For more effective treatments from the viewpoints of an inflammatory pathophysiology perspective

Abstract

Novel Coronavirus Disease (COVID-19) swept the world and led to a global pandemic. SARS-CoV-2, which is thought to have derived from bats as their reservoir hosts, has over time and similarly as with SARS-CoV, combined with human angiotensin converting enzyme 2 (ACE2). Thus, this caused infections in cells and established them into a human infectious disease (COVID-19).

Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines such as G-CSF, IP10, MCPl, to develop an increase the inflammatory responses.

In the case of COVID-19, it revealed that excessive inflammatory responses occur, and that the exaggerated proinflammatory cytokines and chemokines are detected in COVID-19 patients' sera resulting in cytokine release syndrome (CRS) or cytokine storm (CS). This causes coagulation abnormalities, excessive oxidation development, vital organ damages, immune system failure, and finally, progresses to disseminated intravascular coagulation (DIC) and multiple organ failure (MOF).

Additionally, excessive inflammatory responses lead to mitochondrial dysfunction due to progressive and persistent stress which leads to cells and mitochondrial fracturing products containing mitochondrial DNA and damaged cell debris which in turn are involved in the chronic excessive inflammation as damage-associated molecular patterns (DAMPs). Thus, respiratory infection progressively leads to DIC from acute respiratory distress syndrome (ARDS) including vascular endothelial cell damages and coagulation-fibrinolysis system disorders. Then, this worsens to central nervous system disorders, renal failure, liver failure, and finally to MOF.

With regards to treatments for COVID-19, the followings are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. Firstly, the administering of Favipiravir for the suppression of SARS-CoV-2, and Nafamostat for the inhibition of ACE2 function should be considered. Then, the administration of anti-rheumatic drugs (monoclonal antibodies which combine with the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as Tocilizumab). Finally, melatonin may be effective under recognition of the pathology of CRS/CS for the improvement of mitochondrial function.

The paper will further explore these subjects with reports mostly from China and Europe.

Keywords:COVID-19, SARS-CoV-2, cytokine storm, IL-1β, IL-6

Funding. The study was not sponsored.

Conflict of interest. The authors declare no conflicts of interest associated with this manuscript. Yokota S. was involved with the development of Tocilizumab for juvenile idiopathic arthritis (JIA), but has no conflict of interest directly relevant to the content of this article.

Contribution. The authors contributed equally to this article.

For citation: Yokota S., Kuroiwa Y., Nishioka K. Novel coronavirus disease (COVID-19) and cytokine storms. For more effective treatments from the viewpoints of an inflammatory pathophysiology perspective. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2020; 9 (4): 13-25. DOI: https://doi.org/10.33029/2305-3496-2020-9-4-13-25 (in Russian)

References

1. Wu Z., McGoogan J. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13): 1239-42. Epub 2020 Feb 24. URL: https://jamanetwork.com/on03/16/2020

2. Yang Y., Peng F., Wang R., et al. The deadly coronaviruses: the 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China. J Autoimmun. 2020; Mar 3: 102434. DOI: https://doi.org/10.1016/j.aut.2020.102434

3. The WHO MERS-CoV Research Group. State of knowledge and data gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in humans. PLoS Curr Outbreaks. 2013; Nov 12. DOI: https://doi.org/10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8

4. Guo Y.-R., Cao Q.-D., Hong Z.-S., et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status. Mil Med Res. 2020; 7 (1): 11. DOI: https://doi.org/10.1186/s40779-020-00240-0

5. Sarzi-Puttini P., Giorgi V., Sirotti S., et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020; 38 (2): 337-42.

6. Wu Y., Wu X., Chen Z., et al. Nervous system involvement after infection with COVID-19 and other viruses. Brain Behav Immun. 2020; 87: 1822. Epub 2020 Mar 30. DOI: https://doi.org/10.1016/j.bbi.2020.03.031

7. Rodriguez-Morales A.J., Cardona-Ospina J.A., Gutuerrez-Ocampo E., et al. Clinical, laboratory and imaging features of COVID-19: a systemic review and meta-analysis. Travel Med Infect Dis. 2020; Mar 13: 101623. DOI: https://doi.org/10.1016/jrtmaid.2020.101623

8. Huang C., Wang Y., Li X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506.

9. Chen N., Zhou M., Dong X., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395: 507-13.

10. Yokota S., Itoh Y., Morio T., et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with Tocilizumab. J Rheum. 2015; 42: 712-22.

11. Huang L.M., Hu Q., Huang X., et al. Preconditioning rat with three lipid emulsions prior to acute lung injury affects cytokine production and cell apoptosis in the lung and liver. Lipids Health Dis. 2020; 19: 19. DOI: https://doi.org/10.1186/s12944-019-1137-x

12. Usumani G.N., Woda B.A., Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013; 161: 609-22. DOI: https://doi.org/10.1111/bjh.12293

13. Zhang W., Zhao Y., Zhang F., et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020; 214: 108393. DOI: https://doi.org/10.1016/j.clim.2020.108393

14. Sandhir R., Halder A., Sunlaria A. Mitochondria as a centrally positioned hub in the innate immune response. Biochim Biophys Acta Mol Basis Dis. 2017; 1863 (5): 1090-7. DOI: https://doi.org/10.1016/j.bbadis.2016.10.020

15. Mohanty A., Tiwari-Pandey R., Pandey N.R. Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response. J Cell Commun Signal. 2019; 13 (3): 303-18. DOI: https://doi.org/10.1007/s12079-019-00507-9

16. Li W., Moore M.J., Vasilleva N., et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2004; 426: 450-4.

17. South A.M., Diz D., Chappel l. COVID-19, ACE2 and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020; 318 (5): H1084-90. Epub 2020 Mar 31. DOI: https://doi.org/10.1152/ajp-heart.00217.2020.

18. Ortega J.T., Serrano M.L., Pujol F.H., et al. Role of changes in SARS-COV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. 2020; 19: 410-7.

19. Ferro F., Elefante E., Baldini C., et al. COVID-19: the new challenge for rheumatologists. Clin Exp Rheum. 2020; 38: 175-80.

20. Xu Z., Shi L., Wang Y., et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8 (4): 420-2. Epub 2020 Feb 18. DOI: https://doi/org/10.1016/S2213-2600(20)30076-X

21. Tian S., et al. Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J

Thorac Oncol. 2020; 15 (5): 700-4. Epub 2020 Feb 28. DOI: https://doi/org/10.1016/j.jtho.2020.02.010

22. New Coronavirus Pneumonia Treatment Guidelines. 7th Version, March 3, 2020. China Food and Drug Administration (CFDA), National Health Commission of the People’s Republic of China, 2020.

23. Yang M. Cell Pyroptosis, a Potential Pathogenic Mechanism of 2019-nCoV Infection. 2020. DOI: https://doi.org/10.2139/ssrn.3527420

24. Man S.M., Karki R., Kanneganti T.D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017; 277: 61-75.

25. Zhang C., Wu Z., Li J.W., et al. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antago-ni st tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020; 55 (5): 105954. Epub 2020 Mar 29. DOI: https://doi.org/10.1016/j.ijantimicag.2020.105954

26. Gourbal B., Pinaud S., Beckers G.J.M., et al. Innate immune memory: an evolutionary perspective. Immunol Rev. 2018; 283: 21-40.

27. West A.P., Shadel G.S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol. 2017; 17: 363-75.

28. Banoth B., Cassel S.L. Mitochondria in innate immune signaling. Transl Res. 2018; 202: 52-68. DOI: https://doi.org/10.1016/j.trsl.2018.07.0014

29. Collins L.V., Hajizadeh S., Holme E., et al. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol. 2004; 75: 995-1000.

30. Kelley N., Jeltema D., Duan Y., et al. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019; 20 (13): E3328. DOI: https://doi.org/10.3390/ijms2013328

31. Kato H., Sato S., Yoneyama M., et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity. 2005; 23: 19-28.

32. Ishikawa H., Barber G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling. Nature. 2008; 455: 674-8.

33. Letts J.A., Sazanov L.A. Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol. 2017; 24: 800-8.

34. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev. 2020; 19: 149-50.

35. Yamamoto M., Matsuyama S., Li X., et al. Identification of Nafamo-stat as a potent inhibitor of middle east respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based membrane fusion assay. Antimicrob Agents Chemother. 2016; 60 (11): 6532-9. DOI: https://doi.org/10.1128/AAC.01043-16

36. Yokota S., Imagawa T., Mori M., et al. Efficacy and safety of to-cilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008; 371: 998-1006.

37. Xu X., Han M., Li T., et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. 2020.

38. Bannardo F., Buffone C., Giudice A. New therapeutic opportunities for COVID-19 patients with tocilizumab: possible correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws. Oral Oncol. 2020; 106: 104659. Epub 2020 Mar 21. DOI: https://doi.org/10.1016/j.oraloncolgy.2020.14659

39. Wang D. A multi-center, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). Chinese Clinical Trial register. Registration number: ChiCTR2000029765. Date of Registration: 2020-02-13.

40. Shakoory B., Carcillo J.A., Chatham W.W., et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: re-analysis of a prior phase III trial. Crit Care Med. 2016; 44: 275-81.

41. Zhou L. A clinical study for the efficacy and safety of adalimumab injection in the treatment of patients with severe novel coronavirus pneumonia (COVID-19). Chinese Clinical Trial register. Registration number: ChiCTR2000030089. Date of registration: 2020-2-22.

42. Hongzhou L. Study for safety and efficacy of Jakotinib hydrochloride tablets in the treatment severe and acute exacerbation patients of novel coronavirus pneumonia (COVID-19). Chinese Clinical Trial register. Registration number: ChiCTR2000030170. Date of registration: 2020-2-24.

43. Yang C. Severe novel coronavirus pneumonia (COVID-19) patients treated with ruxolitinib in combination with mesenchymal stem cells: a prospective, single blind, randomized controlled clinical trial. Chinese Clinical Trial register. Registration number: ChiCTR2000028580. Date of registration: 2020-2-05.

44. Silvestri M., Rossi G.A. Melatonin: its possible role in the management of viral infections-a brief review. Ital J Pediatr. 2013; 39: 61. DOI: https://doi.org/10.1186/1824-7288-39-61.

45. Galano A., Tan D.-X., Reiter R.J. Melatonin: a versatile protector against oxidative DNA damage. Molecules. 2018; 23: 530. DOI: https://doi.org/10.3390/molecules23030530

46. Mayo J.C., Sainz R.M., Gonzalez-Menendez P Melatonin transport into mitochondria. Cell Mol Life Sci. 2017; 74: 3927-40. DOI: https://doi.org/10.1007/s00018-017-2616-8

47. Zhou Y.-H., Qin Y.-Y. Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial. Chinese Clinical Trial register. Registration number: ChiCTR2000029386. Date of registration: 2020-1-29.

48. Keith P, Day M., Perkins L., et al. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care. 2020; 24 (1): 128. DOI: https://doi.org/10.1186/s13054-020-2836-4

49. Ma J., Xia P, Zhou Y., et al. Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19. Clin Immunol. 2020; 214: 108408. Epub 2020 Apr 1. DOI: https://doi.org/10.1016/j.clim.2020.108408

50. Fu D., Yang B., Xu J., et al. COVID-19 infection in a patient with end-stage kidney disease. Nephron. 2020; 144 (5): 245-7. Epub 2020 Mar 27. DOI: https://doi.org/10.1159/000507261

51. Selewski D., Cornell T.T., Blatt N.B., et al. Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy. Crit Care Med. 2012; 40 (9): 2694-9.

CHIEF EDITOR
CHIEF EDITOR
Yushchuk Nikolay Dmitrievich
Academician of the Russian Academy of Sciences, Professor, head of the Infectious Diseases and Epidemiology Department, President of the Moscow State University of Medicine and Dentistry named after A.I. Evdokimov, Board member of the National Scientific Infectiologists? Society.
Medicine today

Уважаемые коллеги! 31 мая - 1 июня 2021 г. с целью обмена опытом и знаниями между российскими и зарубежными специалистами широкого спектра смежных областей будет проведена Международная научно-практическая конференция "Актуальные вопросы ВИЧ-инфекции. Охрана здоровья матери...

II Конференция онкологов Московской области Москва, 4 июня 2021 года Подмосковье в настоящее время - это регион, переживающий бурный прирост населения и активную урбанизацию. Эти процессы требуют изменений в организации оказания медицинской помощи, в первую очередь,...

Приглашаем вас принять активное участие в работе XII Международной конференции "Актуальные аспекты экстракорпорального очищения крови в интенсивной терапии". Мероприятие пройдет 28-29 мая 2021 года в онлайн-формате. Конференция организована при поддержке Министерства...


Journals of «GEOTAR-Media»