Effect of tocilizumab and thymalin on systemic inflammation in patients with COVID-19

DOI: https://doi.org/10.29296/25877305-2020-11-17
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Issue: 
11
Year: 
2020

Professor B. Kuznik(1, 2), MD; Professor V. Khavinson(3, 4), Corresponding Member of the
Russian Academy of Sciences, MD; S. Lukyanov, Candidate of Medical Sciences; Professor K. Shapovalov(1, 5),
MD; Yu. Smolyakov(1, 2), Candidate of Medical Sciences; P. Tereshkov(1), Candidate of Medical Sciences; Yu.
Shapovalov(1, 5); V. Konnov(1, 5), Candidate of Medical Sciences; Associate Professor D. Zaitsev(1), MD;
Professor E. Magen(6), MD (1)Chita State Medical Academy (2)Innovation Clinic, Academy of Health, Chita
(3)Saint Petersburg Institute of Bioregulation and Gerontology (4)I.P. Pavlov Institute of Physiology,
Russian Academy of Sciences, Saint Petersburg (5)City Clinical Hospital One, Chita (6)David Ben-Gurion
University, Ashdod, Israel

Severe COVID-19 accompanied by acute respiratory failure, acute respiratory distress syndrome, and multiple organ dysfunction is most often observed in older (over 65 years) and relatively young patients with concomitant diseases, such as diabetes mellitus, hypertensive disease, cardiac, renal, or hepatic dysfunction. In this case, the patients develop an excessive inflammatory response accompanied by the development of a cytokine storm, by the imbalance and subsequent depletion of T-cell immunity. Successful therapy for COVID-19 is based on the restoration of impaired immune functions, as well as on the elimination of the cytokine storm. For this purpose, it is recommended that the recombinant monoclonal antibody IL-6 (RIL) receptor inhibitor tocilizumab be used. The paper gives information on the successful use of tocilizumab in patients with severe COVID-19 and shows its substantial disadvantages: the development of adverse reactions, such as lymphocytopenia, thrombocytopenia, and elevated levels of IL6, alanine and aspartate aminotransferase, etc. At the same time, there are rationales that these patients should be given the immunomodulator thymalin that is able to eliminate the cytokine storm, to normalize the immune system, and to prevent disseminated intravascular coagulation. The authors describe typical cases of severe COVID-19 treated with tocilizumab and thymalin alone and in combination.
Keywords: 
инфекционные заболевания
терапия
COVID-19
системное воспаление
«цитокиновый шторм»
иммунитет
гемостаз
тоцилизумаб
тималин

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References: 
  1. Huang C., Wang Y., Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395 (10223): 497–506. DOI: 10.1016/S0140-6736(20)30183-5
  2. Wang D., Hu B., Hu C. et al. Clinical characteristics of 138 hospitalized patients With 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323 (14): 1406–7. DOI: 10.1001/jama.2020.1585
  3. Goh K.J., Choong M.C., Cheong E.H. et al. Rapid Progression to Acute Respiratory Distress Syndrome: Review of Current Understanding of Critical Illness from COVID-19 Infection. Ann Acad Med Singapore. 2020; 49: 108–18.
  4. Izet M., Nabil N., Zildzic M. Public Health Aspects of COVID-19 Infection With Focus on Cardiovascular Disea. Mater Sociomed. 2020; 32 (1): 71–6. DOI: 10.5455/msm.2020.32.71-76
  5. Zhavoronkov A. Geroprotective and Senoremediative Strategies to Reduce the Comorbidity, Infection Rates, Severity, and Lethality in Gerophilic and Gerolavic Infections. Aging (Albany NY). 2020; 12 (8): 6492–510. DOI: 10.18632/aging.102988
  6. Fu B., Xu X., Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020; 18: 164. DOI: 10.1186/s12967-020-02339-3
  7. Russell S.M., Alba-Patiño A., Barón E. et al. Biosensors for Managing the COVID-19 Cytokine Storm: Challenges Ahead. ACS Sens. 2020; 5 (6): 1506–13. DOI: 10.1021/acssensors.0c00979
  8. Tang Y., Liu J., Zhang D. et al. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front Immunol. 2020; 11: 1708. DOI: 10.3389/fimmu.2020.01708
  9. Qin C., Zhou L., Hu Z. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020; 71 (15): 762–8. DOI: 10.1093/ cid/ciaa248
  10. Zhang C., Wu Z., Li J. et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020; 55 (5): 105954. DOI: 10.1016/j.ijantimicag.2020.105954
  11. 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. DOI: 10.1016/S2213-2600(20)30076-X
  12. Chen Y., Feng Z., Diao B. et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv. 2020: 105924. DOI: 10.1101/2020.03.27.20045427
  13. Li J., Guo M., Tian X. et al. Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis. bioRxiv. 2020. DOI: 10.1101/2020.03.31.019216
  14. Dhampalwar S., Saigal S., Soin A. Treatment Armamentarium of COVID-19: Evolving Strategies and Evidence So Far. Clin Exp Hepatol. 2020. DOI: 10.1016/j.jceh.2020.07.001
  15. Conrozier T., Lohse A., Balblanc J.C. et al. Biomarker variation in patients successfully treated with tocilizumab for severe coronavirus disease 2019 (COVID-19): results of a multidisciplinary collaboration. Clin Exp Rheumatol. 2020; 38 (4): 742–7.
  16. Alattar R., Ibrahim T.B.H., Shaar S.H. Tocilizumab for the treatment of severe COVID-19. J Med Virol. 2020. DOI: 10.1002/jmv.25964
  17. Wang D., Hu B., Hu C. et al. Clinical characteristics of 138 hospitalized patients With 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323 (11): 1061–9. DOI: 10.1001/jama.2020.1585
  18. Tang N., Bai H., Chen X. et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020; 18 (5): 1094–9. DOI: 10.1111/jth.14817
  19. Tang N., Li D., Wang X. et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18 (4): 844–7. DOI: 10.1111/jth.14768
  20. Toniati P., Piva S., Cattalini M. et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020; 19 (7): 102568. DOI: 10.1016/j.autrev.2020.102568
  21. Zhao J., Cui W., Tian B. Efficacy of tocilizumab treatment in severely ill COVID-19 patients. Crit Care. 2020; 24 (1): 1–4. DOI: 10.1186/s13054-020-03224
  22. Mullard A. Anti-IL-6Rs falter in COVID-19. Nat Rev Drug Discov. 2020; 19 (9): 577. DOI: 10.1038/d41573-020-00141-w
  23. Havinson V.H., Kuznik B.I., Sturov V.G. i dr. Primenenie preparata Timalin® pri zabolevanijah organov dyhanija. Perspektivy ispol'zovanija pri COVID-19. RMZh. 2020; 9: 24–30 [Khavison V.H, Kuznik B.I., Sturov V.G., et al. Thymalin use for respiratory diseases. application potential in COVID-19. RMJ. 2020; 9: 24–30 (in Russ.)].
  24. Kuznik B.I., Havinson V.H. Vlijanie Timalina na sistemy immuniteta, gemostaza i uroven' tsitokinov u patsientov s razlichnymi zabolevanijami. Perspektivy primenenija pri COVID-19. Vrach. 2020; 31 (7): 18–26 [Kuznik B., Khavinson V. The effect of Thymalin on the immune system, hemostasis and cytokines level in patients with various diseases. Prospects for application in case of COVID-19. Vrach. 2020; 31 (7): 18–26 (in Russ.)]. DOI: 10.29296/25877305-2020-07-03.
  25. Havinson V.H., Kuznik B.I. Oslozhnenija u bol'nyh COVID-19. Predpolagaemye mehanizmy korrektsii. Klinicheskaja meditsina. 2020; 4: 256–65 [Khavinson V.H., Kuznik B.I. Complications in patients with COVID-19. Supposed correction mechanisms. Klinicheskaja medicina. 2020; 4: 256–65 (in Russ)]. DOI: 10.30629/0023-2149-2020-98-4-256-265
  26. Kuznik B.I., Lihanov I.D., Tsepelev V.L. i dr. Teoreticheskie i klinicheskie aspekty bioregulirujuschej terapii v hirurgii i travmatologii. Novosibirsk: Nauka, 2008; 312 s. [Kuznik B.I., Lihanov I.D., Cepelev V.L. et al. Teoreticheskie i klinicheskie aspekty bioregulirujushhej terapii v hirurgii i travmatologii. Novosibirsk: Nauka, 2008; 312 p. (in Russ.)].
  27. Havinson V.H., Kuznik B.I., Ryzhak G.A. Peptidnye geroprotektory – epigeneticheskie reguljatory fiziologicheskih funktsij organizma. SPb: Izd-vo RGPU im. I.A Gertsena, 2014; 279 s. [Khavinson V.H., Kuznik B.I., Ryzhak G.A. Peptide geroprotectors-epigenetic regulators of physiological functions of the body. Saint-Petersburg: Herzen`s RSPU, 2014; 279 p. (in Russ.)].
  28. Kuznik B.I., Vasil'ev V.N., Tsybikov N.N. Immunogenez, gemostaz i nespetsificheskaja rezistentnost' organizma. M.: Meditsina, 1989; 320 s. [Kuznik B.I., Vasil’ev V.N., Cybikov N.N. Immunogenez, gemostaz i nespecificheskaja rezistentnost’ organizma. M.: Medicina, 1989; 320 p. (in Russ.)].
  29. Kuznik B.I., Vitkovskij Ju.A. Ljul'kina E.V. Vozrastnye osobennosti sistemy gemostaza u ljudej. Uspehi gerontologii. 2005; 16: 38–47 [Kuznik B.I., Vitkovsky Y.A. Lyulkina E.V. Age features of hemostasis in humans. Advances in gerontology. 2005; 16: 38–47 (in Russ.)].
  30. Luk'janov S.A., Kuznik B.I., Havinson V.H. i dr. Ispol'zovanie Timalina dlja korrektsii otklonenij immunnogo statusa pri COVID-19 (obosnovanie primenenija preparata i opisanie klinicheskogo sluchaja). Vrach. 2020; 31 (8): 74–82 [Lukyanov S.A., Kuznik B.I., Khavinson V.H. et al. The use of thymaline to correct immune status deviations in COVID-19 (rationale for the use of drug and clinical case). Vrach. 2020; 31 (8): 74–82 (in Russ.)]. DOI: 10.29296/25877305-2020-08-12