HAC (Russian)
RSCI (Russian)
EBSCO
DOI (USA)
Ulrichsweb (Ulrich’s Periodicals Directory)
Scientific Indexing Services

THE USE OF THYMALINE TO CORRECT IMMUNE STATUS DEVIATIONS IN COVID-19 (rationale for the use of drug and clinical case)

DOI: https://doi.org/10.29296/25877305-2020-08-12
Issue: 
8
Year: 
2020

S. Lukyanov(1, 5), Candidate of Medical Sciences; Professor B. Kuznik(1, 2), MD; Professor V.
Khavinson(3, 4), Corresponding Member of RAS; Professor K. Shapovalov(1, 5), MD; Yu. Smolyakov(1, 2),
Candidate of Medical Sciences; P. Tereshkov(1, 2), Candidate of Medical Sciences; Yu. Shapovalov(1, 5); V.
Konnov(1, 5), Candidate of Medical Sciences; Professor E. Magen(6), MD (1)Chita State Medical Academy
(2)Innovative Clinic Academy of Health, Chita (3)Saint-Petersburg Institute of Bioregulation and Gerontology
(4)I.P. Pavlov Institute of Physiology, Saint-Petersburg (5)City Clinical Hospital No.1 of the Ministry of
Health of the Trans-Baikal Territory, Chita (6)Ben Gurion University of Negev, Ashdod, Israel

Data on violations of cellular and humoral immunity in severely patients with COVID-19, as well as the hemostatic system were summarized. It has been shown that patients with COVID-19 have leukocytopenia, lymphocytopenia, neutrophilia, as well as a violation of the ratio between individual subpopulations of T-lymphocytes. The content of pro-inflammatory cytokines increases significantly, which leads to the development of a «cytokine storm». At the same time, such patients develop endothelial dysfunction, hypercoagulation, accompanied by an increase in D-dimer with the subsequent development of microangiopathy (MAP), immunothrombosis, disseminated intravascular coagulation (DIC) and multiple organ failure. A case is given of the use of an immunocorrector thymalin in a patient with a severe course of COVID-19, which contributes to the elimination of disorders in the immune system (including «cytokine storm») and hemostasis.

Keywords: 
therapy
infectious diseases
COVID-19
immunity
«cytokine storm»
blood clotting
multiple organ failure
thymalin
heparin



References: 
  1. Kuznik B.I., Tsybikov N.N. Vzaimosvjaz' mezhdu immunogenezom i sistemoj gemostaza: edinaja sistema zaschity organizma. Uspehi sovremennoj biologii. 1981; 2: 243–60 [Kuznik B.I., Cybikov N.N. Vzaimosvjaz’ mezhdu immunogenezom i sistemoj gemostaza: edinaja sistema zashhity organizma. Uspehi sovremennoj biologii. 1981; 2: 243–60 (in Russ.)].
  2. 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.)].
  3. Lin L., Lu L., Cao W. et al. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020; 9 (1): 727–32. DOI: 10.1080/22221751.2020.1746199
  4. 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
  5. Mehta P., McAuley D.F., Brown M. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395 (10229): 1033–4. DOI: 10.1016/S0140-6736(20)30628-0
  6. Gao Y., Li T., Han M. et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol. 2020; 92 (7): 791–6. DOI:10.1002/jmv.25770.
  7. McGonagle D., Sharif K., O’Regan A. et al. The Role of Cytokines including interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome. Autoimmun Rev. 2020; 19 (6): 102537. DOI: 10.1016/j.autrev.2020.102537
  8. 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
  9. Neurath M.F. Covid-19 and immunomodulation in IBD. Gut. 2020; 69 (7): 1335–42. DOI: 10.1136/gutjnl-2020-321269
  10. Jamilloux Y., Henry T., Belot A. et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020; 19 (7): 102567. DOI: 10.1016/j.autrev.2020.102567
  11. Beristain-Covarrubias N., Perez-Toledo M., Thomas M.R. et al. Understanding infection-induced thrombosis: lessons learned from animal models. Front Immunol. 2019; 10: 2569. DOI: 10.3389/fimmu.2019.02569
  12. Henry B.M., Vikse J., Benoit S. et al. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta. 2020; 507: 167–73. DOI: 10.1016/j.cca.2020.04.027
  13. Vitkovskij Ju.A., Kuznik B.I., Solpov A.V. Patogeneticheskoe znachenie limfotsitarno-trombotsitarnoj adgezii. Meditsinskaja immunologija. 2006; 8 (5–6): 745–53 [Witkowski Y.A., Kuznik B.I., Solov A.V. Pathogenetic significance of lymphocyte-platelet adhesion. Medical immunology. 2006; 8 (5–6): 745–53 (in Russ.)].
  14. Liu Y., Yang Y., Zhang C. et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020; 63: 364–74. DOI: 10.1007/s11427-020-1643-8
  15. Kuznik B.I., Skipetrov V.P. Formennye elementy krovi, sosudistaja stenka, gemostaz i tromboz. M: Meditsina, 1974; 308 s. [Kuznik B.I., Skipetrov V.P. Formennye jelementy krovi, sosudistaja stenka, gemostaz i tromboz. M: Medicina, 1974; 308 p. (in Russ.)].
  16. Nakamura S., Nakamura I., Ma L. et al. Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int. 2000; 58: 251–9. DOI: 10.1046/j.1523-1755.2000.00160.x
  17. Ma J., Weisberg A., Griffin J.P. et al. Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 2006; 69: 1064–72. DOI: 10.1038/sj.ki.5000201
  18. Keragala C.B., Draxler D.F., McQuilten Z.K. et al. Haemostasis and innate immunity – a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. Br J Haematol. 2018; 180: 782–98. DOI: 10.1111/bjh.15062
  19. Kuznik B.I., Lozhkina A.N. Vzaimosvjaz' sistemy komplementa, kallikrein-kininovoj sistemy i sistemy gemostaza. V kn.: Baluda V.P. i dr. Fiziologicheskie sistemy gemostaza. M., 1995; c. 150–60 [Kuznik B.I., Lozhkina A.N. Vzaimosvjaz’ sistemy komplementa, kallikrein-kininovoj sistemy i sistemy gemostaza. V kn.: Baluda V.P. et al. Fiziologicheskie sistemy gemostaza. M., 1995; s. 150–60 (in Russ.)].
  20. Oehmcke S., Mörgelin M., Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun. 2009; 1: 225–30. DOI: 10.1159/000203700
  21. Barnes B.J., Adrover J.M., Baxter-Stoltzfus A. et al , Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020; 217 (6): e20200652. DOI: 10.1084/jem.20200652
  22. Zuo Y., Yalavarthi S., Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020: 138999. DOI: 10.1172/jci.insight.138999
  23. Zubairov D.M., Zubairova L.D. Mikrovezikuly v krovi, funktsija i ih rol' v tromboobrazovanii. M.: GEOTAR-Media, 2009; 168 s. [Zubairov D.M., Zubairova L.D. Mikrovezikuly v krovi, funkcija i ih rol’ v tromboobrazovanii. M.: GEOTAR-Media, 2009; 168 p. (in Russ.)].
  24. Joly B.S., Siguret V., Veyradier A. Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID-19. Intensive Care Med. 2020; 24: 1603–6. DOI: 10.1007/s00134-020-06088-1
  25. 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 (3): 108–18.
  26. Masic Izet, Naser Nabil, Zildzic Muharem. 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
  27. 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
  28. Alijotas-Reig J., Esteve-Valverde E., Belizna C. et al. Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review. Autoimmun Rev. 2020; 19 (7): 102569. DOI: 10.1016/j.autrev.2020.102569
  29. Zhang C., Wu Z., Li J.W. et al. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020; 28: 105954. DOI: 10.1016/j.ijantimicag.2020.105954
  30. Fomina D.S., Poteshkina N.G., Beloglazova I.P. i dr. Sravnitel'nyj analiz primenenija totsilizumaba pri tjazhelyh COVID-19-assotsiirovannyh pnevmonijah. Pul'monologija. 2020; 30 (2): 151–9 [Fomina D.S., Poteshkina N.G., Beloglazova I.P. et al. Comparative analysis of tocilizumab in severe COVID-19-associated pneumonia in patients of different age groups. Pulmonologiya. 2020; 30 (2): 164–72 (in Russ.)]. DOI: 10.18093/0869-0189-2020-30-2-151-159
  31. Sargiacomo C., Sotgia F., Lisanti M.P. COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? Aging (Albany NY). 2020; 12 (8): 6511–7. DOI: 10.18632/aging.103001
  32. Alam M.M., Mahmud S., Rahman M.M. et al. Clinical Outcomes of Early Treatment With Doxycycline for 89 High-Risk COVID-19 Patients in Long-Term Care Facilities in New York. Cureus. 2020; 12 (8): e9658. DOI: 10.7759/cureus.9658
  33. Zhou M., Zhang X., Qu J. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med. 2020; 14 (2): 126–35. DOI: 10.1007/s11684-020-0767-8
  34. 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 [Khavinson V.Kh., Kuznik B.I., Sturov V.G. et al. Application of the drug Timalin® for respiratory diseases. Prospects for use in COVID-19. RMZh. 2020; 9: 24–30 (in Russ.)].
  35. 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
  36. Morozov V.G., Havinson V.H. Vydelenie iz kostnogo mozga, limfotsitov i timusa polipeptidov, regulirujuschih protsessy mezhkletochnoj kooperatsii v sisteme immuniteta. Dokl. AN SSSR. 1981; 261 (1): 235–9 [Morozov V.G., Khavinson V.Kh. Vydelenie iz kostnogo mozga, limfotsitov i timusa polipeptidov, reguliruyushchikh protsessy mezhkletochnoi kooperatsii v sisteme immuniteta. Dokl. AN SSSR. 1981; 261 (1): 235–9 (in Russ.)].
  37. Morozov V.G., Havinson V.H., Malinin V.V. Peptidnye timomimetiki. SPb: Nauka, 2000; 157 s. [Morozov V.G., Khavinson V.Kh., Malinin V.V. Peptidnye timomimetiki. SPb: Nauka, 2000; 157 s. (in Russ.)].
  38. Morozov V.G., Havinson V.H. Vydelenie, ochistka i identifikatsija immunomodulirujuschego polipeptida, soderzhaschegosja v timuse teljat i cheloveka. Biohimija. 1981; 46 (9): 1652–9 [Morozov V.G., Khavinson V.H. Isolation, purification and identification of immunomodulating polypeptide contained in the thymus of calves and humans. Biochemistry. 1981; 46 (9): 1652–9 (in Russ.)].
  39. Havinson V.H., Kuznik B.I., Ryzhak G.A. Peptidnye geroprotektory – epigeneticheskie reguljatory fiziologicheskih funktsij organizma. SPb: Iz-vo RGPU im. I.A Gertsena, 2014; 279 s. [Khavinson V.R., Kuznik B.I., Ryzhak G.A. Peptide geroprotectors-epigenetic regulators of physiological functions of the body. Saint-Petersburg: Publish. Herzen`s RSPU, 2014; 279 p. (in Russ.)].
  40. 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., Likhanov I.D., Tsepelev V.L. et al. Theoretical and clinical aspects of bioregulatory therapy in surgery and traumatology. Novosibirsk: Nauka, 2008; 312 p. (in Russ.)].
  41. Vremennye metodicheskie rekomendatsii. Diagnostika, profilaktika i lechenie novoj koronavirusnoj infektsii (COVID-19). Versija 7 (03.06.2020). M., 2020; 165 s. [Vremennye metodicheskie rekomendacii. Diagnostika, profilaktika i lechenie novoj koronavirusnoj infekcii (COVID-19). Versija 7 (03.06.2020). M., 2020; 165 s. (in Russ.)].
  42. Marfella R., Paolisso P., Sardu C. et al. Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients. Diabetes Metab. 2020; S1262-3636. DOI: 10.1016/j.diabet.2020.05.005