IMMUNOPATHOGENETIC BASES OF SEVERITY OF COVID-19. LITERATURE REVIEW
Relevance. The outbreak of COVID-19 began in late 2019 in Hubei Province, China. Already in the first quarter of 2020, the disease spread around the world. On March 11, 2020, WHO declared a COVID-19 pandemic. The first cases of the disease in Kazakhstan were registered in March 2020. The aim of the study: a systematic search for scientific information about the socially significant disease COVID-19 and its immunopathogenetic basis for the severity of the course. Search strategy: Research publications were searched in PubMed, ResearchGate, GoogleScholar databases. A total of 325 literary sources were found, of which 89 were selected for analysis. Results: To date, clinical experience suggests a wide range of clinical manifestations of COVID-19 from asymptomatic to severe disease with poor survival associated with an aggressive inflammatory response. There is clinical evidence that suggests that cytokine storm is associated with the severity of COVID-19 and is also the leading cause of death. Hyperactivation of the immune system during COVID-19 leads to a sharp increase in the levels of pro-inflammatory cytokines - a cytokine storm that is characterized by systemic inflammation, hyperferritinemia, acute respiratory distress syndrome, systemic inflammatory response syndrome, hemodynamic disturbances, thrombosis, disseminated intravascular coagulation, lung damage and others. organs, multiple organ failure with a poor prognosis. Conclusion. The cytokine storm caused by SARS-CoV-2 infection is a central mediator of lung damage and, as a result, can cause life-threatening complications. We present several leukocyte and cytokine changes that may help determine the progression and severity of COVID-19 from early to advanced in both mild and severe cases.
Assiya A. Yessenbayeva1, Zhanna B. Mussazhanova2,3, Maksut S. Kazymov1, Bakytbek A. Apsalikov1, Dastan N. Saidualiev1, Gulnar M. Shalgumbayeva1, Zhanna U. Kozykenova1, Ainur S. Krykpayeva1, Meruert O. Khamitova4, Meruyert R. Massabayeva1 1 NJSC "Semey Medical University", Semey, Republic of Kazakhstan; 2 Nagasaki University, Department of Tumor and Diagnostic Pathology, Nagasaki, Japan; 3 High Medical School, Faculty of Medicine and Health Care, Al Farabi Kazakh National University, Almaty, Republic of Kazakhstan; 4 NJSC "Astana Medical University", Nur-Sultan, Republic of Kazakhstan.
1. Amanat F., Krammer F. SARS‐CoV‐2 Vaccines: Status Report // Immunity. 2020: 52(4): 583–589. 10.1016/j.immuni.2020.03.007. 2. Anant Parasher. COVID-19: Current understanding of its pathophysiology, clinical presentation and treatment // Postgraduate Medical Journal. 2020-09-25. 25. doi: 10.1136/postgradmedj-2020-138577. 3. Andrew G. Harrison, Tao Lin, Penghua Wang. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis // Trends in Immunology. 2020. 1 December (vol. 41, iss. 12). P. 1100–1115. — ISSN 1471-4981 1471-4906, 1471-4981. doi: 10.1016/j.it.2020.10.004. 4. Borrok M.J., Luheshi N.M., Beyaz N., et al. Enhancement of antibody‐dependent cell‐mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding // mAbs. 2015;7:743‐751. 5. Cameron M.J., Bermejo-Martin J.F., Danesh A., et al. Human immunopathogenesis of severe acute respiratory syndrome (SARS) // Virus Res. (2008). 133:13–9. 10.1016/j.virusres.2007.02.014. 6. Caricchio R., Gallucci M., Dass C., et al. Preliminary predictive criteria for COVID-19 cytokine storm // Ann Rheum Dis 2020. September 25 (Epub ahead of print). 7. Channappanavar R., Fehr AR., Zheng J., et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes // J Clin Invest. 2019. 129:3625–39. 10.1172/JCI126363. 8. Channappanavar R., Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology // SeminImmunopathol. 2017;39:529‐539. 9. Chatenoud L., Ferran C., Reuter A., et al. Systemic reaction to the anti‐T‐cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon‐gamma // N Engl J Med. 1989;320:1420‐1421. 10. Chen G., Wu D., Guo W., et al. Clinical and immunological features of severe and moderate coronavirus disease 2019 // J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244. 11. Chen L., Liu H., Liu W., Liu J., et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia // ZhonghuaJie He He Hu Xi ZaZhi. (2020) 43:203–8. 10.3760/cma.j.issn.1001-0939.2020.0005 12. 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. 10.1016/S0140-67362030211-7. 13. Chen Y., Liu Q., Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis // J. Med. Virol. 2020;92:418–423. doi: 10.1002/jmv.25681. 14. Chen Z., John Wherry E. T cell responses in patients with COVID-19 // Nat. Rev. Immunol. 2020;20:529–536. 15. Chien J.Y., Hsueh P.R, Cheng W.C., et al. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome // Respirology. (2006) 11:715–22. 10.1111/j.1440-1843.2006.00942. 16. Cifaldi L., Prencipe G., Caiello I., et al. Inhibition of natural killer cell cytotoxicity by interleukin‐6: implications for the pathogenesis of macrophage activation syndrome // Arthritis Rheumatol. 2015;67:3037‐3046. 17. Clinical protocol for diagnosis and treatment «COVID-19» Ministry of Health of the Republic of Kazakhstan protocol №106 July 15, 2020 https://online.zakon.kz/Document/doc_id=35690987&pos=6;-108#pos=6;-108. 18. Coperchini F., Chiovato L., Croce L., et al. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system // Cytokine Growth Factor Rev. (2020) 53:1–8. 10.1016/j.cytogfr.2020.05.003. 19. Del Valle DM., Kim Schulze S., Huang HH., et al. An inflammatory cytokine signature predicts COVID-19 severity and survival // NatMed 2020;26:1636-1643. 20. Diao B., Wang C., Tan Y., et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19) // Front Immunol. (2020) 2019:1–14. 10.3389/fimmu.2020.00827. 21. Dina R.,Haitham S. E., Mohamed T, Rasha K., et all. The COVID-19 Cytokine Storm; What We Know So Far // Front. Immunol. 16 June 2020. https://doi.org/10.3389/fimmu.2020.01446 22. Faure E., Poissy J., Goffard A., et al. Distinct immune response in two MERS‐CoV‐infected patients: can we go from bench to bedside. // PLoS One. 2014;9:e88716. 23. Fogarty H., Townsend L., Ni Cheallaigh C., et al. COVID‐19 coagulopathy in Caucasian patients // Br J Haematol. 2020. 24. Gao Y., Li T., Han M., Li X., et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19 // J Med Virol. (2020) 92:791–6. 10.1002/jmv.25770. 25. Haagmans BL., et al. Middle East respiratory syndrome coronavirus in dromedary camels: An outbreak investigation // Lancet Infect. Dis. 2014;14:140–145. doi: 10.1016/S1473-3099(13)70690-X. 26. Hu W., Yen YT., Singh S., et al. SARS-CoV regulates immune function-related gene expression in human monocytic cells // Viral Immunol. (2012) 25:277–88. 10.1089/vim.2011.0099. 27. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. 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. 28. Huang Y., Yang R., Xu Y., Gong P. Clinical characteristics of 36 non‐survivors with COVID‐19 in Wuhan, China // Lancet. 2020.28(10229):1054‐1062. 395. 29. Hunter C.A., Jones S.A. IL-6 as a keystone cytokine in health and disease // Nat Immunol. 2015;16(5):448–457. doi: 10.1038/ni.3153. 30. Jin W., Mengmeng J, Xin C, Luis J. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts // J Leukoc Biol. 2020 Jul;108(1):17-41. doi: 10.1002/JLB.3COVR0520-272R. Epub 2020 Jun 13. 31. Josset L., Menachery V.D., Gralinski L.E. et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus // mBio. 2013.4:e00165‐13. 32. Kemmian D., Christen H, John K. C, et all. Pulmonary and Extra-Pulmonary Clinical Manifestations of COVID-19 // Front. Med., 13 August 2020 | https://doi.org/10.3389/fmed.2020.00526 33. Kerr R., Stirling D., Ludlam C.A. Interleukin 6 and haemostasis // Br J Haematol. 2001.115:3‐12. 34. Kong S.L., Chui P., Lim B., Salto-Tellez M. Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients // Virus Res. 2009. 145:260–9. 10.1016/j.virusres.2009.07.014. 35. Korber B., Fischer W.M., Gnanakaran S. et al. Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 // virus. Cell. 2020;182:812–827. 36. Lai C., Shih T., Ko W. et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges // Int J Antimicrob Agents. 2020. 55:105924. 10.1016/j.ijantimicag.2020.105924. 37. Lau SKP., Lau CCY., Chan K.H. et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment // J GenVirol. 2013. 94:2679–90. 10.1099/vir.0.055533-0. 38. Lemoine M., Chevaliez S., Bastard J.P. et al. Association between IL28B polymorphism, TNFα and biomarkers of insulin resistance in chronic hepatitis C‐related insulin resistance // Journal of viral hepatitis. 2015. Vol.22, №11. Р.890-896. 39. Leonard K., Christian L., Daniel G., et all. Treatment of cytokine storm syndrome with IL-1 receptor antagonist anakinra in a patient with ARDS caused by COVID-19 infection: A case report // Clin Case Rep. 2020 Sep 15;8(12):2990-2994. doi: 10.1002/ccr3.3307. eCollection 2020 Dec. 40. Li H., Liu S.M., Yu X.H., Tang C.L., Tang C.K. Coronavirus disease 2019 (COVID-19): current status and future perspectives // Int. J. Antimicrobial Agents. 2020:105951. doi: 10.1016/j.ijantimicag.2020.105951. 41. Li L., Chen M.X. Critical patients with coronavirus disease 2019: risk factors and outcome nomogram // J InfSecur. 2020. 80(6):e37–e38. doi: 10.1016/j.jinf.2020.03.025. 42. Li T., Xie J., He Y., et al. Long‐term persistence of robust antibody and cytotoxic T cell responses in recovered patients infected with SARS coronavirus // PLoS One. 2006;1:e24. 43. Li X., Geng M., Peng Y., Meng L., Lu S. Molecular immune pathogenesis and diagnosis of COVID-19 // J. Pharm. Analysis. 2020 doi: 10.1016/j.jpha.2020.03.001. 44. Lin L., Lu L., Cao W., Li T. 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):727–732. doi: 10.1080/22221751.2020.1746199. 45. Liu Y., Zhang C., Huang F. et al. Elevated plasma level of selective cytokines in COVID‐19 patients reflect viral load and lung injury // NatlSci Rev. 2020. 10.1093/nsr/nwaa037. 46. Lu R., Zhao X., Li J. et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding // Lancet. 2020;395:565–574. 47. Mathew D., Giles JR., Baxter AE. et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications // Science 2020;369(6508):eabc8511-eabc8511. 48. Mehta P., Mcauley DF., Brown M. et al. COVID-19: consider cytokine storm syndromes and immunosuppression // Lancet. 2020 6736:19–20. 10.1016/S0140-6736(20)30628-0. 49. Ng DL., Al Hosani F., Keating MK. et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of middle east respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014 // Am J Pathol. 2016 186:652–8. 10.1016/j.ajpath.2015.10.024. 50. Nicastri E., D’Abramo A., Faggioni G., De Santis R., Mariano A., Lepore L. Coronavirus disease (COVID-19) in a paucisymptomatic patient: epidemiological and clinical challenge in settings with limited community transmission, Italy, 2020 // Euro Surveill. 2020. 25(11) doi: 10.2807/1560-7917. 51. Pain CE., Felsenstein S., Cleary G., Mayell S., Conrad K. et al. Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms // Lancet Rheumatol. 2020. 2:19–21. 10.1016/s2665-9913(20)30137-5. 52. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis // J Thromb Haemost. 2020;18(7):1738-1742. doi:10.1111/jth.14850 53. Patterson B.K., Seethamraju H., Dhody K. et al. Disruption of the CCL5/RANTES‐CCR5 pathway restores immune homeostasis and reduces plasma viral load in critical COVID‐19 // medRxiv. 10.1101/2020.05.02.20084673. 2020.05.02.20084673. 54. Paules C.I., Marston H.D., Fauci A.S. Coronavirus infections—more than just the common cold // JAMA. 2020. 323(8):707–708. 55. Peng Y., Mentzer A.J., Liu G. et al. T.C.C. Oxford Immunology Network Covid-19 Response, I.C. Investigators Broad and strong memory CD4(+) and CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19 // Nat. Immunol. 2020.21:1336–1345. 56. Qian Z., Travanty E.A., Oko L. et al. Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome‐coronavirus // Am J Respir Cell Mol Biol. 2013;48:742‐748. 57. Rothan H.A., Siddappa N., Byrareddy S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak // J. Autoimmun. 2020. 109 doi: 10.1016/j.jaut.2020.102433. 58. Ruan Q., Yang K., Wang W., Jiang L., Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China // Intensive Care Med. 2020. 46:846–8. 10.1007/s00134-020-06028-z. 59. Shi Y., Wang Y., Shao C. COVID-19 infection: the perspectives on immune responses // Cell Death Differ. 2020. 27:1451–1454. doi: 10.1038/s41418-020-0530-3. 60. Shimizu M. Clinical features of cytokine storm syndrome. In: Cron R, Behrens E. Editors. CytokineStormSyndrome // Cham: Springer. 2019. 31–42. 10.1007/978-3-030-22094-5_3. 61. Тanaka T., Narazaki M., Kishimoto T. IL-6 in inflammation, immunity, and disease // Cold Spring Harb Perspect Biol. 2014. 4doi: 10.1101/cshperspect.a016295. 6(10):a016295. 62. Terpos E., Ntanasis-Stathopoulos I., Elalamy I., et al. Hematological findings and complications of COVID-19 // Am J Hematol. 10.1002/ajh.25829 Online ahead of print. 63. Tisoncik J.R., Korth M.J., Simmons C.P., Farrar J., Martin T.R., Katze M.G. Into the eye of the cytokine storm // Microbiol. Mol. Biol. Rev. 2012. 76:16–32. doi: 10.1128/MMBR.05015-11. 64. Toubiana J., Poirault C., Corsia A., Bajolle F. et al. Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France // medRxiv. 2020. 1–21. 10.1101/2020.05.10.20097394. 65. Tregoning J.S., Brown E.S., Cheeseman H.M., Flight K.E., Higham S.L, et al. Vaccines for COVID-19 // ClinExpImmunol. 2020. Ноя., 202(2):162-192. doi: 10.1111/cei.13517. Epub 2020 18 октября. PMID: 32935331; PMCID: PMC7597597. 66. Vibhuti Kumar., Priyanka F., et all. Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past // Front. Immunol. 07 August 2020. https://doi.org/10.3389/fimmu.2020.01949 67. Wang G., Cao K., Liu K., et al. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells // Cell Death Differ. 2018. 25:1209–1223. doi: 10.1038/s41418-017-0006-2. 68. Wang W.J., He J.X., Lie P.Y. et al. The definition and risks of cytokine release syndrome‐like in 11 COVID‐19‐infected pneumonia critically ill patients: disease characteristics and retrospective analysis // medRxiv. 10.1101/2020.02.26.20026989. 2020.02.26.20026989. 69. Wang Y., Chen X., Cao W., Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications // Nat. Immunol. 2014. 15:1009–1016. doi: 10.1038/ni.3002. 70. Weingartl H., Czub M., Czub S., Neufeld J., Marszal P. et al. Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets // JVirol. 2004. 78:1267–6. doi: 10.1128/JVI.78.22.12672-12676.2004. 71. Weissman D., Alameh M.G., de Silva T., Collini P., et al. Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization // Cell Host & Microbe. 2020 doi: 10.1016/j.chom.2020.11.012. In press. 72. Wen W., Su WR., Tang H, et al. Immune cell profiling of COVID‐19 patients in the recovery stage by single‐cell sequencing // Cell Discov. 2020. 6:31. 73. Wen Zhang., Yan Zhao., Fengchun Zhang., Qian Wang., Taisheng Li, Zhengyin Liu, et al. Anti-inflammation treatment of severe coronavirus disease 2019 (COVID-19): from the perspective of clinical immunologists from China // ClinImmunol. 2020 214:108393. 10.1016/j.clim.2020.108393. 74. Wong CK., Lam CWK., Wu AKL., Ip WK., Lee NLS., et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome // ClinExpImmunol. (2004) 136:95–103. 10.1111/j.1365-2249.2004.02415.x 75. Wu D., Yang XO. TH17 responses in cytokine storm of COVID‐19: an emerging target of JAK2 inhibitor Fedratinib // J MicrobiolImmunol Infect. 2020;53:368‐370. 76. Wu F., Zhao S., Yu B., et al. A new coronavirus associated with human respiratory disease in China // Nature. 2020;579:265‐269. 77. Xiong Y., Liu Y., Cao L., Wang D., et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients // Emerg Microbes Infect. (2020) 9:761–70. 10.1080/22221751.2020.1747363. 78. Xu Z., Shi L., Wang Y., et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome // LancetRespirMed. 2020;8(4):420–422. 79. Yao X., Li T., He Z., Ping Y., et al. A pathological report of three COVID-19 cases by minimally invasive autopsies // Zhonghuabing li xuezazhi Chin J Pathol. 2020;49(0):E009. doi: 10.3760/cma.j.cn112151-20200312-00193. 80. Yu H.Q., Sun B.Q., Fang Z.F., et al. Distinct features of SARS-CoV-2-specific Ig A responsein COVID-19 patients. // Eur. Respir. J. 2020;56. 81. Zhang B., Zhou X., Qiu Y., et al. Clinical characteristics of 82 death cases with COVID‐19 // medRxiv. doi: 10.1101/2020.02.26.20028191. 2020.02.26.20028191. 82. Zhang B., Zhou X., Zhu C., Feng F. et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19 // medRxiv. 10.1101/2020.03.12.20035048. 83. Zhang S., Gan J., Chen BG. et al. Dynamics of peripheral immune cells and their HLA-G and receptor expressions in a patient suffering from critical COVID-19 pneumonia to convalescence // ClinTransl Immunology. 2020 May 10;9(5):e1128. doi: 10.1002/cti2.1128. 84. Zhang W., Zhao Y., Zhang F., Wang Q., Li T., et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the experience of clinical immunologists from China // Clin Immunol:108393. 85. ZhangYan., XiaoMeng, ZhangShulan., et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 // New England Journal of Medicine. 2020;382(17):e38. 86. Zhao Z., Xie J., Yin M., et al. Clinical and laboratory profiles of 75 hospitalized patients with novel coronavirus disease 2019 in Hefei, China // medRxiv. 10.1101/2020.03.01.20029785. 2020.03.01.20029785. 87. Zhe Xu., Lei Shi., Yijin Wang, Jiyuan Zhang, Lei Huang, Chao Zhang, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome // Lancet. Respir Med. 2020. 8:420–2. 10.1016/S2213-2600(20)30076-X. 88. Zhou J., Chu H., Li C., Wong BHY, et al. Active replication of middle east respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis // J Infect Dis. 2014. 209:1331–42. 10.1093/infdis/jit504. 89. Zhou P., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin // Nature. 2020. 579:270–273. doi: 10.1038/s41586-020-2012-7. 90. Zhou Y., Fu B., Zheng X., Wang D., Zhao C., Qi Y, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients // NatlSci Rev. 2020. 7:1–5. 10.1093/nsr/nwaa041. 91. Zhu N., et al. A novel coronavirus from patients with pneumonia in China, 2019 // N. Engl. J. Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017. 92. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., Zhao X., et al. A novel coronavirus from patients with pneumonia in China, 2019 // N. Engl. J. Med. 2020. 382:727–733. 93. Zost S.J., Gilchuk P., Case J.B., et al. Potently neutralizing and protective human antibodies against SARS-CoV-2 // Nature. 2020;584:443–449. 94. Zou Y., Guo H.Y., Zhang Y.Y, et al. Analysis of coagulation parameters in patients with COVID‐19 in Shanghai, China // Biosci Trends. 2020;14(4):285-289. doi:10.5582/bst.2020.03086
Количество просмотров: 336

Ключевые слова:

Библиографическая ссылка

Yessenbayeva A.A., Mussazhanova Zh.B., Kazymov M.S., Apsalikov B.A., Saidualiev D.N., Shalgumbayeva G.M., Kozykenova Zh.U., Krykpayeva A.S., Khamitova M.O., Massabayeva M.R. Immunopathogenetic bases of severity of COVID-19. Literature review // Nauka i Zdravookhranenie [Science & Healthcare]. 2022, (Vol.24) 2, pp. 93-102. doi 10.34689/SH.2022.24.2.012

Авторизируйтесь для отправки комментариев