nmpЖурнал им. Н.В. Склифосовского «Неотложная медицинская помощь»Russian Sklifosovsky Journal "Emergency Medical Care"2223-90222541-8017“N.V. Sklifosovsky Research Institute for Emergency Medicine”10.23934/2223-9022-2023-12-1-122-129nmp-1578Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSОсобенности иммунного ответа при COVID-19Features of the Immune Response in COVID-19https://orcid.org/0000-0003-0296-5538ИнюткинаА. А.InyutkinaA. A.

Инюткина Алиса Андреевна, младший научный сотрудник; старший лаборант кафедры

129090, Москва, Б. Сухаревская пл., д. 3

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1

Alisa A. Inyutkina, Junior Researcher; Senior Laboratory, Assistant of the Department

3 Bolshaya Sukharevskaya Sq., Moscow, 129090

2/1, bldg. 1, Barrikadnaya Str., Moscow, 125993

alisa.inyutkina@yandex.ruhttps://orcid.org/0000-0001-6811-6809НикулинаВ. П.NikulinaV. P.

Никулина Валентина Петровна, кандидат медицинских наук, старший научный сотрудник

129090, Москва, Б. Сухаревская пл., д. 3

Valentina P. Nikulina, Candidate of Medical Sciences, Senior Researcher

3 Bolshaya Sukharevskaya Sq., Moscow, 129090

sa-to@yandex.ruhttps://orcid.org/0000-0001-9612-6705ГодковМ. А.GodkovM. A.

Годков Михаил Андреевич, доктор медицинских наук, руководитель отдела лабораторной диагностики

129090, Москва, Б. Сухаревская пл., д. 3

125993, Москва, ул. Баррикадная, д. 2/1, стр. 1

Michail A. Godkov, Doctor of Medical Sciences, Head of the Department; Head of the Department

3 Bolshaya Sukharevskaya Sq., Moscow, 129090

2/1, bldg. 1, Barrikadnaya Str., Moscow, 125993

mgodkov@yandex.ruЛаборатория клинической иммунологии, ГБУЗ «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского ДЗМ»; ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФРоссияLaboratory of Clinical Immunology, N.V. Sklifosovsky Research Institute for Emergency Medicine; Russian Medical Academy of Continuous Professional EducationRussian FederationЛаборатория клинической иммунологии, ГБУЗ «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского ДЗМ»РоссияN.V. Sklifosovsky Research Institute for Emergency MedicineRussian Federation202317042023121122129Copyright © Инюткина А.А., Никулина В.П., Годков М.А., 20232023Инюткина А.А., Никулина В.П., Годков М.А.Inyutkina A.A., Nikulina V.P., Godkov M.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jnmp.ru/jour/article/view/1578

АКТУАЛЬНОСТЬ Данный обзор посвящен анализу особенностей иммунного ответа при COVID-19. В обзоре указаны клинические проявления COVID-19, рассмотрены современные данные об иммунопатогенезе заболевания и его осложнений.

ЦЕЛЬ Прояснить некоторые патогенетические механизмы иммунного ответа при COVID-19, что может помочь в создании алгоритма обследования пациентов для раннего прогноза и профилактики тяжелого течения и осложнений заболевания.

МАТЕРИАЛ И МЕТОДЫ Для достижения поставленной цели были проанализированы результаты отечественных и зарубежных научных исследований, посвященных патогенезу, диагностике и лечению COVID-19. Поиск литературы проводился в электронных поисковых системах Scopus и PubMed. Для анализа были отобраны научные статьи, опубликованные в период с 2019 по 2021 год; 88% проанализированных работ не старше 5 лет.

ЗАКЛЮЧЕНИЕ Наибольшее значение для развития тяжелой формы COVID-19 имеет поздняя продукция IFN типа I, повышение уровня в крови провоспалительных моноцитов, снижение экспрессии HLA-DR на моноцитах, нарушение презентации вируса и формирования специфических лимфоцитов, гибель Т-лимфоцитов и глубокая иммуносупрессия.

BACKGROUND This review is devoted to the analysis of the features of the immune response in COVID-19. The review indicates the clinical manifestations of COVID-19, modern data on the immunopathogenesis of the disease and its complications are considered.

Aim of STUDY To clarify some pathogenetic mechanisms of the immune response in COVID-19, which can help in creating an algorithm for examining patients for early prognosis and prevention of severe course and complications of the disease.

MATERIAL AND METHODS To achieve this goal, the results of domestic and foreign scientific studies on the pathogenesis, diagnosis and treatment of COVID-19 were analyzed. The literature search was carried out in electronic search engines Scopus and PubMed. For the analysis, scientific articles published in the period from 2019 to 2021 were selected; 88% of analyzed works are not older than 5 years.

CONCLUSION The late production of type I IFN, an increase in the level of pro-inflammatory monocytes, a decrease in the expression of HLA-DR on monocytes, violation of the presentation of the virus and the formation of specific lymphocytes, the death of T-lymphocytes and profound immunosuppression are of greatest importance for the development of a severe form of COVID-19.

COVID-19«цитокиновый шторм»антигенпрезентирующие клеткимоноцитыHLA-DRТ-лимфоцитыILIFNCOVID-19cytokine stormantigen-presenting cellsmonocytesHLA-DRT-lymphocytesILIFNReferencesZhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–733. PMID: 31978945 https://doi.org/10.1056/ NEJMoa2001017Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–733. PMID: 31978945 https://doi.org/10.1056/ NEJMoa2001017WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19 – 11 March 2020. Available at: https://www.who.int/directorgeneral/speeches/detail/who-director-general-s-opening-remarks-atthe-media-briefing-on-covid-19---11-march-2020 [Accessed January 21, 2022].WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19 – 11 March 2020. Available at: https://www.who.int/directorgeneral/speeches/detail/who-director-general-s-opening-remarks-atthe-media-briefing-on-covid-19---11-march-2020 [Accessed Jan 21, 2022].van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564–1567. PMID: 32182409 https://doi.org/10.1056/NEJMc2004973van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564–1567. PMID: 32182409 https://doi.org/10.1056/NEJMc2004973Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol. 2020;94(7):e00127–20. PMID: 31996437 https:// doi.org/10.1128/JVI.00127-20Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol. 2020;94(7):e00127-20. PMID: 31996437 https:// doi.org/10.1128/JVI.00127-20Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280.e8. PMID: 32142651 https://doi.org/10.1016/ j.cell.2020.02.052Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280.e8. PMID: 32142651 https://doi.org/10.1016/ j.cell.2020.02.052Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9(1):558–570. PMID: 32172672 https://doi.org/10.1080/22221751 .2020.1736644Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020;9(1):558–570. PMID: 32172672 https://doi.org/10.1080/22221751 .2020.1736644Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. PMID: 32091533 https:// doi.org/10.1001/jama.2020.2648Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. PMID: 32091533 https:// doi.org/10.1001/jama.2020.2648Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054– 1062. PMID: 32171076 https://doi.org/10.1016/S0140-6736(20)30566-3Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054– 1062. PMID: 32171076 https://doi.org/10.1016/S0140-6736(20)30566-3Cavalcante-Silva LHA, Carvalho DCM, Lima ÉA, Galvão JGFM, da Silva JSF, Sales-Neto JM, et al. Neutrophils and COVID-19: The road so far. Int Immunopharmacol. 2021;90:107233. PMID: 33290963 https://doi. org/10.1016/j.intimp.2020.107233Cavalcante-Silva LHA, Carvalho DCM, Lima ÉA, Galvão JGFM, da Silva JSF, Sales-Neto JM, et al. Neutrophils and COVID-19: The road so far. Int Immunopharmacol. 2021;90:107233. PMID: 33290963 https://doi. org/10.1016/j.intimp.2020.107233Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19): временные методические рекомендации. Версия 13.1 (17.11.2021). Москва; 2021.Profilaktika, diagnostika i lechenie novoy koronavirusnoy infektsii (COVID19): vremennye metodicheskie rekomendatsii. Ed. 13.1 (17.11.2021). Moscow, 2021. (In Russ.).van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. Presence of Genetic Variants Among Young Men with Severe COVID-19. JAMA. 2020;324(7):663–673. PMID: 32706371 https://doi.org/10.1001/jama.2020.13719van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. Presence of Genetic Variants Among Young Men with Severe COVID-19. JAMA. 2020;324(7):663–673. PMID: 32706371. https://doi.org/10.1001/jama.2020.13719Zhu J, Mohan C. Toll-Like receptor signaling pathways—therapeutic opportunities. Mediators Inflamm. 2010;2010:781235. PMID: 20981241 https://doi.org/10.1155/2010/781235Zhu J, Mohan C. Toll-Like receptor signaling pathways—therapeutic opportunities. Mediators Inflamm. 2010;2010:781235. PMID: 20981241 https://doi.org/10.1155/2010/781235Knoll R, Schultze JL, Schulte-Schrepping J. Monocytes and Macrophages in COVID-19. Front Immunol. 2021;12:720109. PMID: 34367190https:// doi.org/10.3389/fimmu.2021.720109Knoll R, Schultze JL, Schulte-Schrepping J. Monocytes and Macrophages in COVID-19. Front Immunol. 2021;12:720109. PMID: 34367190. https:// doi.org/10.3389/fimmu.2021.720109Долгов В.В. (ред.) Клиническая лабораторная диагностика: в 2-х т. Т. 1. Москва: Лабдиаг; 2017.Dolgov VV (ed.). Klinicheskaya laboratornaya diagnostika: in 2 vol. Vol. 1. Moscow: Labdiag Publ.; 2017. (in Russ.)Chowdhury MA, Hossain N, Kashem MA, Shahid MA, Alam A. Immune response in COVID-19: A review. J Infect Public Health. 2020;13(11):1619– 1629. PMID: 32718895 https://doi.org/10.1016/j.jiph.2020.07.001Chowdhury MA, Hossain N, Kashem MA, Shahid MA, Alam A. Immune response in COVID-19: A review. J Infect Public Health. 2020;13(11):1619- 1629. PMID: 32718895 https://doi.org/10.1016/j.jiph.2020.07.001Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev. 2020;7(6):998–1002. PMID: 34676125 https://doi.org/10.1093/nsr/nwaa041Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev. 2020;7(6):998–1002. PMID: 34676125 https://doi.org/10.1093/nsr/nwaa041Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One. 2017;12(4):e0176460. PMID: 28445506 https://doi.org/0.1371/journal.pone.0176460Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One. 2017;12(4):e0176460. PMID: 28445506 https://doi.org/0.1371/journal.pone.0176460Zhuang Y, Peng H, Chen Y, Zhou S, Chen Y. Dynamic monitoring of monocyte HLA-DR expression for the diagnosis, prognosis, and prediction of sepsis. Front Biosci (Landmark Ed). 2017;22:1344–1354. PMID: 28199206 https://doi.org/10.2741/4547Zhuang Y, Peng H, Chen Y, Zhou S, Chen Y. Dynamic monitoring of monocyte HLA-DR expression for the diagnosis, prognosis, and prediction of sepsis. Front Biosci (Landmark Ed). 2017;22:1344–1354. PMID: 28199206 https://doi.org/10.2741/4547Napoli C, Benincasa G, Criscuolo C, Faenza M, Liberato C, Rusciano M. Immune reactivity during COVID-19: Implications for treatment. Immunol Lett. 2021;231:28–34. PMID: 33421440 https://doi.org/10.1016/ j.imlet.2021.01.001Napoli C, Benincasa G, Criscuolo C, Faenza M, Liberato C, Rusciano M. Immune reactivity during COVID-19: Implications for treatment. Immunol Lett. 2021;231:28–34. PMID: 33421440 https://doi.org/10.1016/ j.imlet.2021.01.001Monneret G, Gossez M, Aghaeepour N, Gaudilliere B, Venet F. How Clinical Flow Cytometry Rebooted Sepsis Immunology. Cytometry A. 2019;95(4):431–441. PMID: 30887636 https://doi.org/10.1002/cyto. a.23749Monneret G, Gossez M, Aghaeepour N, Gaudilliere B, Venet F. How Clinical Flow Cytometry Rebooted Sepsis Immunology. Cytometry A. 2019;95(4):431–441. PMID: 30887636 https://doi.org/10.1002/cyto. a.23749Ohno Y, Kitamura H, Takahashi N, Ohtake J, Kaneumi S, Sumida K, et al. IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. Cancer Immunol Immunother. 2016;65(2):193–204. PMID: 26759006 https://doi.org/10.1007/s00262-015-1791-4Ohno Y, Kitamura H, Takahashi N, Ohtake J, Kaneumi S, Sumida K, et al. IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. Cancer Immunol Immunother. 2016;65(2):193–204. PMID: 26759006 https://doi.org/10.1007/s00262-015-1791-4Fu B, Xu X, Wei H.Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18(1):164. PMID: 32290839 https://doi.org/10.1186/s12967-020-02339-3Fu B, Xu X, Wei H.Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18(1):164. PMID: 32290839 https://doi.org/10.1186/s12967-020-02339-3Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992–1000.e3. PMID: 32320677 https://doi.org/10.1016/ j.chom.2020.04.009Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27(6):992–1000.e3. PMID: 32320677 https://doi.org/10.1016/ j.chom.2020.04.009Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes. Life Sci. 2021;269:119010. PMID: 33454368 https://doi.org/10.1016/ j.lfs.2020.119010Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes. Life Sci. 2021;269:119010. PMID: 33454368 https://doi.org/10.1016/ j.lfs.2020.119010Bassler K, Schulte-Schrepping J, Warnat-Herresthal S, Aschenbrenner AC, Schultze JL. The Myeloid Cell Compartment-Cell by Cell. Annu Rev Immunol. 2019;37:269–293. PMID: 30649988 https://doi.org/10.1146/ annurev-immunol-042718-041728Bassler K, Schulte-Schrepping J, Warnat-Herresthal S, Aschenbrenner AC, Schultze JL. The Myeloid Cell Compartment-Cell by Cell. Annu Rev Immunol. 2019;37:269–293. PMID: 30649988 https://doi.org/10.1146/ annurev-immunol-042718-041728Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER, et al. Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases. Front Immunol. 2019;10:2035. PMID: 31543877 https://doi.org/10.3389/fimmu.2019.02035Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER, et al. Human Monocyte Subsets and Phenotypes in Major Chronic Inflammatory Diseases. Front Immunol. 2019;10:2035. PMID: 31543877 https://doi.org/10.3389/fimmu.2019.02035Merino A, Buendia P, Martin-Malo A, Aljama P, Ramirez R. Carracedo J. Senescent CD14+CD16+ Monocytes Exhibit Proinflammatory and Proatherosclerotic Activity. J Immunol. 2011;186(3):1809–1815. PMID: 21191073 https://doi.org/10.4049/jimmunol.1001866Merino A, Buendia P, Martin-Malo A, Aljama P, Ramirez R. Carracedo J. Senescent CD14+CD16+ Monocytes Exhibit Proinflammatory and Proatherosclerotic Activity. J Immunol. 2011;186(3):1809–1815. PMID: 21191073 https://doi.org/10.4049/jimmunol.1001866Васильева Е.Ф., Брусов О.С. Роль моноцитов в клеточно-молекулярных механизмах развития системного иммунного воспаления. Часть 1. Психиатрия. 2020;18(3):76–85. https://doi.org/10.30629/2618- 6667-2020-18-3-76-85Vasilyeva EF, Brusov OS. The Role of Monocytes Cellular and Molecular Mechanisms in the Development of Systemic Immune Inflammation. Part 1. Psikhiatriya. 2020;18(3):76–85. (In Russ.) https://doi. org/10.30629/2618-6667-2020-18-3-76-85.Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82(2):244–52. PMID: 17475785 https://doi.org/10.1189/ jlb.0307191Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82(2):244–252. PMID: 17475785 https://doi.org/10.1189/ jlb.0307191Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–2404. PMID: 28694385 https://doi.org/10.1084/ jem.20162152Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–2404. PMID: 28694385 https://doi.org/10.1084/ jem.20162152Ярилин А.А. Иммунология. Москва: ГЭОТАР-Медиа; 2010.Yarilin AA. Immunologiya. Moscow: GEOTAR-Media Publ.; 2010. (In Russ.).Калашникова А.А., Ворошилова Т.М., Чиненова Л.В., Давыдова Н.И., Калинина Н.М. Субпопуляции моноцитов у здоровых лиц и у пациентов с сепсисом. Медицинская иммунология. 2018;20(6):815– 824.Kalashnikova AA, Voroshilova TM, Chinenova LV, Davydova NI, Kalinina NM. Monocyte subsets in healthy adults and sepsis patients. Medical Immunology (Russia). 2018;20(6):815–824. https://doi. org/10.15789/1563-0625-2018-6-815-824Zhu H, Ding Y, Zhang Y, Ding X, Zhao J, Ouyang W, et al. CTRP3 induces an intermediate switch of CD14++CD16+ monocyte subset with antiinflammatory phenotype. Exp Ther Med. 2020;199(3):2243–2251. PMID: 32104290 https://doi.org/10.3892/etm.2020.8467Zhu H, Ding Y, Zhang Y, Ding X, Zhao J, Ouyang W, et al. CTRP3 induces an intermediate switch of CD14++CD16+ monocyte subset with antiinflammatory phenotype. Exp Ther Med. 2020;199(3):2243–2251. PMID: 32104290 https://doi.org/10.3892/etm.2020.8467Zhu M, Lei L, Zhu Z, Li Q, Guo D, Xu J, et al. Excess TNF-D in the blood activates monocytes with the potential to directly form cholesteryl ester-laden cells. Acta Biochim Biophys Sin (Shanghai). 2015;47(11):899– 907. PMID: 26373842 https://doi.org/10.1093/abbs/gmv092Zhu M, Lei L, Zhu Z, Li Q, Guo D, Xu J, et al. Excess TNF-D in the blood activates monocytes with the potential to directly form cholesteryl ester-laden cells. Acta Biochim Biophys Sin (Shanghai). 2015;47(11):899– 907. PMID: 26373842 https://doi.org/10.1093/abbs/gmv092Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID19. Theranostics. 2021;11(1):316–329. PMID: 33391477 https://doi. org/10.7150/thno.49713Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID19. Theranostics. 2021;11(1):316–329. PMID: 33391477 https://doi. org/10.7150/thno.49713Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–481. PMID: 32105632 https://doi.org/10.1016/S2213- 2600(20)30079-5Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–481. PMID: 32105632 https://doi.org/10.1016/S2213- 2600(20)30079-5Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol. 2020;11:1446. PMID: 32612617 https://doi.org/10.3389/fimmu.2020.01446Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol. 2020;11:1446. PMID: 32612617 https://doi.org/10.3389/fimmu.2020.01446McGonagle D, Sharif K, O’Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537. PMID: 32251717 https://doi.org/10.1016/ j.autrev.2020.102537McGonagle D, Sharif K, O’Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537. PMID: 32251717 https://doi.org/10.1016/ j.autrev.2020.102537Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607–613. PMID: 32283152 https://doi.org/10.1016/j.jinf.2020.03.037Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19. J Infect. 2020;80(6):607–613. PMID: 32283152 https://doi.org/10.1016/j.jinf.2020.03.037Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036–1045.e9. PMID: 32416070 https:// doi.org/10.1016/j.cell.2020.04.026Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R. et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181(5):1036–1045.e9. PMID: 32416070 https:// doi.org/10.1016/j.cell.2020.04.026Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferone activity and inflammatory responses in severe Covid-19 patients. Science. 2020;369(6504):718–724. PMID: 32661059 https://doi.org/10.1126/science.abc6027Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferone activity and inflammatory responses in severe Covid-19 patients. Science. 2020;369(6504):718–724. PMID: 32661059 https://doi.org/10.1126/science.abc6027Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033– 1034. PMID: 32192578 https://doi.org/10.1016/S0140-6736(20)30628-0Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033– 1034. PMID: 32192578 https://doi.org/10.1016/S0140-6736(20)30628-0Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev. 2020;53:66–70. PMID: 32418715 https://doi.org/10.1016/ j.cytogfr.2020.05.002Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev. 2020;53:66–70. PMID: 32418715 https://doi. org/10.1016/j.cytogfr.2020.05.002Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID19. Theranostics. 2021;11(1):316–329. PMID: 33391477 https://doi. org/10.7150/thno.49713Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID19. Theranostics. 2021;11(1):316–329. PMID: 33391477 https://doi. org/10.7150/thno.49713Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol. 2020;92(11):2283–2285. PMID: 32343429 https://doi.org/10.1002/jmv.25948Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol. 2020;92(11):2283–2285. PMID: 32343429 https://doi.org/10.1002/jmv.25948Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. 2020;127:104370. PMID: 32344321 https://doi. org/10.1016/j.jcv.2020.104370Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol. 2020;127:104370. PMID: 32344321 https://doi. org/10.1016/j.jcv.2020.104370Yang P, Ding Y, Xu Z, Pu R, Li P, Yan J, et al. Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. MedRxiv. 2020. Available at: https://www.medrxiv.org/ content/10.1101/2020.02.28.20028068v1 [Accessed January 24, 2022]. https://doi.org/10.1101/2020.02.28.20028068Yang P, Ding Y, Xu Z, Pu R, Li P, Yan J, et al. Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. MedRxiv. 2020. Available at: https://www.medrxiv.org/ content/10.1101/2020.02.28.20028068v1 [Accessed January 24, 2022]. https://doi.org/10.1101/2020.02.28.20028068Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–1130. PMID: 32475230 https://doi.org/10.1080/22221751.2020.1770129Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–1130. PMID: 32475230 https://doi.org/10.1080/22221751.2020.1770129Lu L, Zhang H, Dauphars DJ, He YW A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021;42(1):3–5. PMID: 33214057 https://doi.org/10.1016/j.it.2020.10.012Lu L, Zhang H, Dauphars DJ, He YW A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021;42(1):3–5. PMID: 33214057 https://doi.org/10.1016/j.it.2020.10.012Satış H, Özger HS, Aysert Yıldız P, Hızel K, Gulbahar Ö, Erbaş G, et al. Prognostic value of interleukin-18 and its association with otherinflammatory markers and disease severity in COVID-19. Cytokine. 2021;137:155302. PMID: 33002740 https://doi.org/10.1016/ j.cyto.2020.155302Satış H, Özger HS, Aysert Yıldız P, Hızel K, Gulbahar Ö, Erbaş G, et al. Prognostic value of interleukin-18 and its association with otherinflammatory markers and disease severity in COVID-19. Cytokine. 2021;137:155302. PMID: 33002740 https://doi.org/10.1016/ j.cyto.2020.155302Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, MelguizoRodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62–75. PMID: 32513566 https://doi.org/10.1016/j.cytogfr.2020.06.001Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, MelguizoRodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62–75. PMID: 32513566 https://doi.org/10.1016/j.cytogfr.2020.06.001Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827. PMID: 32425950 https:// doi.org/10.3389/fimmu.2020.00827Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827. PMID: 32425950 https:// doi.org/10.3389/fimmu.2020.00827Pence BD. PenceSevere COVID-19 and aging: are monocytes the key? Geroscience. 2020;42(4):1051–1061. PMID: 32556942 https://doi. org/10.1007/s11357-020-00213-0Pence BD. PenceSevere COVID-19 and aging: are monocytes the key? Geroscience. 2020;42(4):1051–1061. PMID: 32556942 https://doi. org/10.1007/s11357-020-00213-0Zhang F, Gan R, Zhen Z, Hu X, Li X, Zhou F, et al. Adaptive immune responses to SARS-CoV-2 infection in severe versus mild individuals. Signal Transduct Target Ther. 2020;5(1):156. PMID: 32796814 https:// doi.org/10.1038/s41392-020-00263-yZhang F, Gan R, Zhen Z, Hu X, Li X, Zhou F, et al. Adaptive immune responses to SARS-CoV-2 infection in severe versus mild individuals. Signal Transduct Target Ther. 2020;5(1):156. PMID: 32796814 https:// doi.org/10.1038/s41392-020-00263-yWilk AJ, Rustagi A, Zhao NQ, Roque J, Martínez-Colón GJ, McKechnie JL, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med. 2020;26(7):1070–1076. PMID: 32514174 https://doi.org/10.1038/s41591-020-0944-yWilk AJ, Rustagi A, Zhao NQ, Roque J, Martínez-Colón GJ, McKechnie JL, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med. 2020;26(7):1070–1076. PMID: 32514174 https://doi.org/10.1038/s41591-020-0944-yGrant RA, Morales-Nebreda L, Markov NS, Swaminathan S, Querrey M, Guzman ER, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature. 2021;590(7847):635–641. PMID: 33429418 https://doi.org/10.1038/s41586-020-03148-wGrant RA, Morales-Nebreda L, Markov NS, Swaminathan S, Querrey M, Guzman ER, et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature. 2021;590(7847):635–641. PMID: 33429418 https://doi.org/10.1038/s41586-020-03148-wRezaei M, Mahmoudi S, Mortaz E, Marjani M. Immune cell profiling and antibody responses in patients with COVID-19. BMC Infect Dis. 2021;21(1):646. PMID: 34225645 https://doi.org/10.1186/s12879-021- 06278-2Rezaei M, Mahmoudi S, Mortaz E, Marjani M. Immune cell profiling and antibody responses in patients with COVID-19. BMC Infect Dis. 2021;21(1):646. PMID: 34225645 https://doi.org/10.1186/s12879-021- 06278-2López-Collazo E, Avendaño-Ortiz J, Martín-Quirós A, Aguirre LA. Immune Response and COVID-19: A mirror image of Sepsis. Int J Biol Sci. 2020;16(14):2479–2489. PMID: 32792851 https://doi.org/10.7150/ ijbs.48400López-Collazo E, Avendaño-Ortiz J, Martín-Quirós A, Aguirre LA. Immune Response and COVID-19: A mirror image of Sepsis. Int J Biol Sci. 2020;16(14):2479–2489. PMID: 32792851 https://doi.org/10.7150/ ijbs.48400Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021;184(1):149–168.e17. PMID: 33278357 https://doi.org/10.1016/j.cell.2020.11.025Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, et al. Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021;184(1):149–168.e17. PMID: 33278357 https://doi.org/10.1016/j.cell.2020.11.025Anka AU, Tahir MI, Abubakar SD, Alsabbagh M, Zian Z, Hamedifar H, et al. Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management. Scand J Immunol. 2021;93(4):e12998. PMID: 33190302 https://doi.org/10.1111/ sji.12998Anka AU, Tahir MI, Abubakar SD, Alsabbagh M, Zian Z, Hamedifar H, et al. Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management. Scand J Immunol. 2021;93(4):e12998. PMID: 33190302 https://doi.org/10.1111/ sji.12998Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, et al. Targets of T cell responses to SARS-CoV2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020;181(7):1489–1501.e15. PMID: 32473127 https://doi.org/10.1016/ j.cell.2020.05.015Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, et al. Targets of T cell responses to SARS-CoV2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell. 2020;181(7):1489–1501.e15. PMID: 32473127 https://doi.org/10.1016/ j.cell.2020.05.015

The authors declare that there are no conflicts of interest present.