Cytokine storm and translating IL-6 biology into effective treatments for COVID-19

Abstract

As of May 3, 2023, the coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths. Several patients have developed pneumonia, which can deteriorate into acute respiratory distress syndrome. The primary etiology may be attributed to cytokine storm, which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation. Considering that high levels of interleukin-6 (IL-6) have been detected in several highly pathogenic coronavirus-infected diseases, such as severe acute respiratory syndrome in 2002, the Middle East respiratory syndrome in 2012, and COVID-19, the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state. Thus, we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19.

Keywords

SARS-CoV-2 / COVID-19 / cytokine storm / interleukin-6 / tocilizumab

References

[1] Jiang S, Shi Z, Shu Y, Song J, Gao GF, Tan W, Guo D. A distinct name is needed for the new coronavirus. Lancet 2020; 395(10228): 949

[2] World Health Organization. WHO Coronavirus (COVID-19) Dashboard. 2023. Available at the website of WHO

[3] Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708–1720

[4] Infectious Diseases Society of America. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. 2023. Available at the website of Infectious Diseases Society of America

[5] Wu Z, McGoogan JM. 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): 1239–1242

[6] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513

[7] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506

[8] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061–1069

[9] Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, Fan Y, Zheng C. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020; 20(4): 425–434

[10] Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, Diao K, Lin B, Zhu X, Li K, Li S, Shan H, Jacobi A, Chung M. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology 2020; 295(3): 200463

[11] Xu X, Yu C, Qu J, Zhang L, Jiang S, Huang D, Chen B, Zhang Z, Guan W, Ling Z, Jiang R, Hu T, Ding Y, Lin L, Gan Q, Luo L, Tang X, Liu J. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging 2020; 47(5): 1275–1280

[12] Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020; 14(2): 185–192

[13] Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. 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

[14] Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. 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

[15] Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, Boscolo-Rizzo P. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA 2020; 323(20): 2089–2090

[16] Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F, Distinguin L, Chekkoury-Idrissi Y, Hans S, Delgado IL, Calvo-Henriquez C, Lavigne P, Falanga C, Barillari MR, Cammaroto G, Khalife M, Leich P, Souchay C, Rossi C, Journe F, Hsieh J, Edjlali M, Carlier R, Ris L, Lovato A, De Filippis C, Coppee F, Fakhry N, Ayad T, Saussez S. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol 2020; 277(8): 2251–2261

[17] Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang C. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020; 5(7): 802–810

[18] Hendren NS, Drazner MH, Bozkurt B, Cooper LT Jr. Description and proposed management of the acute COVID-19 cardiovascular syndrome. Circulation 2020; 141(23): 1903–1914

[19] Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17(5): 259–260

[20] Chung MK, Zidar DA, Bristow MR, Cameron SJ, Chan T, Harding CV 3rd, Kwon DH, Singh T, Tilton JC, Tsai EJ, Tucker NR, Barnard J, Loscalzo J. COVID-19 and cardiovascular disease: from bench to bedside. Circ Res 2021; 128(8): 1214–1236

[21] Li J, Fan JG. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol 2020; 8(1): 13–17

[22] Kulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, Talukdar R, Sharma M, Qi X, Rao PN, Reddy DN. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020; 52(4): 584–599

[23] Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, Li J, Yao Y, Ge S, Xu G. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020; 97(5): 829–838

[24] Jansen J, Reimer KC, Nagai JS, Varghese FS, Overheul GJ, de Beer M, Roverts R, Daviran D, Fermin LAS, Willemsen B, Beukenboom M, Djudjaj S, von Stillfried S, van Eijk LE, Mastik M, Bulthuis M, Dunnen WD, van Goor H, Hillebrands JL, Triana SH, Alexandrov T, Timm MC, van den Berge BT, van den Broek M, Nlandu Q, Heijnert J, Bindels EMJ, Hoogenboezem RM, Mooren F, Kuppe C, Miesen P, Grünberg K, Ijzermans T, Steenbergen EJ, Czogalla J, Schreuder MF, Sommerdijk N, Akiva A, Boor P, Puelles VG, Floege J, Huber TB; COVID Moonshot consortium; van Rij RP, Costa IG, Schneider RK, Smeets B, Kramann R. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 2022; 29(2): 217–231.e8

[25] Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191: 148–150

[26] DeRosa MACalisiDCarrariniCMazzatentaAMattoliMVNeriGD’ArdesDGiansanteROnofrjMStuppiaLCipolloneFBonanniL. Olfactory dysfunction as a predictor of the future development of parkinsonism in COVID-19 patients: a 18F- FDOPA PET study. Eur J Neurodegener Dis 2023; 12(1): January–April: 20–23

[27] AntoniadesEMelissarisSPanagopoulosDKalloniatiESfakianosG. Pathophysiology and neuroinflammation in COVID-19. Eur J Neurodegener Dis 2022; 11(1): January-June: 7–9

[28] Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020; 77(6): 683–690

[29] Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M, Anheim M, Meziani F. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 2020; 382(23): 2268–2270

[30] Aggarwal K, Agarwal A, Jaiswal N, Dahiya N, Ahuja A, Mahajan S, Tong L, Duggal M, Singh M, Agrawal R, Gupta V. Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. PLoS One 2020; 15(11): e0241661

[31] National Health Commission of the People’s Republic of China. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia. 10th Interim Edition. 2023. Available at the website of National Health Commission of the People’s Republic of China

[32] Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F, Wang F, Li G, Li Y, Xing L, Peng L, Yang M, Cao M, Zheng H, Wu W, Zou R, Li D, Xu Z, Wang H, Zhang M, Zhang Z, Gao GF, Jiang C, Liu L, Liu Y. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J Allergy Clin Immunol 2020; 146(1): 119–127.e4

[33] Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, Sun R, Tian Z, Xu X, Wei H. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev 2020; 7(6): 998–1002

[34] Zhao Q, Meng M, Kumar R, Wu Y, Huang J, Deng Y, Weng Z, Yang L. Lymphopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a systemic review and meta-analysis. Int J Infect Dis 2020; 96: 131–135

[35] Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, Feng Z, Zhang Y, Wu Y, Chen Y. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020; 11: 827

[36] Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420–422

[37] Davies R, Choy E. Clinical experience of IL-6 blockade in rheumatic diseases—implications on IL-6 biology and disease pathogenesis. Semin Immunol 2014; 26(1): 97–104

[38] Paul-Pletzer K. Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today (Barc) 2006; 42(9): 559–576

[39] Nakahara H, Nishimoto N. Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. Endocr Metab Immune Disord Drug Targets 2006; 6(4): 373–381

[40] Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, Pazdur R. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 2018; 23(8): 943–947

[41] Chen F, Teachey DT, Pequignot E, Frey N, Porter D, Maude SL, Grupp SA, June CH, Melenhorst JJ, Lacey SF. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods 2016; 434: 1–8

[42] Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol 2019; 15(8): 813–822

[43] U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Drug for Treatment of COVID-19. 2021. Available at the website of FDA

[44] World Health Organization. Therapeutics and COVID-19: living guideline. 2021. Available at the website of WHO

[45] Vilček J, Feldmann M. Historical review: cytokines as therapeutics and targets of therapeutics. Trends Pharmacol Sci 2004; 25(4): 201–209

[46] Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012; 76(1): 16–32

[47] Cobb DA, Lee DW. Cytokine release syndrome biology and management. Cancer J 2021; 27(2): 119–125

[48] Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383(23): 2255–2273

[49] FerraraJLAbhyankarSGillilandDG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc 1993; 25(1 Pt 2): 1216–1217

[50] Nelemans T, Kikkert M. Viral innate immune evasion and the pathogenesis of emerging RNA virus infections. Viruses 2019; 11(10): 961

[51] MacCann R, Leon AAG, Gonzalez G, Carr MJ, Feeney ER, Yousif O, Cotter AG, de Barra E, Sadlier C, Doran P, Mallon PW. Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity. Front Immunol 2023; 14: 1166574

[52] Primorac D, Vrdoljak K, Brlek P, Pavelić E, Molnar V, Matišić V, Erceg Ivkošić I, Parčina M. Adaptive immune responses and immunity to SARS-CoV-2. Front Immunol 2022; 13: 848582

[53] Toor SM, Saleh R, Sasidharan Nair V, Taha RZ, Elkord E. T-cell responses and therapies against SARS-CoV-2 infection. Immunology 2021; 162(1): 30–43

[54] Chan L, Karimi N, Morovati S, Alizadeh K, Kakish JE, Vanderkamp S, Fazel F, Napoleoni C, Alizadeh K, Mehrani Y, Minott JA, Bridle BW, Karimi K. The roles of neutrophils in cytokine storms. Viruses 2021; 13(11): 2318

[55] Bonaventura A, Vecchié A, Dagna L, Martinod K, Dixon DL, Van Tassell BW, Dentali F, Montecucco F, Massberg S, Levi M, Abbate A. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21(5): 319–329

[56] Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH, Henson PM, Jordan MB. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med 2011; 208(6): 1203–1214

[57] Conti P, Caraffa A, Tetè G, Gallenga CE, Ross R, Kritas SK, Frydas I, Younes A, Di Emidio P, Ronconi G. Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19. J Biol Regul Homeost Agents 2020; 34(5): 1629–1632

[58] Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, Kronbichler A, Shin JI. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics 2021; 11(1): 316–329

[59] Teodoro AGF, Rodrigues WF, Farnesi-de-Assunção TS, Borges AVBE, Obata MMS, Neto JRDC, da Silva DAA, Andrade-Silva LE, Desidério CS, Costa-Madeira JC, Barbosa RM, Cunha ACCH, Pereira LQ, de Vito FB, Vaz Tanaka SCS, Helmo FR, Lemes MR, Barbosa LM, Trevisan RO, Mundim FV, Oliveira-Scussel ACM, Junior PRR, Monteiro IB, Ferreira YM, Machado GH, Ferreira-Paim K, Moraes-Souza H, de Oliveira CJF, Rodrigues Júnior V, Silva MVD. Inflammatory response and activation of coagulation after COVID-19 infection. Viruses 2023; 15(4): 938

[60] Jing H, Wu X, Xiang M, Liu L, Novakovic VA, Shi J. Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol 2022; 13: 992384

[61] Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, Zaheer SA, Iyer SS, Burton C, James D, Zaheer A. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation. Neuroscientist 2020; 26(5–6): 402–414

[62] D’OvidioC. The response of immune sentinels causing inflammation in glioma and glioblastoma. Eur J Neurodegener Dis 2023; 12(2): May–August: 46–50

[63] Ghasemzadeh M, Ghasemzadeh A, Hosseini E. Exhausted NK cells and cytokine storms in COVID-19: whether NK cell therapy could be a therapeutic choice. Hum Immunol 2022; 83(1): 86–98

[64] Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, Strippoli R. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol 2015; 67(11): 3037–3046

[65] Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74(1): 5–17

[66] Sallusto F. Heterogeneity of human CD4⁺ T cells against microbes. Annu Rev Immunol 2016; 34(1): 317–334

[67] Weiskopf D, Schmitz KS, Raadsen MP, Grifoni A, Okba NMA, Endeman H, van den Akker JPC, Molenkamp R, Koopmans MPG, van Gorp ECM, Haagmans BL, de Swart RL, Sette A, de Vries RD. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol 2020; 5(48): eabd2071

[68] Antonioli L, Fornai M, Pellegrini C, Blandizzi C. NKG2A and COVID-19: another brick in the wall. Cell Mol Immunol 2020; 17(6): 672–674

[69] Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, Xu Y, Tian Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020; 17(5): 533–535

[70] Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS. Cytokine release syndrome. J Immunother Cancer 2018; 6(1): 56

[71] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188–195

[72] Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J, Luo W, Chen T, Qin Q, Deng P. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 2005; 171(8): 850–857

[73] Zhou J, Chu H, Li C, Wong BH, Cheng ZS, Poon VK, Sun T, Lau CC, Wong KK, Chan JY, Chan JF, To KK, Chan KH, Zheng BJ, Yuen KY. 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(9): 1331–1342

[74] Anka AU, Tahir MI, Abubakar SD, Alsabbagh M, Zian Z, Hamedifar H, Sabzevari A, Azizi G. Coronavirus disease 2019 (COVID-19): an overview of the immunopathology, serological diagnosis and management. Scand J Immunol 2021; 93(4): e12998

[75] Morris G, Bortolasci CC, Puri BK, Olive L, Marx W, O’Neil A, Athan E, Carvalho AF, Maes M, Walder K, Berk M. The pathophysiology of SARS-CoV-2: a suggested model and therapeutic approach. Life Sci 2020; 258: 118166

[76] Perl M, Chung CS, Perl U, Lomas-Neira J, de Paepe M, Cioffi WG, Ayala A. Fas-induced pulmonary apoptosis and inflammation during indirect acute lung injury. Am J Respir Crit Care Med 2007; 176(6): 591–601

[77] Kitamura Y, Hashimoto S, Mizuta N, Kobayashi A, Kooguchi K, Fujiwara I, Nakajima H. Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am J Respir Crit Care Med 2001; 163(3): 762–769

[78] Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Corazza N, Brunner T, Seeger W, Lohmeyer J. Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med 2008; 205(13): 3065–3077

[79] Högner K, Wolff T, Pleschka S, Plog S, Gruber AD, Kalinke U, Walmrath HD, Bodner J, Gattenlöhner S, Lewe-Schlosser P, Matrosovich M, Seeger W, Lohmeyer J, Herold S. Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLoS Pathog 2013; 9(2): e1003188

[80] Ishikawa E, Nakazawa M, Yoshinari M, Minami M. Role of tumor necrosis factor-related apoptosis-inducing ligand in immune response to influenza virus infection in mice. J Virol 2005; 79(12): 7658–7663

[81] Sauler M, Bazan IS, Lee PJ. Cell death in the lung: the apoptosis-necroptosis axis. Annu Rev Physiol 2019; 81(1): 375–402

[82] Laffey JG, Misak C, Kavanagh BP. Acute respiratory distress syndrome. BMJ 2017; 359: j5055

[83] Lee KY. Pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy. Int J Mol Sci 2017; 18(2): 388

[84] Nakajima N, Sato Y, Katano H, Hasegawa H, Kumasaka T, Hata S, Tanaka S, Amano T, Kasai T, Chong JM, Iizuka T, Nakazato I, Hino Y, Hamamatsu A, Horiguchi H, Tanaka T, Hasegawa A, Kanaya Y, Oku R, Oya T, Sata T. Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection. Mod Pathol 2012; 25(1): 1–13

[85] Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol 2003; 200(3): 282–289

[86] Ng DL, Al Hosani F, Keating MK, Gerber SI, Jones TL, Metcalfe MG, Tong S, Tao Y, Alami NN, Haynes LM, Mutei MA, Abdel-Wareth L, Uyeki TM, Swerdlow DL, Barakat M, Zaki SR. 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(3): 652–658

[87] Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39(5): 529–539

[88] Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15(5): 327–347

[89] Drosten C, Günther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguière AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Müller S, Rickerts V, Stürmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1967–1976

[90] Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367(19): 1814–1820

[91] Kirtipal N, Bharadwaj S, Kang SG. From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses. Infect Genet Evol 2020; 85: 104502

[92] World Health Organization. Summary of Probable SARS Cases with Onset of Illness from 1 November 2002 to 31 July 2003. 2015. Available at the website of WHO

[93] Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, Zhuang H, Wu B, Zhong H, Shao H, Fang W, Gao D, Pei F, Li X, He Z, Xu D, Shi X, Anderson VM, Leong AS. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005; 202(3): 415–424

[94] Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003; 361(9371): 1773–1778

[95] Sheng WH, Chiang BL, Chang SC, Ho HN, Wang JT, Chen YC, Hsiao CH, Hseuh PR, Chie WC, Yang PC. Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J Formos Med Assoc 2005; 104(10): 715–723

[96] Chien JY, Hsueh PR, Cheng WC, Yu CJ, Yang PC. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 2006; 11(6): 715–722

[97] Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, Wu MH, Chan KH, Yuen KY, Gordon S, Guan Y, Peiris JS. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol 2005; 79(12): 7819–7826

[98] Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, Nicholls JM, Peiris JS, Lau YL. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood 2005; 106(7): 2366–2374

[99] Yao Z, Zheng Z, Wu K, Junhua Z. Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2. Aging (Albany NY) 2020; 12(9): 7639–7651

[100] Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY. An interferon-γ-related cytokine storm in SARS patients. J Med Virol 2005; 75(2): 185–194

[101] Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004; 136(1): 95–103

[102] Theron M, Huang KJ, Chen YW, Liu CC, Lei HY. A probable role for IFN-gamma in the development of a lung immunopathology in SARS. Cytokine 2005; 32(1): 30–38

[103] Cameron MJ, Ran L, Xu L, Danesh A, Bermejo-Martin JF, Cameron CM, Muller MP, Gold WL, Richardson SE, Poutanen SM, Willey BM, DeVries ME, Fang Y, Seneviratne C, Bosinger SE, Persad D, Wilkinson P, Greller LD, Somogyi R, Humar A, Keshavjee S, Louie M, Loeb MB, Brunton J, McGeer AJ; Canadian SARS Research Network; Kelvin DJ. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol 2007; 81(16): 8692–8706

[104] World Health Organization. Middle East Respiratory Syndrome Coronavirus (MERS-CoV). 2023. Available at the website of WHO

[105] Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018; 104: 8–13

[106] Kim ES, Choe PG, Park WB, Oh HS, Kim EJ, Nam EY, Na SH, Kim M, Song KH, Bang JH, Park SW, Kim HB, Kim NJ, Oh MD. Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 2016; 31(11): 1717–1725

[107] Lau SKP, Lau CCY, Chan KH, Li CPY, Chen H, Jin DY, Chan JFW, Woo PCY, Yuen KY. 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 Gen Virol 2013; 94(12): 2679–2690

[108] Prete M, Favoino E, Catacchio G, Racanelli V, Perosa F. SARS-CoV-2 inflammatory syndrome. Int J Mol Sci 2020; 21(9): 3377

[109] Xiong Y, Liu Y, Cao L, Wang D, Guo M, Jiang A, Guo D, Hu W, Yang J, Tang Z, Wu H, Lin Y, Zhang M, Zhang Q, Shi M, Liu Y, Zhou Y, Lan K, Chen Y. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect 2020; 9(1): 761–770

[110] Zhou Z, Ren L, Zhang L, Zhong J, Xiao Y, Jia Z, Guo L, Yang J, Wang C, Jiang S, Yang D, Zhang G, Li H, Chen F, Xu Y, Chen M, Gao Z, Yang J, Dong J, Liu B, Zhang X, Wang W, He K, Jin Q, Li M, Wang J. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe 2020; 27(6): 883–890.e2

[111] Ichikawa A, Kuba K, Morita M, Chida S, Tezuka H, Hara H, Sasaki T, Ohteki T, Ranieri VM, dos Santos CC, Kawaoka Y, Akira S, Luster AD, Lu B, Penninger JM, Uhlig S, Slutsky AS, Imai Y. CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin. Am J Respir Crit Care Med 2013; 187(1): 65–77

[112] Khalil BA, Shakartalla SB, Goel S, Madkhana B, Halwani R, Maghazachi AA, AlSafar H, Al-Omari B, Al Bataineh MT. Immune profiling of COVID-19 in correlation with SARS and MERS. Viruses 2022; 14(1): 164

[113] Tan M, Liu Y, Zhou R, Deng X, Li F, Liang K, Shi Y. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China. Immunology 2020; 160(3): 261–268

[114] García-Nicolás O, Godel A, Zimmer G, Summerfield A. Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation. Cell Mol Immunol 2023; 20(7): 835–849

[115] Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, Cheng L, Li J, Wang X, Wang F, Liu L, Amit I, Zhang S, Zhang Z. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020; 26(6): 842–844

[116] Zhou R, To KK, Wong YC, Liu L, Zhou B, Li X, Huang H, Mo Y, Luk TY, Lau TT, Yeung P, Chan WM, Wu AK, Lung KC, Tsang OT, Leung WS, Hung IF, Yuen KY, Chen Z. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity 2020; 53(4): 864–877.e5

[117] van der Sluis RM, Cham LB, Gris-Oliver A, Gammelgaard KR, Pedersen JG, Idorn M, Ahmadov U, Hernandez SS, Cémalovic E, Godsk SH, Thyrsted J, Gunst JD, Nielsen SD, Jørgensen JJ, Bjerg TW, Laustsen A, Reinert LS, Olagnier D, Bak RO, Kjolby M, Holm CK, Tolstrup M, Paludan SR, Kristensen LS, Søgaard OS, Jakobsen MR. TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. EMBO J 2022; 41(10): e109622

[118] Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020; 368(6490): 473–474

[119] Mansell A, Jenkins BJ. Dangerous liaisons between interleukin-6 cytokine and toll-like receptor families: a potent combination in inflammation and cancer. Cytokine Growth Factor Rev 2013; 24(3): 249–256

[120] Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991; 77(8): 1627–1652

[121] Netea MG, Kullberg BJ, Verschueren I, Van Der Meer JW. Interleukin-18 induces production of proinflammatory cytokines in mice: no intermediate role for the cytokines of the tumor necrosis factor family and interleukin-1beta. Eur J Immunol 2000; 30(10): 3057–3060

[122] Shalaby MR, Waage A, Aarden L, Espevik T. Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo. Clin Immunol Immunopathol 1989; 53(3): 488–498

[123] Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 1990; 75(1): 40–47

[124] Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813(5): 878–888

[125] Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995; 86(4): 1243–1254

[126] Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50(4): 1007–1023

[127] Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci USA 2013; 110(42): 16975–16980

[128] Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2012; 122(4): 143–159

[129] Bouezzedine F, Fardel O, Gripon P. Interleukin 6 inhibits HBV entry through NTCP down regulation. Virology 2015; 481: 34–42

[130] Dienz O, Rud JG, Eaton SM, Lanthier PA, Burg E, Drew A, Bunn J, Suratt BT, Haynes L, Rincon M. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol 2012; 5(3): 258–266

[131] Yang ML, Wang CT, Yang SJ, Leu CH, Chen SH, Wu CL, Shiau AL. IL-6 ameliorates acute lung injury in influenza virus infection. Sci Rep 2017; 7(1): 43829

[132] Hou W, Jin YH, Kang HS, Kim BS. Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function. J Virol 2014; 88(15): 8479–8489

[133] Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, Barrett DM, Weiss SL, Fitzgerald JC, Berg RA, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White JC, Nazimuddin F, Wertheim G, Levine BL, June CH, Porter DL, Grupp SA. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 2016; 6(6): 664–679

[134] Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, López JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 2017; 130(21): 2295–2306

[135] Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 2018; 24(6): 739–748

[136] Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020; 71(15): 762–768

[137] Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, Cheng J, Zhang X, Zhao Y, Xia Z, Zhang L, Wu G, Yi J. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med 2020; 12(7): e12421

[138] Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: a systematic review and meta-analysis. Rev Med Virol 2020; 30(6): 1–9

[139] Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: a meta-analysis. J Med Virol 2020; 92(11): 2283–2285

[140] Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty 2023; 12(1): 43

[141] Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, Caricchio R, Mahmud S, Hazen MM, Halyabar O, Hoyt KJ, Han J, Grom AA, Gattorno M, Ravelli A, De Benedetti F, Behrens EM, Cron RQ, Nigrovic PA. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol 2020; 72(7): 1059–1063

[142] Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, Damoraki G, Gkavogianni T, Adami ME, Katsaounou P, Ntaganou M, Kyriakopoulou M, Dimopoulos G, Koutsodimitropoulos I, Velissaris D, Koufargyris P, Karageorgos A, Katrini K, Lekakis V, Lupse M, Kotsaki A, Renieris G, Theodoulou D, Panou V, Koukaki E, Koulouris N, Gogos C, Koutsoukou A. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020; 27(6): 992–1000.e3

[143] Saki N, Javan M, Moghimian-Boroujeni B, Kast RE. Interesting effects of interleukins and immune cells on acute respiratory distress syndrome. Clin Exp Med 2023; 23(7): 2979–2996

[144] Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005; 106(8): 2627–2632

[145] Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008; 67(11): 1516–1523

[146] Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58(10): 2968–2980

[147] Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer L, Seitz M, Reichenbach S. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387(10031): 1921–1927

[148] Stone JH, Klearman M, Collinson N. Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017; 377(15): 1494–1495

[149] Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, Lu P, Cuttica R, Keltsev V, Xavier RM, Calvo I, Nikishina I, Rubio-Pérez N, Alexeeva E, Chasnyk V, Horneff G, Opoka-Winiarska V, Quartier P, Silva CA, Silverman E, Spindler A, Baildam E, Gámir ML, Martin A, Rietschel C, Siri D, Smolewska E, Lovell D, Martini A, De Benedetti F; Paediatric Rheumatology International Trials Organisation PRINTO; Pediatric Rheumatology Collaborative Study Group (PRCSG). Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis 2015; 74(6): 1110–1117

[150] Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371(9617): 998–1006

[151] De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, Cuttica R, Ravelli A, Schneider R, Woo P, Wouters C, Xavier R, Zemel L, Baildam E, Burgos-Vargas R, Dolezalova P, Garay SM, Merino R, Joos R, Grom A, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A; PRINTO; PRCSG. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367(25): 2385–2395

[152] Khanna D, Lin CJF, Furst DE, Goldin J, Kim G, Kuwana M, Allanore Y, Matucci-Cerinic M, Distler O, Shima Y, van Laar JM, Spotswood H, Wagner B, Siegel J, Jahreis A, Denton CP; focuSSced investigators. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8(10): 963–974

[153] Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020; 117(20): 10970–10975

[154] Wang D, Fu B, Peng Z, Yang D, Han M, Li M, Yang Y, Yang T, Sun L, Li W, Shi W, Yao X, Ma Y, Xu F, Wang X, Chen J, Xia D, Sun Y, Dong L, Wang J, Zhu X, Zhang M, Zhou Y, Pan A, Hu X, Mei X, Wei H, Xu X. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial. Front Med 2021; 15(3): 486–494

[155] AnthonyLKomaroffM. Tocilizumab Might Attenuate the “Cytokine Storm” in COVID-19 Patients. 2020. Available at the website of NEJM Journal Watch

[156] National Health Commission of the People’s Republic of China. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia in China. 7th Interim Edition. 2020. Available at the website of National Health Commission of the People’s Republic of China

[157] Infectious Diseases Society of America. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. 2020. Available at the website of Infectious Diseases Society of America

[158] National Institutes of Health. COVID-19 Treatment Guidelines. 2020. Available at the website of NIH

[159] Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, Criner GJ, Kaplan-Lewis E, Baden R, Pandit L, Cameron ML, Garcia-Diaz J, Chávez V, Mekebeb-Reuter M, Lima de Menezes F, Shah R, González-Lara MF, Assman B, Freedman J, Mohan SV. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021; 384(1): 20–30

[160] Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D’Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med 2020; 383(24): 2333–2344

[161] Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P; CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med 2021; 181(1): 32–40

[162] Rosas IO, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, Skiest D, Aziz MS, Cooper N, Douglas IS, Savic S, Youngstein T, Del Sorbo L, Cubillo Gracian A, De La Zerda DJ, Ustianowski A, Bao M, Dimonaco S, Graham E, Matharu B, Spotswood H, Tsai L, Malhotra A. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med 2021; 384(16): 1503–1516

[163] Colaneri M, Bogliolo L, Valsecchi P, Sacchi P, Zuccaro V, Brandolino F, Montecucco C, Mojoli F, Giusti EM, Bruno R, The Covid Irccs San Matteo Pavia Task Force. Tocilizumab for treatment of severe COVID-19 patients: preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms 2020; 8(5): 695

[164] Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, Tomelleri A, Baldissera E, Rovere-Querini P, Ruggeri A, Monti G, De Cobelli F, Zangrillo A, Tresoldi M, Castagna A, Dagna L; TOCI-RAF Study Group. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med 2020; 76: 43–49

[165] Soin AS, Kumar K, Choudhary NS, Sharma P, Mehta Y, Kataria S, Govil D, Deswal V, Chaudhry D, Singh PK, Gupta A, Agarwal V, Kumar S, Sangle SA, Chawla R, Narreddy S, Pandit R, Mishra V, Goel M, Ramanan AV. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Respir Med 2021; 9(5): 511–521

[166] Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turrà C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med 2021; 181(1): 24–31

[167] Veiga VC, Prats J, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, Machado FR, Lopes RD, Berwanger O, Azevedo LCP, Avezum A, Lisboa TC, Rojas SSO, Coelho JC, Leite RT, Carvalho JC, Andrade LEC, Sandes AF, Pintao MCT, Castro CG. , Santos SV, de Almeida TML, Costa AN, Gebara OCE, de Freitas FGR, Pacheco ES, Machado DJB, Martin J, Conceicao FG, Siqueira SRR, Damiani LP, Ishihara LM, Schneider D, de Souza D, Cavalcanti AB, Scheinberg P; Coalition covid-19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ 2021; 372: n84

[168] Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airò P, Bazzani C, Beindorf EA, Berlendis M, Bezzi M, Bossini N, Castellano M, Cattaneo S, Cavazzana I, Contessi GB, Crippa M, Delbarba A, De Peri E, Faletti A, Filippini M, Filippini M, Frassi M, Gaggiotti M, Gorla R, Lanspa M, Lorenzotti S, Marino R, Maroldi R, Metra M, Matteelli A, Modina D, Moioli G, Montani G, Muiesan ML, Odolini S, Peli E, Pesenti S, Pezzoli MC, Pirola I, Pozzi A, Proto A, Rasulo FA, Renisi G, Ricci C, Rizzoni D, Romanelli G, Rossi M, Salvetti M, Scolari F, Signorini L, Taglietti M, Tomasoni G, Tomasoni LR, Turla F, Valsecchi A, Zani D, Zuccalà F, Zunica F, Focà E, Andreoli L, Latronico N. 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

[169] Snow TAC, Saleem N, Ambler G, Nastouli E, Singer M, Arulkumaran N. Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. Intensive Care Med 2021; 47(6): 641–652

[170] Kyriakopoulos C, Ntritsos G, Gogali A, Milionis H, Evangelou E, Kostikas K. Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis. Respirology 2021; 26(11): 1027–1040

[171] RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2021; 397(10285): 1637–1645

[172] Broman N, Feuth T, Vuorinen T, Valtonen M, Hohenthal U, Löyttyniemi E, Hirvioja T, Jalava-Karvinen P, Marttila H, Nordberg M, Oksi J. Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM—a prospective, randomized, single-centre, open-label study. Clin Microbiol Infect 2022; 28(6): 844–851

[173] Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, Bonora S, Calcagno A, Cecchi I, Cinnirella G, Converso M, Cozzi M, Crosasso P, De Iaco F, Di Perri G, Eandi M, Fenoglio R, Giusti M, Imperiale D, Imperiale G, Livigni S, Manno E, Massara C, Milone V, Natale G, Navarra M, Oddone V, Osella S, Piccioni P, Radin M, Roccatello D, Rossi D. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020; 38(3): 529–532

[174] Galván-Román JM, Rodríguez-García SC, Roy-Vallejo E, Marcos-Jiménez A, Sánchez-Alonso S, Fernández-Díaz C, Alcaraz-Serna A, Mateu-Albero T, Rodríguez-Cortes P, Sánchez-Cerrillo I, Esparcia L, Martínez-Fleta P, López-Sanz C, Gabrie L, Del Campo Guerola L, Suárez-Fernández C, Ancochea J, Canabal A, Albert P, Rodríguez-Serrano DA, Aguilar JM, Del Arco C, de Los Santos I, García-Fraile L, de la Cámara R, Serra JM, Ramírez E, Alonso T, Landete P, Soriano JB, Martín-Gayo E, Fraile Torres A, Zurita Cruz ND, García-Vicuña R, Cardeñoso L, Sánchez-Madrid F, Alfranca A, Muñoz-Calleja C, González-Álvaro I; REINMUN-COVID Group. IL-6 serum levels predict severity and response to tocilizumab in COVID-19: an observational study. J Allergy Clin Immunol 2021; 147(1): 72–80.e8

[175] Strohbehn GW, Heiss BL, Rouhani SJ, Trujillo JA, Yu J, Kacew AJ, Higgs EF, Bloodworth JC, Cabanov A, Wright RC, Koziol AK, Weiss A, Danahey K, Karrison TG, Edens CC, Bauer Ventura I, Pettit NN, Patel BK, Pisano J, Strek ME, Gajewski TF, Ratain MJ, Reid PD. COVIDOSE: a phase II clinical trial of low-dose tocilizumab in the treatment of noncritical COVID-19 pneumonia. Clin Pharmacol Ther 2021; 109(3): 688–696

[176] Hashimoto S, Yoshizaki K, Uno K, Kitajima H, Arai T, Tamura Y, Morishita H, Matsuoka H, Han Y, Minamoto S, Hirashima T, Yamada T, Kashiwa Y, Kameda M, Yamaguchi S, Tsuchihashi Y, Iwahashi M, Nakayama E, Shioda T, Nagai T, Tanaka T. Prompt reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1 and a relatively low basal ratio of ferritin/CRP is possibly associated with the efficacy of tocilizumab monotherapy in severely to critically ill patients with COVID-19. Front Med (Lausanne) 2021; 8: 734838

[177] Gokhale Y, Mehta R, Kulkarni U, Karnik N, Gokhale S, Sundar U, Chavan S, Kor A, Thakur S, Trivedi T, Kumar N, Baveja S, Wadal A, Kolte S, Deolankar A, Pednekar S, Kalekar L, Padiyar R, Londhe C, Darole P, Pol S, Gokhe SB, Padwal N, Pandey D, Yadav D, Joshi A, Badgujar H, Trivedi M, Shah P, Bhavsar P. Tocilizumab improves survival in severe COVID-19 pneumonia with persistent hypoxia: a retrospective cohort study with follow-up from Mumbai, India. BMC Infect Dis 2021; 21(1): 241

[178] Zeraatkar D, Cusano E, Martínez JPD, Qasim A, Mangala S, Kum E, Bartoszko JJ, Devji T, Agoritsas T, Guyatt G, Izcovich A, Khamis AM, Lamontagne F, Rochwerg B, Vandvik P, Brignardello-Petersen R, Siemieniuk RAC. Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis. BMJ Med 2022; 1(1): e000036

[179] Rossotti R, Travi G, Ughi N, Corradin M, Baiguera C, Fumagalli R, Bottiroli M, Mondino M, Merli M, Bellone A, Basile A, Ruggeri R, Colombo F, Moreno M, Pastori S, Perno CF, Tarsia P, Epis OM, Puoti M; Niguarda COVID-19 Working Group. Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: a comparative analysis. J Infect 2020; 81(4): e11–e17

[180] Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J, Kavanaugh A, Investigators AS. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013; 381(9877): 1541–1550

[181] World Health Organization. Therapeutics and COVID-19: living guideline. 2023. Available at the website of WHO

[182] National Health Service. NHS patients to receive life-saving COVID-19 treatments that could cut hospital time by 10 days. 2021. Available at the website of NHS

[183] WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Spiga F, Savovic J, Tierney J, Baron G, Benbenishty JS, Berry LR, Broman N, Cavalcanti AB, Colman R, De Buyser SL, Derde LPG, Domingo P, Omar SF, Fernandez-Cruz A, Feuth T, Garcia F, Garcia-Vicuna R, Gonzalez-Alvaro I, Gordon AC, Haynes R, Hermine O, Horby PW, Horick NK, Kumar K, Lambrecht BN, Landray MJ, Leal L, Lederer DJ, Lorenzi E, Mariette X, Merchante N, Misnan NA, Mohan SV, Nivens MC, Oksi J, Perez-Molina JA, Pizov R, Porcher R, Postma S, Rajasuriar R, Ramanan AV, Ravaud P, Reid PD, Rutgers A, Sancho-Lopez A, Seto TB, Sivapalasingam S, Soin AS, Staplin N, Stone JH, Strohbehn GW, Sunden-Cullberg J, Torre-Cisneros J, Tsai LW, van Hoogstraten H, van Meerten T, Veiga VC, Westerweel PE, Murthy S, Diaz JV, Marshall JC, Sterne JAC. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 2021; 326(6): 499–518

[184] Yamakawa K, Yamamoto R, Terayama T, Hashimoto H, Ishihara T, Ishimaru G, Imura H, Okano H, Narita C, Mayumi T, Yasuda H, Yamada K, Yamada H, Kawasaki T, Shime N, Doi K, Egi M, Ogura H, Aihara M, Kushimoto S, Nishida O; Special Committee of the Japanese Clinical Practice Guidelines for the Management of Sepsis, Septic Shock 2020 (J-SSCG 2020), the COVID-19 Task Force. Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022). Acute Med Surg 2022; 9(1): e789

[185] Bartoletti M, Azap O, Barac A, Bussini L, Ergonul O, Krause R, Paño-Pardo JR, Power NR, Sibani M, Szabo BG, Tsiodras S, Verweij PE, Zollner-Schwetz I, Rodríguez-Baño J. ESCMID COVID-19 living guidelines: drug treatment and clinical management. Clin Microbiol Infect 2022; 28(2): 222–238

RIGHTS & PERMISSIONS

Higher Education Press