1. Department of Geriatric Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China 2. Respiratory and Critical Care Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China 3. Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230001, China 4. Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230001, China
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.
Recommendation for severe and critical patients with significantly elevated IL-6 levels
WHOb (Updated on January 13, 2023)
Strong recommendation for severe or critical patients in combination with corticosteroids
IDSAc (Updated on June 26, 2023)
Conditional recommendation for severe or critical patients who exhibit elevated markers of systemic inflammation (low certainty of evidence)
Australian National Clinical Evidence Taskforce (Updated on May 30, 2023)
Conditional recommendation for patients (including adults, pregnant or breastfeeding women, children, and adolescents) who require supplemental oxygen, particularly in the presence of systemic inflammation
NICEd (Updated on August 9, 2023)
Recommendation for adult patients who are having systemic corticosteroids and need supplemental oxygen or MVe
NIHf (Updated on July 21, 2023)
Moderate recommendation for hospitalized patients who are receiving dexamethasone, have systemic inflammation, experience rapidly increasing oxygen needs, and require HFNCg oxygen, NIVh, MVe or ECMOi (moderate quality of evidence)
ESCMIDl (Published online on November 21, 2021)
Recommendation for severe patients (quality of evidence: moderate for mortality, high for MVe)
J-SSCG 2020 Special Committeem (Updated in July 2022)
Weak recommendation for moderate patients who require oxygen/hospitalization (moderate certainty of evidence: GRADE 2B); weak recommendation for severe patients who require MVe/intensive care (low certainty of evidence: GRADE 2C)
World Health Organization. WHO Coronavirus (COVID-19) Dashboard. 2023. Available at the website of WHO
3
WJ Guan, ZY Ni, Y Hu, WH Liang, CQ Ou, JX He, L Liu, H Shan, CL Lei, DSC Hui, B Du, LJ Li, G Zeng, KY Yuen, RC Chen, CL Tang, T Wang, PY Chen, J Xiang, SY Li, JL Wang, ZJ Liang, YX Peng, L Wei, Y Liu, YH Hu, P Peng, JM Wang, JY Liu, Z Chen, G Li, ZJ Zheng, SQ Qiu, J Luo, CJ Ye, SY Zhu, NS; China Medical Treatment Expert Group for Covid-19 Zhong. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708–1720 https://doi.org/10.1056/NEJMoa2002032
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
Z Wu, JM McGoogan. 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 https://doi.org/10.1001/jama.2020.2648
6
N Chen, M Zhou, X Dong, J Qu, F Gong, Y Han, Y Qiu, J Wang, Y Liu, Y Wei, J Xia, T Yu, X Zhang, L Zhang. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223): 507–513 https://doi.org/10.1016/S0140-6736(20)30211-7
7
C Huang, Y Wang, X Li, L Ren, J Zhao, Y Hu, L Zhang, G Fan, J Xu, X Gu, Z Cheng, T Yu, J Xia, Y Wei, W Wu, X Xie, W Yin, H Li, M Liu, Y Xiao, H Gao, L Guo, J Xie, G Wang, R Jiang, Z Gao, Q Jin, J Wang, B Cao. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506 https://doi.org/10.1016/S0140-6736(20)30183-5
8
D Wang, B Hu, C Hu, F Zhu, X Liu, J Zhang, B Wang, H Xiang, Z Cheng, Y Xiong, Y Zhao, Y Li, X Wang, Z Peng. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061–1069 https://doi.org/10.1001/jama.2020.1585
9
H Shi, X Han, N Jiang, Y Cao, O Alwalid, J Gu, Y Fan, C Zheng. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020; 20(4): 425–434 https://doi.org/10.1016/S1473-3099(20)30086-4
10
A Bernheim, X Mei, M Huang, Y Yang, ZA Fayad, N Zhang, K Diao, B Lin, X Zhu, K Li, S Li, H Shan, A Jacobi, M Chung. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology 2020; 295(3): 200463 https://doi.org/10.1148/radiol.2020200463
11
X Xu, C Yu, J Qu, L Zhang, S Jiang, D Huang, B Chen, Z Zhang, W Guan, Z Ling, R Jiang, T Hu, Y Ding, L Lin, Q Gan, L Luo, X Tang, J Liu. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging 2020; 47(5): 1275–1280 https://doi.org/10.1007/s00259-020-04735-9
12
X Zou, K Chen, J Zou, P Han, J Hao, Z Han. 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 https://doi.org/10.1007/s11684-020-0754-0
13
X Yang, Y Yu, J Xu, H Shu, J Xia, H Liu, Y Wu, L Zhang, Z Yu, M Fang, T Yu, Y Wang, S Pan, X Zou, S Yuan, Y Shang. 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 https://doi.org/10.1016/S2213-2600(20)30079-5
14
F Zhou, T Yu, R Du, G Fan, Y Liu, Z Liu, J Xiang, Y Wang, B Song, X Gu, L Guan, Y Wei, H Li, X Wu, J Xu, S Tu, Y Zhang, H Chen, B Cao. 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 https://doi.org/10.1016/S0140-6736(20)30566-3
15
G Spinato, C Fabbris, J Polesel, D Cazzador, D Borsetto, C Hopkins, P Boscolo-Rizzo. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA 2020; 323(20): 2089–2090 https://doi.org/10.1001/jama.2020.6771
16
JR Lechien, CM Chiesa-Estomba, DR De Siati, M Horoi, SD Le Bon, A Rodriguez, D Dequanter, S Blecic, F El Afia, L Distinguin, Y Chekkoury-Idrissi, S Hans, IL Delgado, C Calvo-Henriquez, P Lavigne, C Falanga, MR Barillari, G Cammaroto, M Khalife, P Leich, C Souchay, C Rossi, F Journe, J Hsieh, M Edjlali, R Carlier, L Ris, A Lovato, C De Filippis, F Coppee, N Fakhry, T Ayad, S Saussez. 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 https://doi.org/10.1007/s00405-020-05965-1
17
S Shi, M Qin, B Shen, Y Cai, T Liu, F Yang, W Gong, X Liu, J Liang, Q Zhao, H Huang, B Yang, C Huang. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020; 5(7): 802–810 https://doi.org/10.1001/jamacardio.2020.0950
18
NS Hendren, MH Drazner, B Bozkurt, LT Jr Cooper. Description and proposed management of the acute COVID-19 cardiovascular syndrome. Circulation 2020; 141(23): 1903–1914 https://doi.org/10.1161/CIRCULATIONAHA.120.047349
MK Chung, DA Zidar, MR Bristow, SJ Cameron, T Chan, CV 3rd Harding, DH Kwon, T Singh, JC Tilton, EJ Tsai, NR Tucker, J Barnard, J Loscalzo. COVID-19 and cardiovascular disease: from bench to bedside. Circ Res 2021; 128(8): 1214–1236 https://doi.org/10.1161/CIRCRESAHA.121.317997
21
J Li, JG Fan. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol 2020; 8(1): 13–17 https://doi.org/10.14218/JCTH.2020.00019
22
AV Kulkarni, P Kumar, HV Tevethia, M Premkumar, JP Arab, R Candia, R Talukdar, M Sharma, X Qi, PN Rao, DN Reddy. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020; 52(4): 584–599 https://doi.org/10.1111/apt.15916
23
Y Cheng, R Luo, K Wang, M Zhang, Z Wang, L Dong, J Li, Y Yao, S Ge, G Xu. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020; 97(5): 829–838 https://doi.org/10.1016/j.kint.2020.03.005
24
J Jansen, KC Reimer, JS Nagai, FS Varghese, GJ Overheul, Beer M de, R Roverts, D Daviran, LAS Fermin, B Willemsen, M Beukenboom, S Djudjaj, Stillfried S von, Eijk LE van, M Mastik, M Bulthuis, WD Dunnen, Goor H van, JL Hillebrands, SH Triana, T Alexandrov, MC Timm, den Berge BT van, den Broek M van, Q Nlandu, J Heijnert, EMJ Bindels, RM Hoogenboezem, F Mooren, C Kuppe, P Miesen, K Grünberg, T Ijzermans, EJ Steenbergen, J Czogalla, MF Schreuder, N Sommerdijk, A Akiva, P Boor, VG Puelles, J Floege, TB; COVID Moonshot consortium; van Rij RP Huber, IG Costa, RK Schneider, B Smeets, R Kramann. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 2022; 29(2): 217–231.e8 https://doi.org/10.1016/j.stem.2021.12.010
25
FA Klok, MJHA Kruip, NJM van der Meer, MS Arbous, D Gommers, KM Kant, FHJ Kaptein, J van Paassen, MAM Stals, MV Huisman, H Endeman. 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 https://doi.org/10.1016/j.thromres.2020.04.041
26
Rosa MA DeD CalisiC CarrariniA MazzatentaMV MattoliG NeriD D’ArdesR GiansanteM OnofrjL StuppiaF CipolloneL Bonanni. 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
E AntoniadesS MelissarisD PanagopoulosE KalloniatiG Sfakianos. Pathophysiology and neuroinflammation in COVID-19. Eur J Neurodegener Dis 2022; 11(1): January-June: 7–9
28
L Mao, H Jin, M Wang, Y Hu, S Chen, Q He, J Chang, C Hong, Y Zhou, D Wang, X Miao, Y Li, B Hu. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020; 77(6): 683–690 https://doi.org/10.1001/jamaneurol.2020.1127
29
J Helms, S Kremer, H Merdji, R Clere-Jehl, M Schenck, C Kummerlen, O Collange, C Boulay, S Fafi-Kremer, M Ohana, M Anheim, F Meziani. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 2020; 382(23): 2268–2270 https://doi.org/10.1056/NEJMc2008597
30
K Aggarwal, A Agarwal, N Jaiswal, N Dahiya, A Ahuja, S Mahajan, L Tong, M Duggal, M Singh, R Agrawal, V Gupta. Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. PLoS One 2020; 15(11): e0241661 https://doi.org/10.1371/journal.pone.0241661
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
Y Yang, C Shen, J Li, J Yuan, J Wei, F Huang, F Wang, G Li, Y Li, L Xing, L Peng, M Yang, M Cao, H Zheng, W Wu, R Zou, D Li, Z Xu, H Wang, M Zhang, Z Zhang, GF Gao, C Jiang, L Liu, Y Liu. 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 https://doi.org/10.1016/j.jaci.2020.04.027
33
Y Zhou, B Fu, X Zheng, D Wang, C Zhao, Y Qi, R Sun, Z Tian, X Xu, H Wei. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev 2020; 7(6): 998–1002 https://doi.org/10.1093/nsr/nwaa041
34
Q Zhao, M Meng, R Kumar, Y Wu, J Huang, Y Deng, Z Weng, L Yang. 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 https://doi.org/10.1016/j.ijid.2020.04.086
35
B Diao, C Wang, Y Tan, X Chen, Y Liu, L Ning, L Chen, M Li, Y Liu, G Wang, Z Yuan, Z Feng, Y Zhang, Y Wu, Y Chen. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020; 11: 827 https://doi.org/10.3389/fimmu.2020.00827
36
Z Xu, L Shi, Y Wang, J Zhang, L Huang, C Zhang, S Liu, P Zhao, H Liu, L Zhu, Y Tai, C Bai, T Gao, J Song, P Xia, J Dong, J Zhao, FS Wang. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8(4): 420–422 https://doi.org/10.1016/S2213-2600(20)30076-X
37
R Davies, E Choy. Clinical experience of IL-6 blockade in rheumatic diseases—implications on IL-6 biology and disease pathogenesis. Semin Immunol 2014; 26(1): 97–104 https://doi.org/10.1016/j.smim.2013.12.002
38
K Paul-Pletzer. Tocilizumab: blockade of interleukin-6 signaling pathway as a therapeutic strategy for inflammatory disorders. Drugs Today (Barc) 2006; 42(9): 559–576 https://doi.org/10.1358/dot.2006.42.9.1025692
39
H Nakahara, N Nishimoto. Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. Endocr Metab Immune Disord Drug Targets 2006; 6(4): 373–381 https://doi.org/10.2174/187153006779025694
40
RQ Le, L Li, W Yuan, SS Shord, L Nie, BA Habtemariam, D Przepiorka, AT Farrell, R Pazdur. 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 https://doi.org/10.1634/theoncologist.2018-0028
41
F Chen, DT Teachey, E Pequignot, N Frey, D Porter, SL Maude, SA Grupp, CH June, JJ Melenhorst, SF Lacey. 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 https://doi.org/10.1016/j.jim.2016.03.005
42
C Kotch, D Barrett, DT Teachey. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol 2019; 15(8): 813–822 https://doi.org/10.1080/1744666X.2019.1629904
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
J Vilček, M Feldmann. Historical review: cytokines as therapeutics and targets of therapeutics. Trends Pharmacol Sci 2004; 25(4): 201–209 https://doi.org/10.1016/j.tips.2004.02.011
46
JR Tisoncik, MJ Korth, CP Simmons, J Farrar, TR Martin, MG Katze. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012; 76(1): 16–32 https://doi.org/10.1128/MMBR.05015-11
JL FerraraS AbhyankarDG Gilliland. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc 1993; 25(1 Pt 2): 1216–1217
pmid: 8442093
50
T Nelemans, M Kikkert. Viral innate immune evasion and the pathogenesis of emerging RNA virus infections. Viruses 2019; 11(10): 961 https://doi.org/10.3390/v11100961
51
R MacCann, AAG Leon, G Gonzalez, MJ Carr, ER Feeney, O Yousif, AG Cotter, E de Barra, C Sadlier, P Doran, PW Mallon. Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity. Front Immunol 2023; 14: 1166574 https://doi.org/10.3389/fimmu.2023.1166574
52
D Primorac, K Vrdoljak, P Brlek, E Pavelić, V Molnar, V Matišić, Ivkošić I Erceg, M Parčina. Adaptive immune responses and immunity to SARS-CoV-2. Front Immunol 2022; 13: 848582 https://doi.org/10.3389/fimmu.2022.848582
53
SM Toor, R Saleh, V Sasidharan Nair, RZ Taha, E Elkord. T-cell responses and therapies against SARS-CoV-2 infection. Immunology 2021; 162(1): 30–43 https://doi.org/10.1111/imm.13262
54
L Chan, N Karimi, S Morovati, K Alizadeh, JE Kakish, S Vanderkamp, F Fazel, C Napoleoni, K Alizadeh, Y Mehrani, JA Minott, BW Bridle, K Karimi. The roles of neutrophils in cytokine storms. Viruses 2021; 13(11): 2318 https://doi.org/10.3390/v13112318
55
A Bonaventura, A Vecchié, L Dagna, K Martinod, DL Dixon, Tassell BW Van, F Dentali, F Montecucco, S Massberg, M Levi, A Abbate. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21(5): 319–329 https://doi.org/10.1038/s41577-021-00536-9
56
EE Zoller, JE Lykens, CE Terrell, J Aliberti, AH Filipovich, PM Henson, MB Jordan. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med 2011; 208(6): 1203–1214 https://doi.org/10.1084/jem.20102538
57
P Conti, A Caraffa, G Tetè, CE Gallenga, R Ross, SK Kritas, I Frydas, A Younes, Emidio P Di, G Ronconi. 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
JS Kim, JY Lee, JW Yang, KH Lee, M Effenberger, W Szpirt, A Kronbichler, JI Shin. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics 2021; 11(1): 316–329 https://doi.org/10.7150/thno.49713
59
AGF Teodoro, WF Rodrigues, TS Farnesi-de-Assunção, AVBE Borges, MMS Obata, JRDC Neto, Silva DAA da, LE Andrade-Silva, CS Desidério, JC Costa-Madeira, RM Barbosa, ACCH Cunha, LQ Pereira, Vito FB de, Tanaka SCS Vaz, FR Helmo, MR Lemes, LM Barbosa, RO Trevisan, FV Mundim, ACM Oliveira-Scussel, PRR Junior, IB Monteiro, YM Ferreira, GH Machado, K Ferreira-Paim, H Moraes-Souza, Oliveira CJF de, Júnior V Rodrigues, MVD Silva. Inflammatory response and activation of coagulation after COVID-19 infection. Viruses 2023; 15(4): 938 https://doi.org/10.3390/v15040938
60
H Jing, X Wu, M Xiang, L Liu, VA Novakovic, J Shi. Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol 2022; 13: 992384 https://doi.org/10.3389/fimmu.2022.992384
61
D Kempuraj, GP Selvakumar, ME Ahmed, SP Raikwar, R Thangavel, A Khan, SA Zaheer, SS Iyer, C Burton, D James, A Zaheer. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation. Neuroscientist 2020; 26(5–6): 402–414 https://doi.org/10.1177/1073858420941476
62
C D’Ovidio. The response of immune sentinels causing inflammation in glioma and glioblastoma. Eur J Neurodegener Dis 2023; 12(2): May–August: 46–50
63
M Ghasemzadeh, A Ghasemzadeh, E Hosseini. 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 https://doi.org/10.1016/j.humimm.2021.09.004
64
L Cifaldi, G Prencipe, I Caiello, C Bracaglia, F Locatelli, F De Benedetti, R Strippoli. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol 2015; 67(11): 3037–3046 https://doi.org/10.1002/art.39295
65
I Raphael, S Nalawade, TN Eagar, TG Forsthuber. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74(1): 5–17 https://doi.org/10.1016/j.cyto.2014.09.011
D Weiskopf, KS Schmitz, MP Raadsen, A Grifoni, NMA Okba, H Endeman, JPC van den Akker, R Molenkamp, MPG Koopmans, ECM van Gorp, BL Haagmans, RL de Swart, A Sette, RD de Vries. 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 https://doi.org/10.1126/sciimmunol.abd2071
68
L Antonioli, M Fornai, C Pellegrini, C Blandizzi. NKG2A and COVID-19: another brick in the wall. Cell Mol Immunol 2020; 17(6): 672–674 https://doi.org/10.1038/s41423-020-0450-7
69
M Zheng, Y Gao, G Wang, G Song, S Liu, D Sun, Y Xu, Z Tian. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020; 17(5): 533–535 https://doi.org/10.1038/s41423-020-0402-2
70
A Shimabukuro-Vornhagen, P Gödel, M Subklewe, HJ Stemmler, HA Schlößer, M Schlaak, M Kochanek, B Böll, Bergwelt-Baildon MS von. Cytokine release syndrome. J Immunother Cancer 2018; 6(1): 56 https://doi.org/10.1186/s40425-018-0343-9
71
DW Lee, R Gardner, DL Porter, CU Louis, N Ahmed, M Jensen, SA Grupp, CL Mackall. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188–195 https://doi.org/10.1182/blood-2014-05-552729
72
Y Jiang, J Xu, C Zhou, Z Wu, S Zhong, J Liu, W Luo, T Chen, Q Qin, P Deng. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 2005; 171(8): 850–857 https://doi.org/10.1164/rccm.200407-857OC
73
J Zhou, H Chu, C Li, BH Wong, ZS Cheng, VK Poon, T Sun, CC Lau, KK Wong, JY Chan, JF Chan, KK To, KH Chan, BJ Zheng, KY Yuen. 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 https://doi.org/10.1093/infdis/jit504
74
AU Anka, MI Tahir, SD Abubakar, M Alsabbagh, Z Zian, H Hamedifar, A Sabzevari, G Azizi. Coronavirus disease 2019 (COVID-19): an overview of the immunopathology, serological diagnosis and management. Scand J Immunol 2021; 93(4): e12998 https://doi.org/10.1111/sji.12998
75
G Morris, CC Bortolasci, BK Puri, L Olive, W Marx, A O’Neil, E Athan, AF Carvalho, M Maes, K Walder, M Berk. The pathophysiology of SARS-CoV-2: a suggested model and therapeutic approach. Life Sci 2020; 258: 118166 https://doi.org/10.1016/j.lfs.2020.118166
76
M Perl, CS Chung, U Perl, J Lomas-Neira, M de Paepe, WG Cioffi, A Ayala. Fas-induced pulmonary apoptosis and inflammation during indirect acute lung injury. Am J Respir Crit Care Med 2007; 176(6): 591–601 https://doi.org/10.1164/rccm.200611-1743OC
77
Y Kitamura, S Hashimoto, N Mizuta, A Kobayashi, K Kooguchi, I Fujiwara, H Nakajima. 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 https://doi.org/10.1164/ajrccm.163.3.2003065
78
S Herold, M Steinmueller, W von Wulffen, L Cakarova, R Pinto, S Pleschka, M Mack, WA Kuziel, N Corazza, T Brunner, W Seeger, J Lohmeyer. 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 https://doi.org/10.1084/jem.20080201
79
K Högner, T Wolff, S Pleschka, S Plog, AD Gruber, U Kalinke, HD Walmrath, J Bodner, S Gattenlöhner, P Lewe-Schlosser, M Matrosovich, W Seeger, J Lohmeyer, S Herold. Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLoS Pathog 2013; 9(2): e1003188 https://doi.org/10.1371/journal.ppat.1003188
80
E Ishikawa, M Nakazawa, M Yoshinari, M Minami. 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 https://doi.org/10.1128/JVI.79.12.7658-7663.2005
KY Lee. Pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy. Int J Mol Sci 2017; 18(2): 388 https://doi.org/10.3390/ijms18020388
84
N Nakajima, Y Sato, H Katano, H Hasegawa, T Kumasaka, S Hata, S Tanaka, T Amano, T Kasai, JM Chong, T Iizuka, I Nakazato, Y Hino, A Hamamatsu, H Horiguchi, T Tanaka, A Hasegawa, Y Kanaya, R Oku, T Oya, T Sata. Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection. Mod Pathol 2012; 25(1): 1–13 https://doi.org/10.1038/modpathol.2011.125
85
Y Ding, H Wang, H Shen, Z Li, J Geng, H Han, J Cai, X Li, W Kang, D Weng, Y Lu, D Wu, L He, K Yao. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol 2003; 200(3): 282–289 https://doi.org/10.1002/path.1440
86
DL Ng, F Al Hosani, MK Keating, SI Gerber, TL Jones, MG Metcalfe, S Tong, Y Tao, NN Alami, LM Haynes, MA Mutei, L Abdel-Wareth, TM Uyeki, DL Swerdlow, M Barakat, SR Zaki. 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 https://doi.org/10.1016/j.ajpath.2015.10.024
87
R Channappanavar, S Perlman. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39(5): 529–539 https://doi.org/10.1007/s00281-017-0629-x
88
A Zumla, JF Chan, EI Azhar, DS Hui, KY Yuen. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15(5): 327–347 https://doi.org/10.1038/nrd.2015.37
89
C Drosten, S Günther, W Preiser, der Werf S van, HR Brodt, S Becker, H Rabenau, M Panning, L Kolesnikova, RA Fouchier, A Berger, AM Burguière, J Cinatl, M Eickmann, N Escriou, K Grywna, S Kramme, JC Manuguerra, S Müller, V Rickerts, M Stürmer, S Vieth, HD Klenk, AD Osterhaus, H Schmitz, HW Doerr. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003; 348(20): 1967–1976 https://doi.org/10.1056/NEJMoa030747
90
AM Zaki, S van Boheemen, TM Bestebroer, AD Osterhaus, RA Fouchier. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367(19): 1814–1820 https://doi.org/10.1056/NEJMoa1211721
91
N Kirtipal, S Bharadwaj, SG Kang. From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses. Infect Genet Evol 2020; 85: 104502 https://doi.org/10.1016/j.meegid.2020.104502
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
J Gu, E Gong, B Zhang, J Zheng, Z Gao, Y Zhong, W Zou, J Zhan, S Wang, Z Xie, H Zhuang, B Wu, H Zhong, H Shao, W Fang, D Gao, F Pei, X Li, Z He, D Xu, X Shi, VM Anderson, AS Leong. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005; 202(3): 415–424 https://doi.org/10.1084/jem.20050828
94
JM Nicholls, LL Poon, KC Lee, WF Ng, ST Lai, CY Leung, CM Chu, PK Hui, KL Mak, W Lim, KW Yan, KH Chan, NC Tsang, Y Guan, KY Yuen, JS Peiris. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003; 361(9371): 1773–1778 https://doi.org/10.1016/S0140-6736(03)13413-7
95
WH Sheng, BL Chiang, SC Chang, HN Ho, JT Wang, YC Chen, CH Hsiao, PR Hseuh, WC Chie, PC Yang. Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J Formos Med Assoc 2005; 104(10): 715–723
96
JY Chien, PR Hsueh, WC Cheng, CJ Yu, PC Yang. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 2006; 11(6): 715–722 https://doi.org/10.1111/j.1440-1843.2006.00942.x
97
CY Cheung, LL Poon, IH Ng, W Luk, SF Sia, MH Wu, KH Chan, KY Yuen, S Gordon, Y Guan, JS Peiris. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol 2005; 79(12): 7819–7826 https://doi.org/10.1128/JVI.79.12.7819-7826.2005
98
HK Law, CY Cheung, HY Ng, SF Sia, YO Chan, W Luk, JM Nicholls, JS Peiris, YL Lau. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood 2005; 106(7): 2366–2374 https://doi.org/10.1182/blood-2004-10-4166
99
Z Yao, Z Zheng, K Wu, Z Junhua. 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 https://doi.org/10.18632/aging.103101
100
KJ Huang, IJ Su, M Theron, YC Wu, SK Lai, CC Liu, HY Lei. An interferon-γ-related cytokine storm in SARS patients. J Med Virol 2005; 75(2): 185–194 https://doi.org/10.1002/jmv.20255
101
CK Wong, CW Lam, AK Wu, WK Ip, NL Lee, IH Chan, LC Lit, DS Hui, MH Chan, SS Chung, JJ Sung. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004; 136(1): 95–103 https://doi.org/10.1111/j.1365-2249.2004.02415.x
102
M Theron, KJ Huang, YW Chen, CC Liu, HY Lei. A probable role for IFN-gamma in the development of a lung immunopathology in SARS. Cytokine 2005; 32(1): 30–38 https://doi.org/10.1016/j.cyto.2005.07.007
103
MJ Cameron, L Ran, L Xu, A Danesh, JF Bermejo-Martin, CM Cameron, MP Muller, WL Gold, SE Richardson, SM Poutanen, BM Willey, ME DeVries, Y Fang, C Seneviratne, SE Bosinger, D Persad, P Wilkinson, LD Greller, R Somogyi, A Humar, S Keshavjee, M Louie, MB Loeb, J Brunton, AJ; Canadian SARS Research Network; Kelvin DJ McGeer. 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 https://doi.org/10.1128/JVI.00527-07
104
World Health Organization. Middle East Respiratory Syndrome Coronavirus (MERS-CoV). 2023. Available at the website of WHO
105
WH Mahallawi, OF Khabour, Q Zhang, HM Makhdoum, BA Suliman. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018; 104: 8–13 https://doi.org/10.1016/j.cyto.2018.01.025
106
ES Kim, PG Choe, WB Park, HS Oh, EJ Kim, EY Nam, SH Na, M Kim, KH Song, JH Bang, SW Park, HB Kim, NJ Kim, MD Oh. Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 2016; 31(11): 1717–1725 https://doi.org/10.3346/jkms.2016.31.11.1717
107
SKP Lau, CCY Lau, KH Chan, CPY Li, H Chen, DY Jin, JFW Chan, PCY Woo, KY Yuen. 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 https://doi.org/10.1099/vir.0.055533-0
108
M Prete, E Favoino, G Catacchio, V Racanelli, F Perosa. SARS-CoV-2 inflammatory syndrome. Int J Mol Sci 2020; 21(9): 3377 https://doi.org/10.3390/ijms21093377
109
Y Xiong, Y Liu, L Cao, D Wang, M Guo, A Jiang, D Guo, W Hu, J Yang, Z Tang, H Wu, Y Lin, M Zhang, Q Zhang, M Shi, Y Liu, Y Zhou, K Lan, Y Chen. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect 2020; 9(1): 761–770 https://doi.org/10.1080/22221751.2020.1747363
110
Z Zhou, L Ren, L Zhang, J Zhong, Y Xiao, Z Jia, L Guo, J Yang, C Wang, S Jiang, D Yang, G Zhang, H Li, F Chen, Y Xu, M Chen, Z Gao, J Yang, J Dong, B Liu, X Zhang, W Wang, K He, Q Jin, M Li, J Wang. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe 2020; 27(6): 883–890.e2 https://doi.org/10.1016/j.chom.2020.04.017
111
A Ichikawa, K Kuba, M Morita, S Chida, H Tezuka, H Hara, T Sasaki, T Ohteki, VM Ranieri, CC dos Santos, Y Kawaoka, S Akira, AD Luster, B Lu, JM Penninger, S Uhlig, AS Slutsky, Y Imai. 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 https://doi.org/10.1164/rccm.201203-0508OC
112
BA Khalil, SB Shakartalla, S Goel, B Madkhana, R Halwani, AA Maghazachi, H AlSafar, B Al-Omari, MT Al Bataineh. Immune profiling of COVID-19 in correlation with SARS and MERS. Viruses 2022; 14(1): 164 https://doi.org/10.3390/v14010164
113
M Tan, Y Liu, R Zhou, X Deng, F Li, K Liang, Y Shi. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China. Immunology 2020; 160(3): 261–268 https://doi.org/10.1111/imm.13223
114
O García-Nicolás, A Godel, G Zimmer, A Summerfield. Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation. Cell Mol Immunol 2023; 20(7): 835–849 https://doi.org/10.1038/s41423-023-01039-4
115
M Liao, Y Liu, J Yuan, Y Wen, G Xu, J Zhao, L Cheng, J Li, X Wang, F Wang, L Liu, I Amit, S Zhang, Z Zhang. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020; 26(6): 842–844 https://doi.org/10.1038/s41591-020-0901-9
116
R Zhou, KK To, YC Wong, L Liu, B Zhou, X Li, H Huang, Y Mo, TY Luk, TT Lau, P Yeung, WM Chan, AK Wu, KC Lung, OT Tsang, WS Leung, IF Hung, KY Yuen, Z Chen. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity 2020; 53(4): 864–877.e5 https://doi.org/10.1016/j.immuni.2020.07.026
117
der Sluis RM van, LB Cham, A Gris-Oliver, KR Gammelgaard, JG Pedersen, M Idorn, U Ahmadov, SS Hernandez, E Cémalovic, SH Godsk, J Thyrsted, JD Gunst, SD Nielsen, JJ Jørgensen, TW Bjerg, A Laustsen, LS Reinert, D Olagnier, RO Bak, M Kjolby, CK Holm, M Tolstrup, SR Paludan, LS Kristensen, OS Søgaard, MR Jakobsen. TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS-CoV-2 infection. EMBO J 2022; 41(10): e109622 https://doi.org/10.15252/embj.2021109622
A Mansell, BJ Jenkins. 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 https://doi.org/10.1016/j.cytogfr.2013.03.007
MG Netea, BJ Kullberg, I Verschueren, JW Van Der Meer. 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 https://doi.org/10.1002/1521-4141(200010)30:10<3057::AID-IMMU3057>3.0.CO;2-P
122
MR Shalaby, A Waage, L Aarden, T Espevik. Endotoxin, tumor necrosis factor-alpha and interleukin 1 induce interleukin 6 production in vivo. Clin Immunol Immunopathol 1989; 53(3): 488–498 https://doi.org/10.1016/0090-1229(89)90010-X
123
R Schindler, J Mancilla, S Endres, R Ghorbani, SC Clark, CA Dinarello. 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 https://doi.org/10.1182/blood.V75.1.40.40
124
J Scheller, A Chalaris, D Schmidt-Arras, S Rose-John. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813(5): 878–888 https://doi.org/10.1016/j.bbamcr.2011.01.034
Y Wang, AH van Boxel-Dezaire, H Cheon, J Yang, GR Stark. 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 https://doi.org/10.1073/pnas.1315862110
128
M Mihara, M Hashizume, H Yoshida, M Suzuki, M Shiina. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2012; 122(4): 143–159 https://doi.org/10.1042/CS20110340
O Dienz, JG Rud, SM Eaton, PA Lanthier, E Burg, A Drew, J Bunn, BT Suratt, L Haynes, M Rincon. 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 https://doi.org/10.1038/mi.2012.2
131
ML Yang, CT Wang, SJ Yang, CH Leu, SH Chen, CL Wu, AL Shiau. IL-6 ameliorates acute lung injury in influenza virus infection. Sci Rep 2017; 7(1): 43829 https://doi.org/10.1038/srep43829
132
W Hou, YH Jin, HS Kang, BS Kim. 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 https://doi.org/10.1128/JVI.00724-14
133
DT Teachey, SF Lacey, PA Shaw, JJ Melenhorst, SL Maude, N Frey, E Pequignot, VE Gonzalez, F Chen, J Finklestein, DM Barrett, SL Weiss, JC Fitzgerald, RA Berg, R Aplenc, C Callahan, SR Rheingold, Z Zheng, S Rose-John, JC White, F Nazimuddin, G Wertheim, BL Levine, CH June, DL Porter, SA Grupp. 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 https://doi.org/10.1158/2159-8290.CD-16-0040
134
KA Hay, LA Hanafi, D Li, J Gust, WC Liles, MM Wurfel, JA López, J Chen, D Chung, S Harju-Baker, S Cherian, X Chen, SR Riddell, DG Maloney, CJ Turtle. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood 2017; 130(21): 2295–2306 https://doi.org/10.1182/blood-2017-06-793141
135
M Norelli, B Camisa, G Barbiera, L Falcone, A Purevdorj, M Genua, F Sanvito, M Ponzoni, C Doglioni, P Cristofori, C Traversari, C Bordignon, F Ciceri, R Ostuni, C Bonini, M Casucci, A Bondanza. 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 https://doi.org/10.1038/s41591-018-0036-4
136
C Qin, L Zhou, Z Hu, S Zhang, S Yang, Y Tao, C Xie, K Ma, K Shang, W Wang, DS Tian. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020; 71(15): 762–768 https://doi.org/10.1093/cid/ciaa248
137
T Liu, J Zhang, Y Yang, H Ma, Z Li, J Zhang, J Cheng, X Zhang, Y Zhao, Z Xia, L Zhang, G Wu, J Yi. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med 2020; 12(7): e12421 https://doi.org/10.15252/emmm.202012421
138
EA Coomes, H Haghbayan. Interleukin-6 in Covid-19: a systematic review and meta-analysis. Rev Med Virol 2020; 30(6): 1–9 https://doi.org/10.1002/rmv.2141
139
M Aziz, R Fatima, R Assaly. Elevated interleukin-6 and severe COVID-19: a meta-analysis. J Med Virol 2020; 92(11): 2283–2285 https://doi.org/10.1002/jmv.25948
140
JX Yin, YL Agbana, ZS Sun, SW Fei, HQ Zhao, XN Zhou, JH Chen, K Kassegne. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty 2023; 12(1): 43 https://doi.org/10.1186/s40249-023-01086-z
141
LA Henderson, SW Canna, GS Schulert, S Volpi, PY Lee, KF Kernan, R Caricchio, S Mahmud, MM Hazen, O Halyabar, KJ Hoyt, J Han, AA Grom, M Gattorno, A Ravelli, F De Benedetti, EM Behrens, RQ Cron, PA Nigrovic. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol 2020; 72(7): 1059–1063 https://doi.org/10.1002/art.41285
142
EJ Giamarellos-Bourboulis, MG Netea, N Rovina, K Akinosoglou, A Antoniadou, N Antonakos, G Damoraki, T Gkavogianni, ME Adami, P Katsaounou, M Ntaganou, M Kyriakopoulou, G Dimopoulos, I Koutsodimitropoulos, D Velissaris, P Koufargyris, A Karageorgos, K Katrini, V Lekakis, M Lupse, A Kotsaki, G Renieris, D Theodoulou, V Panou, E Koukaki, N Koulouris, C Gogos, A Koutsoukou. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020; 27(6): 992–1000.e3 https://doi.org/10.1016/j.chom.2020.04.009
143
N Saki, M Javan, B Moghimian-Boroujeni, RE Kast. Interesting effects of interleukins and immune cells on acute respiratory distress syndrome. Clin Exp Med 2023; 23(7): 2979–2996 https://doi.org/10.1007/s10238-023-01118-w
144
N Nishimoto, Y Kanakura, K Aozasa, T Johkoh, M Nakamura, S Nakano, N Nakano, Y Ikeda, T Sasaki, K Nishioka, M Hara, H Taguchi, Y Kimura, Y Kato, H Asaoku, S Kumagai, F Kodama, H Nakahara, K Hagihara, K Yoshizaki, T Kishimoto. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005; 106(8): 2627–2632 https://doi.org/10.1182/blood-2004-12-4602
145
P Emery, E Keystone, HP Tony, A Cantagrel, R van Vollenhoven, A Sanchez, E Alecock, J Lee, J Kremer. 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 https://doi.org/10.1136/ard.2008.092932
146
MC Genovese, JD McKay, EL Nasonov, EF Mysler, NA da Silva, E Alecock, T Woodworth, JJ Gomez-Reino. 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 https://doi.org/10.1002/art.23940
147
PM Villiger, S Adler, S Kuchen, F Wermelinger, D Dan, V Fiege, L Bütikofer, M Seitz, S Reichenbach. 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 https://doi.org/10.1016/S0140-6736(16)00560-2
148
JH Stone, M Klearman, N Collinson. Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017; 377(15): 1494–1495
149
HI Brunner, N Ruperto, Z Zuber, C Keane, O Harari, A Kenwright, P Lu, R Cuttica, V Keltsev, RM Xavier, I Calvo, I Nikishina, N Rubio-Pérez, E Alexeeva, V Chasnyk, G Horneff, V Opoka-Winiarska, P Quartier, CA Silva, E Silverman, A Spindler, E Baildam, ML Gámir, A Martin, C Rietschel, D Siri, E Smolewska, D Lovell, A Martini, Benedetti F; Paediatric Rheumatology International Trials Organisation PRINTO; Pediatric Rheumatology Collaborative Study Group (PRCSG) De. 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 https://doi.org/10.1136/annrheumdis-2014-205351
150
S Yokota, T Imagawa, M Mori, T Miyamae, Y Aihara, S Takei, N Iwata, H Umebayashi, T Murata, M Miyoshi, M Tomiita, N Nishimoto, T Kishimoto. 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 https://doi.org/10.1016/S0140-6736(08)60454-7
151
Benedetti F De, HI Brunner, N Ruperto, A Kenwright, S Wright, I Calvo, R Cuttica, A Ravelli, R Schneider, P Woo, C Wouters, R Xavier, L Zemel, E Baildam, R Burgos-Vargas, P Dolezalova, SM Garay, R Merino, R Joos, A Grom, N Wulffraat, Z Zuber, F Zulian, D Lovell, A; PRINTO; PRCSG Martini. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367(25): 2385–2395 https://doi.org/10.1056/NEJMoa1112802
152
D Khanna, CJF Lin, DE Furst, J Goldin, G Kim, M Kuwana, Y Allanore, M Matucci-Cerinic, O Distler, Y Shima, Laar JM van, H Spotswood, B Wagner, J Siegel, A Jahreis, CP; focuSSced investigators Denton. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020; 8(10): 963–974 https://doi.org/10.1016/S2213-2600(20)30318-0
153
X Xu, M Han, T Li, W Sun, D Wang, B Fu, Y Zhou, X Zheng, Y Yang, X Li, X Zhang, A Pan, H Wei. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020; 117(20): 10970–10975 https://doi.org/10.1073/pnas.2005615117
154
D Wang, B Fu, Z Peng, D Yang, M Han, M Li, Y Yang, T Yang, L Sun, W Li, W Shi, X Yao, Y Ma, F Xu, X Wang, J Chen, D Xia, Y Sun, L Dong, J Wang, X Zhu, M Zhang, Y Zhou, A Pan, X Hu, X Mei, H Wei, X Xu. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial. Front Med 2021; 15(3): 486–494 https://doi.org/10.1007/s11684-020-0824-3
155
L AnthonyM Komaroff. 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
C Salama, J Han, L Yau, WG Reiss, B Kramer, JD Neidhart, GJ Criner, E Kaplan-Lewis, R Baden, L Pandit, ML Cameron, J Garcia-Diaz, V Chávez, M Mekebeb-Reuter, de Menezes F Lima, R Shah, MF González-Lara, B Assman, J Freedman, SV Mohan. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021; 384(1): 20–30 https://doi.org/10.1056/NEJMoa2030340
160
JH Stone, MJ Frigault, NJ Serling-Boyd, AD Fernandes, L Harvey, AS Foulkes, NK Horick, BC Healy, R Shah, AM Bensaci, AE Woolley, S Nikiforow, N Lin, M Sagar, H Schrager, DS Huckins, M Axelrod, MD Pincus, J Fleisher, CA Sacks, M Dougan, CM North, YD Halvorsen, TK Thurber, Z Dagher, A Scherer, RS Wallwork, AY Kim, S Schoenfeld, P Sen, TG Neilan, CA Perugino, SH Unizony, DS Collier, MA Matza, JM Yinh, KA Bowman, E Meyerowitz, A Zafar, ZD Drobni, MB Bolster, M Kohler, KM D’Silva, J Dau, MM Lockwood, C Cubbison, BN Weber, MK; BACC Bay Tocilizumab Trial Investigators Mansour. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med 2020; 383(24): 2333–2344 https://doi.org/10.1056/NEJMoa2028836
161
O Hermine, X Mariette, PL Tharaux, M Resche-Rigon, R Porcher, P; CORIMUNO-19 Collaborative Group Ravaud. 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 https://doi.org/10.1001/jamainternmed.2020.6820
162
IO Rosas, N Bräu, M Waters, RC Go, BD Hunter, S Bhagani, D Skiest, MS Aziz, N Cooper, IS Douglas, S Savic, T Youngstein, Sorbo L Del, Gracian A Cubillo, La Zerda DJ De, A Ustianowski, M Bao, S Dimonaco, E Graham, B Matharu, H Spotswood, L Tsai, A Malhotra. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med 2021; 384(16): 1503–1516 https://doi.org/10.1056/NEJMoa2028700
163
M Colaneri, L Bogliolo, P Valsecchi, P Sacchi, V Zuccaro, F Brandolino, C Montecucco, F Mojoli, EM Giusti, R Bruno, Covid Irccs San Matteo Pavia Task Force The. Tocilizumab for treatment of severe COVID-19 patients: preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms 2020; 8(5): 695 https://doi.org/10.3390/microorganisms8050695
164
C Campochiaro, E Della-Torre, G Cavalli, Luca G De, M Ripa, N Boffini, A Tomelleri, E Baldissera, P Rovere-Querini, A Ruggeri, G Monti, Cobelli F De, A Zangrillo, M Tresoldi, A Castagna, L; TOCI-RAF Study Group Dagna. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med 2020; 76: 43–49 https://doi.org/10.1016/j.ejim.2020.05.021
165
AS Soin, K Kumar, NS Choudhary, P Sharma, Y Mehta, S Kataria, D Govil, V Deswal, D Chaudhry, PK Singh, A Gupta, V Agarwal, S Kumar, SA Sangle, R Chawla, S Narreddy, R Pandit, V Mishra, M Goel, AV Ramanan. 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 https://doi.org/10.1016/S2213-2600(21)00081-3
166
C Salvarani, G Dolci, M Massari, DF Merlo, S Cavuto, L Savoldi, P Bruzzi, F Boni, L Braglia, C Turrà, PF Ballerini, R Sciascia, L Zammarchi, O Para, PG Scotton, WO Inojosa, V Ravagnani, ND Salerno, PP Sainaghi, A Brignone, M Codeluppi, E Teopompi, M Milesi, P Bertomoro, N Claudio, M Salio, M Falcone, G Cenderello, L Donghi, Bono V Del, PL Colombelli, A Angheben, A Passaro, G Secondo, R Pascale, I Piazza, N Facciolongo, M; RCT-TCZ-COVID-19 Study Group Costantini. 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 https://doi.org/10.1001/jamainternmed.2020.6615
167
VC Veiga, J Prats, DLC Farias, RG Rosa, LK Dourado, FG Zampieri, FR Machado, RD Lopes, O Berwanger, LCP Azevedo, A Avezum, TC Lisboa, SSO Rojas, JC Coelho, RT Leite, JC Carvalho, LEC Andrade, AF Sandes, MCT Pintao, CG Castro. , 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 https://doi.org/10.1136/bmj.n84
168
P Toniati, S Piva, M Cattalini, E Garrafa, F Regola, F Castelli, F Franceschini, P Airò, C Bazzani, EA Beindorf, M Berlendis, M Bezzi, N Bossini, M Castellano, S Cattaneo, I Cavazzana, GB Contessi, M Crippa, A Delbarba, Peri E De, A Faletti, M Filippini, M Filippini, M Frassi, M Gaggiotti, R Gorla, M Lanspa, S Lorenzotti, R Marino, R Maroldi, M Metra, A Matteelli, D Modina, G Moioli, G Montani, ML Muiesan, S Odolini, E Peli, S Pesenti, MC Pezzoli, I Pirola, A Pozzi, A Proto, FA Rasulo, G Renisi, C Ricci, D Rizzoni, G Romanelli, M Rossi, M Salvetti, F Scolari, L Signorini, M Taglietti, G Tomasoni, LR Tomasoni, F Turla, A Valsecchi, D Zani, F Zuccalà, F Zunica, E Focà, L Andreoli, N Latronico. 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 https://doi.org/10.1016/j.autrev.2020.102568
169
TAC Snow, N Saleem, G Ambler, E Nastouli, M Singer, N Arulkumaran. 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 https://doi.org/10.1007/s00134-021-06416-z
170
C Kyriakopoulos, G Ntritsos, A Gogali, H Milionis, E Evangelou, K Kostikas. Tocilizumab administration for the treatment of hospitalized patients with COVID-19: a systematic review and meta-analysis. Respirology 2021; 26(11): 1027–1040 https://doi.org/10.1111/resp.14152
171
Collaborative Group RECOVERY. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2021; 397(10285): 1637–1645 https://doi.org/10.1016/S0140-6736(21)00676-0
172
N Broman, T Feuth, T Vuorinen, M Valtonen, U Hohenthal, E Löyttyniemi, T Hirvioja, P Jalava-Karvinen, H Marttila, M Nordberg, J Oksi. 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 https://doi.org/10.1016/j.cmi.2022.02.027
173
S Sciascia, F Aprà, A Baffa, S Baldovino, D Boaro, R Boero, S Bonora, A Calcagno, I Cecchi, G Cinnirella, M Converso, M Cozzi, P Crosasso, Iaco F De, Perri G Di, M Eandi, R Fenoglio, M Giusti, D Imperiale, G Imperiale, S Livigni, E Manno, C Massara, V Milone, G Natale, M Navarra, V Oddone, S Osella, P Piccioni, M Radin, D Roccatello, D Rossi. 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
JM Galván-Román, SC Rodríguez-García, E Roy-Vallejo, A Marcos-Jiménez, S Sánchez-Alonso, C Fernández-Díaz, A Alcaraz-Serna, T Mateu-Albero, P Rodríguez-Cortes, I Sánchez-Cerrillo, L Esparcia, P Martínez-Fleta, C López-Sanz, L Gabrie, Campo Guerola L Del, C Suárez-Fernández, J Ancochea, A Canabal, P Albert, DA Rodríguez-Serrano, JM Aguilar, Arco C Del, Los Santos I de, L García-Fraile, la Cámara R de, JM Serra, E Ramírez, T Alonso, P Landete, JB Soriano, E Martín-Gayo, Torres A Fraile, Cruz ND Zurita, R García-Vicuña, L Cardeñoso, F Sánchez-Madrid, A Alfranca, C Muñoz-Calleja, I; REINMUN-COVID Group González-Álvaro. 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 https://doi.org/10.1016/j.jaci.2020.09.018
175
GW Strohbehn, BL Heiss, SJ Rouhani, JA Trujillo, J Yu, AJ Kacew, EF Higgs, JC Bloodworth, A Cabanov, RC Wright, AK Koziol, A Weiss, K Danahey, TG Karrison, CC Edens, I Bauer Ventura, NN Pettit, BK Patel, J Pisano, ME Strek, TF Gajewski, MJ Ratain, PD Reid. 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 https://doi.org/10.1002/cpt.2117
176
S Hashimoto, K Yoshizaki, K Uno, H Kitajima, T Arai, Y Tamura, H Morishita, H Matsuoka, Y Han, S Minamoto, T Hirashima, T Yamada, Y Kashiwa, M Kameda, S Yamaguchi, Y Tsuchihashi, M Iwahashi, E Nakayama, T Shioda, T Nagai, T Tanaka. 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 https://doi.org/10.3389/fmed.2021.734838
177
Y Gokhale, R Mehta, U Kulkarni, N Karnik, S Gokhale, U Sundar, S Chavan, A Kor, S Thakur, T Trivedi, N Kumar, S Baveja, A Wadal, S Kolte, A Deolankar, S Pednekar, L Kalekar, R Padiyar, C Londhe, P Darole, S Pol, SB Gokhe, N Padwal, D Pandey, D Yadav, A Joshi, H Badgujar, M Trivedi, P Shah, P Bhavsar. 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 https://doi.org/10.1186/s12879-021-05912-3
178
D Zeraatkar, E Cusano, JPD Martínez, A Qasim, S Mangala, E Kum, JJ Bartoszko, T Devji, T Agoritsas, G Guyatt, A Izcovich, AM Khamis, F Lamontagne, B Rochwerg, P Vandvik, R Brignardello-Petersen, RAC Siemieniuk. 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 https://doi.org/10.1136/bmjmed-2021-000036
179
R Rossotti, G Travi, N Ughi, M Corradin, C Baiguera, R Fumagalli, M Bottiroli, M Mondino, M Merli, A Bellone, A Basile, R Ruggeri, F Colombo, M Moreno, S Pastori, CF Perno, P Tarsia, OM Epis, M; Niguarda COVID-19 Working Group Puoti. 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 https://doi.org/10.1016/j.jinf.2020.07.008
180
C Gabay, P Emery, R van Vollenhoven, A Dikranian, R Alten, K Pavelka, M Klearman, D Musselman, S Agarwal, J Green, A Kavanaugh, AS Investigators. 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 https://doi.org/10.1016/S0140-6736(13)60250-0
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
Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M WHO, CL Vale, PJ Godolphin, D Fisher, JPT Higgins, F Spiga, J Savovic, J Tierney, G Baron, JS Benbenishty, LR Berry, N Broman, AB Cavalcanti, R Colman, Buyser SL De, LPG Derde, P Domingo, SF Omar, A Fernandez-Cruz, T Feuth, F Garcia, R Garcia-Vicuna, I Gonzalez-Alvaro, AC Gordon, R Haynes, O Hermine, PW Horby, NK Horick, K Kumar, BN Lambrecht, MJ Landray, L Leal, DJ Lederer, E Lorenzi, X Mariette, N Merchante, NA Misnan, SV Mohan, MC Nivens, J Oksi, JA Perez-Molina, R Pizov, R Porcher, S Postma, R Rajasuriar, AV Ramanan, P Ravaud, PD Reid, A Rutgers, A Sancho-Lopez, TB Seto, S Sivapalasingam, AS Soin, N Staplin, JH Stone, GW Strohbehn, J Sunden-Cullberg, J Torre-Cisneros, LW Tsai, Hoogstraten H van, Meerten T van, VC Veiga, PE Westerweel, S Murthy, JV Diaz, JC Marshall, JAC Sterne. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 2021; 326(6): 499–518 https://doi.org/10.1001/jama.2021.11330
184
K Yamakawa, R Yamamoto, T Terayama, H Hashimoto, T Ishihara, G Ishimaru, H Imura, H Okano, C Narita, T Mayumi, H Yasuda, K Yamada, H Yamada, T Kawasaki, N Shime, K Doi, M Egi, H Ogura, M Aihara, S Kushimoto, O; Special Committee of the Japanese Clinical Practice Guidelines for the Management of Sepsis Nishida, Shock 2020 (J-SSCG 2020) Septic, COVID-19 Task Force the. Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022). Acute Med Surg 2022; 9(1): e789 https://doi.org/10.1002/ams2.789
185
M Bartoletti, O Azap, A Barac, L Bussini, O Ergonul, R Krause, JR Paño-Pardo, NR Power, M Sibani, BG Szabo, S Tsiodras, PE Verweij, I Zollner-Schwetz, J Rodríguez-Baño. ESCMID COVID-19 living guidelines: drug treatment and clinical management. Clin Microbiol Infect 2022; 28(2): 222–238 https://doi.org/10.1016/j.cmi.2021.11.007
