The Role of Inflammatory Cytokines (Interleukin-1 and Interleukin-6) as a Potential Biomarker in the Different Stages of COVID-19 (Mild, Severe, and Critical)
Publication: Journal of Interferon & Cytokine Research
Volume 43, Issue Number 4
Abstract
Cytokine storm refers to the overproduction of immune and inflammatory cells and their proteins (cytokines) [interleukin (IL)-1 and IL-6] causing acute respiratory distress syndrome in COVID-19. COVID-19 causes inflammatory reactions, and patients with COVID-19 had categorized as mild, severe, and critical after reviewing previous studies. Then, it is crucial to find immune-inflammatory indicators that might predict the disorder severity and the prognosis primarily for guiding medical therapy in the face of this unexpectedly developing unique infectious disease. Higher levels of IL-6 and IL-1 levels might be seen in patients with COVID-19 at each stage. In addition, IL-1-induced IL-6 assists in the synthesis of liver C-reactive protein (CRP) in acute phase responses. Recent studies suggested that IL-6 levels are an independent predictor of COVID-19 illness because they were significantly higher in patients with severe than with mild COVID-19 symptoms. Anakinra and tocilizumab (TCZ) are beneficial in lowing mortality in COVID-19 patients; however, information on their safety and efficacy is scarce. The aim of this study was to investigate the role of inflammatory cytokines (IL-1 and IL-6) as potential biomarkers in the different stages (mild, severe, and critical) of COVID-19. A systematic search during the years 2021–2022 using the keywords SARS-CoV-2, COVID-19, IL-6, IL-1, CRP, mild stage, severe stage, critical stage, cytokine storm, tocilizumab, and anakinra was performed in PubMed and Google Scholar databases. This study reviews studies that have investigated the role of high levels of these cytokines in the severity of the disease in patients with COVID-19 and the inhibitory function of TCZ and anakinra in preventing mechanical ventilation and patient mortality. According to the result, studies suggest that decreased innate immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in association with the production of inflammatory cytokines is the determining and driving function of COVID-19.
Get full access to this article
View all available purchase options and get full access to this article.
References
Akhmerov A, Marbán E. COVID-19 and the heart. Circ Res 2020;126(10):1443–1455;
Alijotas-Reig J, Esteve-Valverde E, Belizna C, et al. Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review. Autoimmunity Rev 2020;19(7):102569.
Alsuliman T, Alasadi L, Alkharat B, et al. A review of potential treatments to date in COVID-19 patients according to the stage of the disease. Curr Res Transl Med 2020;68(3):93–104;
Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: Case series. Ann Rheum Dis 2020;79(10):1381–1382;
Atagündüz P, Keser G, Soy M. Interleukin-1 inhibitors and vaccination including COVID-19 in inflammatory rheumatic diseases: A nonsystematic review. Front Immunol 2021;12:734279;
Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol 2020;92(11):2283–2285;
Baig AM, Khaleeq A, Ali U, et al. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host–virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci 2020;11(7):995–998.
Bailie CR, Franklin L, Nicholson S, et al. Symptoms and laboratory manifestations of mild COVID-19 in a repatriated cruise ship cohort. Epidemiol Infect 2021;149:e44;
Baj J, Karakuła-Juchnowicz H, Teresiński G, et al. COVID-19: Specific and non-specific clinical manifestations and symptoms: The current state of knowledge. J Clin Med 2020;9(6):1753;
Behrens EM, Koretzky GA. Review: Cytokine storm syndrome: Looking toward the precision medicine era. Arthritis Rheumatol 2017;69(6):1135–1143;
Biggioggero M, Crotti C, Becciolini A, et al. Tocilizumab in the treatment of rheumatoid arthritis: An evidence-based review and patient selection. Drug Des Devel Ther 2019;13:57–70;
Birra D, Benucci M, Landolfi L, et al. COVID 19: A clue from innate immunity. Immunol Res 2020;68(3):161–168.
Blanco-Melo D, Nilsson-Payant BE, Liu W-C, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020;181(5):1036–1045.e1039;
Brocker C, Thompson D, Matsumoto A, et al. Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum Genomics 2010;5(1):30–55;
Cai Q, Huang D, Ou P, et al. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy 2020;75(7):1742–1752;
Campochiaro C, Della-Torre E, Cavalli G, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: Aa single-centre retrospective cohort study. Eur J Intern Med 2020;76:43–49;
Cappanera S, Palumbo M, Kwan SH, et al. When does the cytokine storm begin in COVID-19 patients? A quick score to recognize it. J Clin Med 2021;10(2):297;
Cauchois R, Koubi M, Delarbre D, et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19. Proc Natl Acad Sci U S A 2020;117(32):18951–18953.
Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study. Lancet Rheumatol 2020a;2(6):e325–e331;
Cavalli G, Dinarello CA. Anakinra therapy for non-cancer inflammatory diseases. Front Pharmacol 2018;9:1157;
Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (Oxford) 2015;54(12):2134–2144;
Cavalli G, Farina N, Campochiaro C, et al. Repurposing of biologic and targeted synthetic anti-rheumatic drugs in COVID-19 and hyper-inflammation: A comprehensive review of available and emerging evidence at the peak of the pandemic. Front Pharmacol 2020b;11:598308;
Cavalli G, Larcher A, Tomelleri A, et al. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: A cohort study. Lancet Rheumatol 2021a;3(4):e253–e261;
Cavalli G, Larcher A, Tomelleri A, et al. Interleukin-1 and interleukin-6 inhibition in patients with COVID-19 and hyperinflammation—Authors' reply. Lancet Rheumatol 2021b;3(4):e248–e249;
Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 2016;19(2):181–193;
Channappanavar R, Perlman S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39(5):529–539;
Chen L, Liu HG, Liu W, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2020a;43(0):E005;
Chen LYC, Hoiland RL, Stukas S, et al. Confronting the controversy: Interleukin-6 and the COVID-19 cytokine storm syndrome. Eur Respir J 2020b;56(4):2003006;
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020c;395(10223):507–513;
Chen X, Zhao B, Qu Y, et al. Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019. Clin Infect Dis 2020d;71(8):1937–1942;
Cheung CY, Poon LL, Ng IH, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol 2005;79(12):7819–7826;
China TSCotPsRo. Diagnosis and treatment protocol for novel coronavirus pneumonia. 7th edition. 2020. Available from: www.gov.cn/zhengce/zhengceku/2020-03/04/5486705/files/ae61004f930d47598711a0d4cbf874a9.pdf [Last accessed: July 26, 2022].
Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 2017;39(5):517–528;
Conti P, Caraffa A, Gallenga C, et al. Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: A promising inhibitory strategy. J Biol Regul Homeost Agents 2020a;34(6):1971–1975;
Conti P, Caraffa A, Tetè G, et al. 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 2020b;34(5):1629–1632;.
Conti P, Gallenga C, Tetè Get al. How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1. J Biol Regul Homeost Agents 2020c;34(2):333–338;
Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents 2020d;34(2):327–331;
Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-analysis. Rev Med Virol 2020;30(6):1–9.
Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, et al. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020;54:62–75;
Cox MA, Kahan SM, Zajac AJ. Anti-viral CD8 T cells and the cytokines that they love. Virology 2013;435(1):157–169;
Cron RQ. COVID-19 cytokine storm: Targeting the appropriate cytokine. Lancet Rheumatol 2021;3(4):e236–e237;
Darif D, Hammi I, Kihel A, et al. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong? Microb Pathog 2021;153:104799;
Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res 2015;35(4):252–264;
Day JW, Fox TA, Halsey R, et al. IL-1 blockade with anakinra in acute leukaemia patients with severe COVID-19 pneumonia appears safe and may result in clinical improvement. Br J Haematol 2020;190(2):e80–e83.
Del Sole F, Farcomeni A, Loffredo L, et al. Features of severe COVID-19: A systematic review and meta-analysis. Eur J Clin Invest 2020;50(10):e13378;
Della-Torre E, Lanzillotta M, Campochiaro C, et al. Respiratory impairment predicts response to IL-1 and IL-6 blockade in COVID-19 patients with severe pneumonia and hyper-inflammation. Front Immunol 2021;12:1564.
Dhimolea E. Canakinumab. MAbs 2010;2(1):3–13;
Dholaria BR, Bachmeier CA, Locke F. Mechanisms and management of chimeric antigen receptor T-cell therapy-related toxicities. BioDrugs 2019;33(1):45–60;
Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020;11:827;
Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 2009;27:519–550.
Ding C, Jones G. Anti-interleukin-6 receptor antibody treatment in inflammatory autoimmune diseases. Rev Recent Clin Trials 2006;1(3):193–200;
Donina ZA, Baranova EV, Aleksandrova NP. A comparative assessment of effects of major mediators of acute phase response (IL-1, TNF-α, IL-6) on breathing pattern and survival rate in rats with acute progressive hypoxia. J Evol Biochem Physiol 2021;57(4):936–944;
Eskilsson A, Mirrasekhian E, Dufour S, et al. Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis. J Neurosci 2014;34(48):15957–15961
Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 2015;15(6):335–349.
Fang Y, Zhang H, Xu Y, et al. CT manifestations of two cases of 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology 2020;295(1):208–209.
Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol 2015;1282:1–23;
Filocamo G, Mangioni D, Tagliabue P, et al. Use of anakinra in severe COVID-19: A case report. Int J Infect Dis 2020;96:607–609.
Focà E. Vademecum for the treatment of people with COVID-2.0, 13 March 2020: Lombardy section of the italian society of infectious and tropical diseases. Infez Med 2020;28(2):143–152.
Franzetti M, Pozzetti U, Carugati M, et al. Interleukin-1 receptor antagonist anakinra in association with remdesivir in severe COVID-19: A case report. Int J Infect Dis 2020;97:215–218.
Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect 2020;80(6):656–665;
Fung S-Y, Yuen K-S, Ye Z-W, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: Lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9(1):558–570.
Gao Y, Li T, Han M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020;92(7):791–796;
Gordon AC, Angus DC, Derde LPG. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. Reply. N Engl J Med 2021a;385(12):1147–1149;
Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med 2021b;384(16):1491–1502;
Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 2016;12(5):259–268;
Gubernatorova EO, Gorshkova EA, Polinova AI, et al. IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev 2020;53:13–24;
Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369(6504):718–724;
Hahn WH, Song JH, Kim H, et al. Is procalcitonin to C-reactive protein ratio useful for the detection of late onset neonatal sepsis? J Matern Fetal Neonatal Med 2018;31(6):822–826;
Harnack U, Johnen H, Pecher G. IL-1 receptor antagonist anakinra enhances tumour growth inhibition in mice receiving peptide vaccination and beta-(1–3),(1–6)-D-glucan. Anticancer Res 2010;30(10):3959–3965
Hassan SA, Sheikh FN, Jamal S, et al. Coronavirus (COVID-19): A review of clinical features, diagnosis, and treatment. Cureus 2020;12(3):e7355;
Henderson LA, Canna SW, Schulert GS, et al. On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol 2020;72(7):1059–1063.
Henry BM, de Oliveira MHS, Benoit S, et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis. Clin Chem Lab Med 2020;58(7):1021–1028;
Hocker AD, Stokes JA, Powell FL, et al. The impact of inflammation on respiratory plasticity. Exp Neurol 2017;287(Pt 2):243–253;
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271–280.e278;
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497–506;
Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: A cohort study. Lancet Rheumatol 2020;2(7):e393–e400.
Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: Structure-function relationship(s). Microsc Res Tech 2000;50(3):184–195;
Ikonomidis I, Lekakis JP, Nikolaou M, et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 2008;117(20):2662–2669;
Jafarzadeh A, Chauhan P, Saha B, et al. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci 2020;257:118102;
Jones G, Ding C. Tocilizumab: A review of its safety and efficacy in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 2010;3:81–89;
Kandere-Grzybowska K, Letourneau R, Kempuraj D, et al. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol 2003;171(9):4830–4836;
Kaneko N, Kurata M, Yamamoto T, et al. The role of interleukin-1 in general pathology. Inflamm Regen 2019;39(1):1–16.
Kaur S, Bansal Y, Kumar R, et al. A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. Bioorg Med Chem 2020;28(5):115327.
Khiali S, Rezagholizadeh A, Entezari-Maleki T. A comprehensive review on sarilumab in COVID-19. Expert Opin Biol Ther 2021;21(5):615-626;
Kim JS, Lee JY, Yang JW, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics 2021;11(1):316–329;
Kritas SK, Ronconi G, Caraffa A, et al. Mast cells contribute to coronavirus-induced inflammation: New anti-inflammatory strategy. J Biol Regul Homeost Agents 2020;34(1):9–14;
Leon LR. Invited review: Cytokine regulation of fever: Studies using gene knockout mice. J Appl Physiol (1985) 2002;92(6):2648–2655;
Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 2020;10(2):102–108.
Lin L, Lu L, Cao W, et al. Hypothesis for potential pathogenesis of SARS-CoV-2 infection—A review of immune changes in patients with viral pneumonia. Emerg Microbes Infect 2020;9(1):727–732;
Liu B, Li M, Zhou Z, et al. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun 2020a;111:102452;
Liu F, Li L, Xu M, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020b;127:104370;
Liu J, Li S, Liu J, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020c;55:102763;
Liu QQ, Cheng A, Wang Y, et al. Cytokines and their relationship with the severity and prognosis of coronavirus disease 2019 (COVID-19): A retrospective cohort study. BMJ Open 2020d;10(11):e041471;
Lotfi M, Hamblin MR, Rezaei N. COVID-19: Transmission, prevention, and potential therapeutic opportunities. Clin Chim Acta 2020;508:254–266;
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395(10224):565–574;
Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92(7):814–818.
Mardi A, Meidaninikjeh S, Nikfarjam S, et al. Interleukin-1 in COVID-19 infection: Immunopathogenesis and possible therapeutic perspective. Viral Immunol 2021;34(10):679–688.
Mastroianni A, Greco S, Chidichimo L, et al. Early use of canakinumab to prevent mechanical ventilation in select COVID-19 patients: A retrospective, observational analysis. Int J Immunopathol Pharmacol 2021;35:20587384211059675;
McCarty D, Robinson A. Efficacy and safety of sarilumab in patients with active rheumatoid arthritis. Ther Adv Musculoskelet Dis 2018;10(3):61–67;
McGonagle D, Sharif K, O'Regan A, et al. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19(6):102537;
Mehta P, McAuley DF, Brown M, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033–1034;
Merza MY, Hwaiz RA, Hamad BK, et al. Analysis of cytokines in SARS-CoV-2 or COVID-19 patients in Erbil city, Kurdistan Region of Iraq. PLoS One 2021;16(4):e0250330;
Mooiweer E, Luijk B, Bonten MJ, et al. C-Reactive protein levels but not CRP dynamics predict mortality in patients with pneumococcal pneumonia. J Infect 2011;62(4):314–316;
Morris G, Bortolasci CC, Puri BK, et al. The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all? Cytokine 2021;144:155593;
Morris G, Bortolasci CC, Puri BK, et al. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sci 2020;258:118166;
Mravec B, Horvathova L, Padova A. Brain under stress and Alzheimer's disease. Cell Mol Neurobiol 2018;38(1):73–84.
Ng PC, Lam CW, Li AM, et al. Inflammatory cytokine profile in children with severe acute respiratory syndrome. Pediatrics 2004;113(1 Pt 1):e7–e14;
NIH. Clinical Spectrum of SARS-CoV-2 Infection. 2021. Available from: https://www.covid19treatmentguidelines.nih.gov/overview/ [Last accessed: October 30, 2022].
NIH. Introduction to Critical Care Management of Adults with COVID-19. May 31, 2022. Available from: Covid-19 treatment guide lines.nih.gov/management/critical-care-for-adults/introduction-to-critical-care-for-adults/
Nishiura H, Kobayashi T, Miyama T, et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J Infect Dis 2020;94:154–155;
Okabayashi T, Kariwa H, Yokota S, et al. Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections. J Med Virol 2006;78(4):417–424;
Ouassou H, Kharchoufa L, Bouhrim M, et al. The pathogenesis of coronavirus disease 2019 (COVID-19): Evaluation and prevention. J Immunol Res 2020;2020:1357983;
Paniri A, Akhavan-Niaki H. Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation. Life Sci 2020;257:118114;
Pedersen SF, Ho YC. SARS-CoV-2: A storm is raging. J Clin Invest 2020;130(5):2202–2205;
Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111(12):1805–1812;
Perlman S, Netland J. Coronaviruses post-SARS: Update on replication and pathogenesis. Nat Rev Microbiol 2009;7(6):439–450;
Perricone C, Triggianese P, Bartoloni E, et al. The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19. J Autoimmun 2020;111:102468.
Pontali E, Volpi S, Antonucci G, et al. Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease. J Allergy Clin Immunol 2020;146(1):213–215.
Powers NE, Swartzwelter B, Marchetti C, et al. PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis. J Biol Chem 2020;295(3):868–882;
Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020;38(1):1–9;
Puhlmann M, Weinreich DM, Farma JM, et al. Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity. J Transl Med 2005;3:37;
Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020;71(15):762–768;
Ragab D, Salah Eldin H, Taeimah M, et al. The COVID-19 cytokine storm; what we know so far. Front Immunol 2020;11:1446;
Rocio L, Alberto U, Paloma T, et al. Interleukin-6-based mortality risk model for hospitalised COVID-19 patients. J Allergy Clin Immunol 2020;146(4):799–807.e9.
Romagnoli S, Peris A, De Gaudio AR, et al. SARS-CoV-2 and COVID-19: From the bench to the bedside. Physiol Rev 2020;100(4):1455–1466;
Rostamian A, Ghazanfari T, Arabkheradmand J, et al. Interleukin-6 as a potential predictor of COVID-19 disease severity in hospitalized patients and its association with clinical laboratory routine tests. Immunoregulation 2020;3(1):29–36;
Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46(5):846–848;
Russell B, Moss C, George G, et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19—A systematic review of current evidence. Ecancermedicalscience 2020;14:1022;
Saha A, Sharma AR, Bhattacharya M, et al. Tocilizumab: A therapeutic option for the treatment of cytokine storm syndrome in COVID-19. Arch Med Res 2020;51(6):595–597;
Salvatierra J, Aomar-Millán IF, Hernández-Quero J. Interleukin-1 and interleukin-6 inhibition in patients with COVID-19 and hyperinflammation. Lancet Rheumatol 2021;3(4):e248;
Santa Cruz A, Mendes-Frias A, Oliveira AI, et al. Interleukin-6 is a biomarker for the development of fatal severe acute respiratory syndrome coronavirus 2 pneumonia. Front Immunol 2021;12:613422;
Scavone C, Brusco S, Bertini M, et al. Current pharmacological treatments for COVID-19: What's next? Br J Pharmacol 2020;177(21):4813–4824.
Scherger S, Henao-Martínez A, Franco-Paredes C, et al. Rethinking interleukin-6 blockade for treatment of COVID-19. Med Hypotheses 2020;144:110053;
Schön MP, Berking C, Biedermann T, et al. COVID-19 and immunological regulations—From basic and translational aspects to clinical implications. J Dtsch Dermatol Ges 2020;18(8):795–807;
Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a prior phase III trial. Crit Care Med 2016;44(2):275–281;
Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013;13(12):875–887;
Shetty R, Ghosh A, Honavar SG, et al. Therapeutic opportunities to manage COVID-19/SARS-CoV-2 infection: Present and future. Indian J Ophthalmol 2020;68(5):693.
Shi Y, Wang Y, Shao C, et al. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020;27(5):1451–1454;
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer 2018;6(1):56;
Shimizu M. Clinical Features of Cytokine Storm Syndrome. In: Cytokine Storm Syndrome. (Cron RQ and Behrens EM, eds). Springer; 2019; pp. 31–41.
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39(5):405–407;
Sinha P, Matthay MA, Calfee CS. Is a “Cytokine Storm” Relevant to COVID-19? JAMA Intern Med 2020;180(9):1152–1154;
Slaats J, Ten Oever J, van de Veerdonk FL, et al. IL-1β/IL-6/CRP and IL-18/ferritin: Distinct inflammatory programs in infections. PLoS Pathog 2016;12(12):e1005973;
Somagutta MKR, Lourdes Pormento MK, Hamid P, et al. The safety and efficacy of anakinra, an interleukin-1 antagonist in severe cases of COVID-19: A systematic review and meta-analysis. Infect Chemother 2021;53(2):221–237;
Somers EC, Eschenauer GA, Troost JP, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis 2021;73(2):e445–e454;
Song P, Li W, Xie J, et al. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta 2020;509:280–287.
Soy M, Keser G, Atagündüz P, et al. Cytokine storm in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39(7):2085–2094;
Stebbing J, Phelan A, Griffin I, et al. COVID-19: Combining antiviral and anti-inflammatory treatments. Lancet Infect Dis 2020;20(4):400–402;
Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med 2020;383(24):2333–2344.
Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016;24(6):490–502;
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014;6(10):a016295;
Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy 2016;8(8):959–970;
Tau G, Rothman P. Biologic functions of the IFN-gamma receptors. Allergy 1999;54(12):1233–1251;
Theoblad SJ, Simonis A, Kreer C, et al. The SARS-CoV-2 spike protein primes inflammasome-mediated interleukin-1-beta secretion in COVID-19 patient-derived macrophages. Res Square 2020;
Tisoncik JR, Korth MJ, Simmons CP, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76(1):16–32;
To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: An observational cohort study. Lancet Infect Dis 2020;20(5):565–574;
Toldo S, Bussani R, Nuzzi V, et al. Inflammasome formation in the lungs of patients with fatal COVID-19. Inflamm Res 2021;70(1):7–10;
Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect 2020;50(4):382–383;
Vallejo S, Palacios E, Romacho T, et al. The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats. Cardiovasc Diabetol 2014;13:158;
Végran F, Berger H, Boidot R, et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH 9 cells. Nat Immunol 2014;15(8):758–766.
Vultaggio A, Vivarelli E, Virgili G, et al. Prompt predicting of early clinical deterioration of moderate-to-severe COVID-19 patients: Usefulness of a combined score using IL-6 in a preliminary study. J Allergy Clin Immunol Pract 2020;8(8):2575–2581.e2572;
Wan S, Yi Q, Fan S, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv 2020;2020:20021832.
Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med 2008;26(6):711–715;
Wang Z, Yang B, Li Q, et al. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis 2020;71(15):769–777.
Weiss SR, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 2005;69(4):635–664;
Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136(1):95–103;
World Health Organization. Laboratory Testing for Coronavirus Disease 2019 (COVID-19) in Suspected Human Cases: Interim Guidance. World Health Organization: Geneva; 2020.
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;
Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020a;117(20):10970–10975;
Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020b;8(4):420–422;
Yan W, Chen D, Bigambo FM, et al. Differences of blood cells, lymphocyte subsets and cytokines in COVID-19 patients with different clinical stages: A network meta-analysis. BMC Infect Dis 2021;21(1):156;
Yang P, Ding Y, Xu Z, et al. Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. medRXiv 2020a;2020:20028068.
Yang Y, Shen C, Li J, et al. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. medRxiv 2020b;2020:20029975.
Yao XH, Li TY, He ZC, et al. A pathological report of three COVID-19 cases by minimal invasive autopsies [in Chinese]. Zhonghua Bing Li Xue Za Zhi 2020;49(5):411–417;
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect 2020;80(6):607–613;
Yongwen C, Feng Z, Diao B, et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv 2020;2020:20045427.
Zhang C, Durer S, Thandra KC, et al. Chimeric Antigen Receptor T-Cell Therapy. StatPearls Publishing LLC.: Treasure Island, FL; 2022.
Zhang C, Wu Z, Jia-Wen L, et al. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor antagonist Tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 2020a;55(5):105954.
Zhang C, Wu Z, Li JW, et al. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 2020b;55(5):105954;
Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol 2020c;214:108393.
Zhao Y, Qin L, Zhang P, et al. Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight 2020;5(13):e139834;
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020a;395(10229):1054–1062;
Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRXiv 2020b;2020:945576.
Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev 2020c;7(6):998–1002.
Zumla A, Hui DS, Azhar EI, et al. Reducing mortality from 2019-nCoV: Host-directed therapies should be an option. Lancet 2020;395(10224):e35–e36;
Information & Authors
Information
Published In
Journal of Interferon & Cytokine Research
Volume 43 • Issue Number 4 • April 2023
Pages: 147 - 163
PubMed: 37062817
Copyright
Copyright 2023, Mary Ann Liebert, Inc., publishers.
History
Published online: 12 April 2023
Published in print: April 2023
Accepted: 16 February 2023
Received: 4 December 2022
Topics
Authors
Authors' Contributions
M.G.N., G.J., O.K., and A.N.: drafting of the article. A.N. and S.C.: conception, design, and supervision.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
Metrics & Citations
Metrics
Citations
Export Citation
Export citation
Select the format you want to export the citations of this publication.
View Options
Get Access
Access content
To read the fulltext, please use one of the options below to sign in or purchase access.⚠ Society Access
If you are a member of a society that has access to this content please log in via your society website and then return to this publication.