The pathogenesis and treatment of the `Cytokine Storm' in COVID-19

  • Qing Ye
    Affiliations
    National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children's Hospital, Zhejiang University School of Medicine, No 3333, Binsheng Road, Hangzhou 310052, China
    Search for articles by this author
  • Bili Wang
    Affiliations
    National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children's Hospital, Zhejiang University School of Medicine, No 3333, Binsheng Road, Hangzhou 310052, China
    Search for articles by this author
  • Jianhua Mao
    Correspondence
    Corresponding author.
    Affiliations
    National Clinical Research Center for Child Health, National Children's Regional Medical Center, the Children's Hospital, Zhejiang University School of Medicine, No 3333, Binsheng Road, Hangzhou 310052, China
    Search for articles by this author
Published:April 10, 2020DOI:https://doi.org/10.1016/j.jinf.2020.03.037

      Summary

      Cytokine storm is a general term applied to maladaptive cytokine release in response to infection and other stimuli. The pathogenesis is complex but includes loss of regulatory control of proinflammatory cytokine production, both at local and systemic levels. The disease progresses rapidly, and the mortality is high. Some evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, severe deterioration in some patients has been closely associated with dysregulated and excessive cytokine release. This article reviews what we know of the mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in an attempt to provide some background to inform future guidance for clinical treatment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Infection
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lai C.-C.
        • Shih T.-P.
        • Ko W.-C.
        • Tang H.-J.
        • Hsueh P.-R.
        Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges.
        Int J Antimicrob Agents. 2020; (2020/02/17/)105924
        • Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association
        An update on the epidemiological characteristics of novel coronavirus pneumonia (COVID-19).
        Chin J Epidemiol. 2020; : 41
        • Chousterman B.G.
        • Swirski F.K.
        • Weber G.F.
        Cytokine storm and sepsis disease pathogenesis.
        Seminars Immunopathol. 2017; 39 (2017/07/01): 517-528
        • Shimabukuro-Vornhagen A.
        • Gödel P.
        • Subklewe M.
        • Stemmler H.J.
        • Schlößer H.A.
        • Schlaak M.
        • et al.
        Cytokine release syndrome.
        J ImmunoTherapy Cancer. 2018; 6 (2018/06/15): 56
      1. Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L., et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). 2020:medRxiv2020.02.10.20021832.

        • Peck K.M.
        • Burch C.L.
        • Heise M.T.
        • Baric R.S.
        Coronavirus host range expansion and middle east respiratory syndrome coronavirus emergence: biochemical mechanisms and evolutionary perspectives.
        Ann Rev Virol. 2015; 2 (PubMed PMID: 26958908. Epub 2015/08/07. eng): 95-117
        • Su S.
        • Wong G.
        • Shi W.
        • Liu J.
        • Lai A.C.K.
        • Zhou J.
        • et al.
        Epidemiology, genetic recombination, and pathogenesis of coronaviruses.
        Trends Microbiol. Jun 2016; 24 (PubMed PMID: 27012512. Epub 2016/03/26. eng): 490-502
        • Weiss S.R.
        • Navas-Martin S.
        Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus.
        Microbiol Mol Biol Rev. Dec 2005; 69 (PubMed PMID: 16339739. Pubmed Central PMCID: PMC1306801. Epub 2005/12/13. eng): 635-664
        • Perlman S.
        • Netland J.
        Coronaviruses post-SARS: update on replication and pathogenesis.
        Nature Rev Microbiol. 2009; 7 (PubMed PMID: 19430490. eng): 439-450
        • Heugel J.
        • Martin E.T.
        • Kuypers J.
        • Englund J.A.
        Coronavirus-associated pneumonia in previously healthy children.
        Pediatr Infect Disease J. 2007; 26 (PubMed PMID: 17848893. eng): 753-755
        • Kuypers J.
        • Martin E.T.
        • Heugel J.
        • Wright N.
        • Morrow R.
        • Englund J.A.
        Clinical disease in children associated with newly described coronavirus subtypes.
        Pediatrics. 2007; 119 (PubMed PMID: 17130280. Epub 2006/11/27. eng): e70-ee6
        • Kuiken T.
        • Fouchier R.A.M.
        • Schutten M.
        • Rimmelzwaan G.F.
        • van Amerongen G.
        • van Riel D.
        • et al.
        Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.
        Lancet. 2003; 362 (London, England)PubMed PMID: 12892955. eng: 263-270
        • Peiris J.S.M.
        • Lai S.T.
        • Poon L.L.M.
        • Guan Y.
        • Yam L.Y.C.
        • Lim W.
        • et al.
        Coronavirus as a possible cause of severe acute respiratory syndrome.
        Lancet. 2003; 361 (London, England)PubMed PMID: 12711465. eng: 1319-1325
        • Zaki A.M.
        • van Boheemen S.
        • Bestebroer T.M.
        • Osterhaus A.D.M.E.
        • Fouchier R.A.M.
        Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.
        Engl J Med. 2012; 367 (PubMed PMID: 23075143. Epub 2012/10/17. eng): 1814-1820
        • Channappanavar R.
        • Fehr A.R.
        • Vijay R.
        • Mack M.
        • Zhao J.
        • Meyerholz D.K.
        • et al.
        Dysregulated Type I Interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-Infected Mice.
        Cell Host Microbe. 2016; 19 (PubMed PMID: 26867177. eng): 181-193
        • Davidson S.
        • Maini M.K.
        • Wack A.
        Disease-promoting effects of type I interferons in viral, bacterial, and coinfections.
        J Interf Cytokine Res Offic J Int Soc Interf Cytokine Res. 2015; 35 (PubMed PMID: 25714109. Epub 2015/02/25. eng): 252-264
        • Shaw A.C.
        • Goldstein D.R.
        • Montgomery R.R.
        Age-dependent dysregulation of innate immunity.
        Nature Rev Immunol. 2013; 13 (PubMed PMID: 24157572. Epub 2013/10/25. eng): 875-887
        • Law H.K.W.
        • Cheung C.Y.
        • Ng H.Y.
        • Sia S.F.
        • Chan Y.O.
        • Luk W.
        • et al.
        Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells.
        Blood. 2005; 106 (PubMed PMID: 15860669. Epub 2005/04/28. eng): 2366-2374
        • Cheung C.Y.
        • Poon L.L.M.
        • Ng I.H.Y.
        • Luk W.
        • Sia S.-F.
        • Wu M.H.S.
        • et al.
        Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis.
        J Virol. 2005; 79 (PubMed PMID: 15919935. eng): 7819-7826
        • Lau S.K.P.
        • Lau C.C.Y.
        • Chan K.-H.
        • Li C.P.Y.
        • Chen H.
        • Jin D.-Y.
        • et al.
        Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
        J Gen Virol. 2013; 94 (PubMed PMID: 24077366. Epub 2013/09/28. eng): 2679-2690
        • Tynell J.
        • Westenius V.
        • Rönkkö E.
        • Munster V.J.
        • Melén K.
        • Österlund P.
        • et al.
        Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells.
        J Gen Virol. 2016; 97 (PubMed PMID: 26602089. Epub 2015/11/24. eng): 344-355
        • Zhou J.
        • Chu H.
        • Li C.
        • Wong B.H.-Y.
        • Cheng Z.-S.
        • Poon V.K.-M.
        • et al.
        Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis.
        J Infect Diseases. 2014; 209 (PubMed PMID: 24065148. Epub 2013/09/24. eng): 1331-1342
        • Scheuplein V.A.
        • Seifried J.
        • Malczyk A.H.
        • Miller L.
        • Höcker L.
        • Vergara-Alert J.
        • et al.
        High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus.
        J Virol. 2015; 89 (PubMed PMID: 25609809. Epub 2015/01/21. eng): 3859-3869
        • Kim E.S.
        • Choe P.G.
        • Park W.B.
        • Oh H.S.
        • Kim E.J.
        • Nam E.Y.
        • et al.
        Clinical progression and cytokine profiles of middle east respiratory syndrome coronavirus infection.
        J Korean Med Sci. 2016; 31 (PubMed PMID: 27709848. eng): 1717-1725
        • Min C.-K.
        • Cheon S.
        • Ha N.-Y.
        • Sohn K.M.
        • Kim Y.
        • Aigerim A.
        • et al.
        Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity.
        Scient Rep. 2016; 6 (PubMed PMID: 27146253. eng): 25359
        • Ng D.L.
        • Al Hosani F.
        • Keating M.K.
        • Gerber S.I.
        • Jones T.L.
        • Metcalfe M.G.
        • et al.
        Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of middle east respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014.
        Am J Pathol. 2016; 186 (PubMed PMID: 26857507. Epub 2016/02/05. eng): 652-658
        • JY C.
        • PR H.
        • WC C.
        • CJ Y.
        • PC Y.
        Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome.
        Respirol (Carlton, Vic). 2006; 11 (PubMed PMID: 17052299): 715-722
        • CH W.
        • CY L.
        • YL W.
        • CL C.
        • KH H.
        • HC L.
        • et al.
        Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS.
        Respirat Res. 2005; 6 (PubMed PMID: 15888207): 42
        • CK W.
        • CW L.
        • AK W.
        • WK I.
        • NL L.
        • IH C.
        • et al.
        Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome.
        Clin Exper Immunol. 2004; 136 (PubMed PMID: 15030519): 95-103
        • Y Z.
        • J L.
        • Y Z.
        • L W.
        • X Y.
        • W Z.
        • et al.
        Analysis of serum cytokines in patients with severe acute respiratory syndrome.
        Infect Immun. 2004; 72 (PubMed PMID: 15271897): 4410-4415
        • Chien J.-Y.
        • Hsueh P.-R.
        • Cheng W.-C.
        • Yu C.-J.
        • Yang P.-C.
        Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome.
        Respirol (Carlton, Vic). 2006; 11 (PubMed PMID: 17052299. eng): 715-722
        • Wang C.-H.
        • Liu C.-Y.
        • Wan Y.-L.
        • Chou C.-L.
        • Huang K.-H.
        • Lin H.-C.
        • et al.
        Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS.
        Respirat Res. 2005; 6 (-. PubMed PMID: 15888207. eng): 42
        • Wong C.K.
        • Lam C.W.K.
        • Wu A.K.L.
        • Ip W.K.
        • Lee N.L.S.
        • Chan I.H.S.
        • et al.
        Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome.
        Clinical Exper Immunol. 2004; 136 (PubMed PMID: 15030519. eng): 95-103
        • Zhang Y.
        • Li J.
        • Zhan Y.
        • Wu L.
        • Yu X.
        • Zhang W.
        • et al.
        Analysis of serum cytokines in patients with severe acute respiratory syndrome.
        Infect Immun. 2004; 72 (PubMed PMID: 15271897. eng): 4410-4415
        • A G.-S.
        • CA B.
        Type 1 interferons and the virus-host relationship: a lesson in détente.
        Science. 2006; 312 (New York, NY)PubMed PMID: 16690858: 879-882
        • R C.
        • AR F.
        • J Z.
        • C W.-L.
        • JE A.
        • M M.
        • et al.
        IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes.
        J Clin Invest. 2019; 130 (PubMed PMID: 31355779): 3625-3639
        • Smits S.L.
        • de Lang A.
        • van den Brand J.M.A.
        • Leijten L.M.
        • van Ijcken W.F.
        • Eijkemans M.J.C.
        • et al.
        Exacerbated innate host response to SARS-CoV in aged non-human primates.
        PLoS Pathogens. 2010; 6 (e1000756-e. PubMed PMID: 20140198. eng)
        • Rockx B.
        • Baas T.
        • Zornetzer G.A.
        • Haagmans B.
        • Sheahan T.
        • Frieman M.
        • et al.
        Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection.
        J Virol. 2009; 83 (PubMed PMID: 19420084. Epub 2009/05/06. eng): 7062-7074
        • Herold S.
        • Steinmueller M.
        • von Wulffen W.
        • Cakarova L.
        • Pinto R.
        • Pleschka S.
        • et al.
        Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand.
        J Exper Med. 2008; 205 (PubMed PMID: 19064696. Epub 2008/12/08. eng): 3065-3077
        • Högner K.
        • Wolff T.
        • Pleschka S.
        • Plog S.
        • Gruber A.D.
        • Kalinke U.
        • et al.
        Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia.
        PLoS Pathogens. 2013; 9 (e1003188-e. PubMed PMID: 23468627. Epub 2013/02/28. eng)
        • Rodrigue-Gervais I.G.
        • Labbé K.
        • Dagenais M.
        • Dupaul-Chicoine J.
        • Champagne C.
        • Morizot A.
        • et al.
        Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival.
        Cell Host Microbe. 2014; 15 (PubMed PMID: 24439895. eng): 23-35
        • Drosten C.
        • Seilmaier M.
        • Corman V.M.
        • Hartmann W.
        • Scheible G.
        • Sack S.
        • et al.
        Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection.
        Lancet Infect Diseases. 2013; 13 (PubMed PMID: 23782859. Epub 2013/06/17. eng): 745-751
        • Lew T.W.K.
        • Kwek T.-K.
        • Tai D.
        • Earnest A.
        • Loo S.
        • Singh K.
        • et al.
        Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome.
        JAMA. 2003; 290 (PubMed PMID: 12865379. eng): 374-380
        • Jiang Y.
        • Xu J.
        • Zhou C.
        • Wu Z.
        • Zhong S.
        • Liu J.
        • et al.
        Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.
        Am J Respirat Critical Care Med. 2005; 171 (PubMed PMID: 15657466. Epub 2005/01/18. eng): 850-857
        • Reghunathan R.
        • Jayapal M.
        • Hsu L.-Y.
        • Chng H.-H.
        • Tai D.
        • Leung B.P.
        • et al.
        Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome.
        BMC Immunol. 2005; 6 (-. PubMed PMID: 15655079. eng): 2
        • Cameron M.J.
        • Bermejo-Martin J.F.
        • Danesh A.
        • Muller M.P.
        • Kelvin D.J.
        Human immunopathogenesis of severe acute respiratory syndrome (SARS).
        Virus Res. 2008; 133 (PubMed PMID: 17374415. Epub 2007/03/19. eng): 13-19
        • Huang C.
        • Wang Y.
        • Li X.
        • Ren L.
        • Zhao J.
        • Hu Y.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        Lancet. 2020; 395 (2020/02/15/): 497-506
        • Marchingo J.M.
        • Sinclair L.V.
        • Howden A.J.M.
        • Cantrell D.A.
        Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation.
        eLife. 2020; 9 (2020/02/05): e53725
        • Chen L.
        • Liu H.-G.
        • Liu W.
        • Liu J.
        • Liu K.
        • Shang J.
        • et al.
        Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia.
        Chin J Tuberc Respir Dis. 2020; 43
        • Yang X.
        • Yu Y.
        • Xu J.
        • Shu H.
        • Ja X.i.a.
        • Liu H.
        • et al.
        Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
        Lancet Respirat Med. 2020; (S2213-600(20)30079-5. PubMed PMID: 32105632. eng)
        • Force* TADT
        Acute respiratory distress syndrome: the berlin definition.
        JAMA. 2012; 307: 2526-2533
        • Douda D.N.
        • Jackson R.
        • Grasemann H.
        • Palaniyar N.
        Innate immune collectin surfactant protein D simultaneously binds both neutrophil extracellular traps and carbohydrate ligands and promotes bacterial trapping.
        J Immunol (Baltimore, Md: 1950). 2011; 187 (PubMed PMID: 21724991. Epub 2011/07/01. eng): 1856-1865
        • Parsons P.E.
        • Eisner M.D.
        • Thompson B.T.
        • Matthay M.A.
        • Ancukiewicz M.
        • Bernard G.R.
        • et al.
        Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury.
        Critical Care Med. 2005; 33 (PubMed PMID: 15644641. eng): 1-232
        • 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 (PubMed PMID: 18606328. eng): 711-715
        • Stockman L.J.
        • Bellamy R.
        • Garner P.
        SARS: systematic review of treatment effects.
        PLoS Med. 2006; 3 (e343-e. PubMed PMID: 16968120. eng)
        • Arabi Y.M.
        • Shalhoub S.
        • Mandourah Y.
        • Al-Hameed F.
        • Al-Omari A.
        • Al Qasim E.
        • et al.
        Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study.
        Clinical Infect Diseas Offic Publ Infect Diseases Soc Am. 2019; (ciz544. PubMed PMID: 31925415. eng)
        • Falzarano D.
        • de Wit E.
        • Rasmussen A.L.
        • Feldmann F.
        • Okumura A.
        • Scott D.P.
        • et al.
        Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques.
        Nature Med. 2013; 19 (PubMed PMID: 24013700. Epub 2013/09/08. eng): 1313-1317
        • Omrani A.S.
        • Saad M.M.
        • Baig K.
        • Bahloul A.
        • Abdul-Matin M.
        • Alaidaroos A.Y.
        • et al.
        Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study.
        Lancet Inf Diseases. 2014; 14 (PubMed PMID: 25278221. Epub 2014/09/29. eng): 1090-1095
        • Davidson S.
        • McCabe T.M.
        • Crotta S.
        • Gad H.H.
        • Hessel E.M.
        • Beinke S.
        • et al.
        IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment.
        EMBO Molecul Med. 2016; 8 (PubMed PMID: 27520969. eng): 1099-1112
        • Blazek K.
        • Eames H.L.
        • Weiss M.
        • Byrne A.J.
        • Perocheau D.
        • Pease J.E.
        • et al.
        IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production.
        J Exper Med. 2015; 212 (PubMed PMID: 25941255. Epub 2015/05/04. eng): 845-853
        • Arabi Y.M.
        • Shalhoub S.
        • Mandourah Y.
        • Al-Hameed F.
        • Al-Omari A.
        • Al Qasim E.
        • et al.
        Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study.
        Clinical Infect Diseases. 2019;
        • Omrani A.S.
        • Saad M.M.
        • Baig K.
        • Bahloul A.
        • Abdul-Matin M.
        • Alaidaroos A.Y.
        • et al.
        Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study.
        Lancet Infect Diseases. 2014; 14 (2014/11/01/): 1090-1095
        • Zumla A.
        • Chan J.F.W.
        • Azhar E.I.
        • Hui D.S.C.
        • Yuen K.-Y.
        Coronaviruses — drug discovery and therapeutic options.
        Nature Rev Drug Discov. 2016; 15 (2016/05/01): 327-347
        • Auyeung T.W.
        • Lee J.S.W.
        • Lai W.K.
        • Choi C.H.
        • Lee H.K.
        • Lee J.S.
        • et al.
        The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study.
        J Infect. 2005; 51 (PubMed PMID: 16038758. eng): 98-102
        • Ho J.C.
        • Ooi G.C.
        • Mok T.Y.
        • Chan J.W.
        • Hung I.
        • Lam B.
        • et al.
        High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome.
        Am J Resp Crit Care Med. 2003; 168 (PubMed PMID: 12947028. Epub 2003/08/28. eng): 1449-1456
        • Yam L.Y.-C.
        • Lau A.C.-W.
        • Lai F.Y.-L.
        • Shung E.
        • Chan J.
        • Wong V.
        • et al.
        Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong.
        J Infect. 2007; 54 (PubMed PMID: 16542729. Epub 2006/03/15. eng): 28-39
        • Chen R.-c.
        • Tang X.-p.
        • Tan S.-y.
        • Liang B.-l.
        • Wan Z.-y.
        • Fang J.-q.
        • et al.
        Treatment of Severe Acute Respiratory Syndrome With Glucosteroids: The Guangzhou Experience.
        Chest. 2006; 129 (2006/06/01/): 1441-1452
        • Zhao J.-p.
        • Hu Y.
        • Du R.-h.
        • Chen Z.-s.
        • Jin Y.
        • Zhou M.
        • et al.
        Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia.
        Chin J Tuberc Respir Dis. 2020; (E007-E. chi)
        • Zhou Y.-H.
        • Qin Y.-Y.
        • Lu Y.-Q.
        • Sun F.
        • Yang S.
        • Harypursat V.
        • et al.
        Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial.
        Chin Med J. 2020; (E020-E. chi)
        • Chen N.
        • Zhou M.
        • Dong X.
        • Qu J.
        • Gong F.
        • Han Y.
        • et al.
        Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
        Lancet. 2020; 395 (2020/02/15/): 507-513
        • Shakoory B.
        • Carcillo J.A.
        • Chatham W.W.
        • Amdur R.L.
        • Zhao H.
        • Dinarello C.A.
        • 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.
        Critical Care Med. 2016; 44 (PubMed PMID: 26584195. eng): 275-281
        • Biggioggero M.
        • Crotti C.
        • Becciolini A.
        • Favalli E.G.
        Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection.
        Drug Design, Devel Therapy. 2018; 13 (PubMed PMID: 30587928. eng): 57-70
        • Tanaka T.
        • Narazaki M.
        • Kishimoto T.
        Immunotherapeutic implications of IL-6 blockade for cytokine storm.
        Immunotherapy. 2016; 8 (PubMed PMID: 27381687. eng): 959-970
        • Qiu P.
        • Cui X.
        • Sun J.
        • Welsh J.
        • Natanson C.
        • Eichacker P.Q.
        Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis.
        Critical Care Med. 2013; 41 (PubMed PMID: 23887234. eng): 2419-2429
        • Udalova I.
        • Monaco C.
        • Nanchahal J.
        • Feldmann M.
        Anti-TNF Therapy.
        Microbiol Spect. 2016; 4
        • McDermott J.E.
        • Mitchell H.D.
        • Gralinski L.E.
        • Eisfeld A.J.
        • Josset L.
        • Bankhead A.
        • et al.
        The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus.
        BMC Syst Biol. 2016; 10 (-. PubMed PMID: 27663205. eng): 93
        • J G.
        • Z T.
        • X Y.
        Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
        Biosci Trends. 2020; 14 (PubMed PMID: 32074550): 72-73
        • multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia
        Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia.
        Chinese J Tubercul Respirat Diseases. 2020; 43 (E019-E. PubMed PMID: 32075365)
        • H W.
        • B L.
        • Y T.
        • P C.
        • L Y.
        • B H.
        • et al.
        Improvement of sepsis prognosis by Ulinastatin: a systematic review and meta-analysis of randomized controlled trials.
        Frontiers Pharmacol. 2019; 10 (PubMed PMID: 31849646): 1370
        • M J.
        • H H.
        • S C.
        • Y L.
        • Y L.
        • S P.
        • et al.
        Ulinastatin ameliorates LPS-induced pulmonary inflammation and injury by blocking the MAPK/NF-κB signaling pathways in rats.
        Molecul Med Rep. 2019; 20 (PubMed PMID: 31432172): 3347-3354
        • Imai Y.
        • Kuba K.
        • Neely G.G.
        • Yaghubian-Malhami R.
        • Perkmann T.
        • van Loo G.
        • et al.
        Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
        Cell. 2008; 133 (PubMed PMID: 18423196. eng): 235-249
        • Shirey K.A.
        • Perkins D.J.
        • Lai W.
        • Zhang W.
        • Fernando L.R.
        • Gusovsky F.
        • et al.
        Influenza "Trains" the host for enhanced susceptibility to secondary bacterial infection.
        mBio. 2019; 10 (PubMed PMID: 31064834. eng): e00810-e00819
        • Maceyka M.
        • Harikumar K.B.
        • Milstien S.
        • Spiegel S.
        Sphingosine-1-phosphate signaling and its role in disease.
        Trends Cell Biol. 2012; 22 (PubMed PMID: 22001186. Epub 2011/10/14. eng): 50-60
        • Walsh K.B.
        • Teijaro J.R.
        • Rosen H.
        • Oldstone M.B.A.
        Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm.
        Immunol Res. 2011; 51 (2011/09/08): 15
        • Teijaro J.R.
        • Walsh K.B.
        • Cahalan S.
        • Fremgen D.M.
        • Roberts E.
        • Scott F.
        • et al.
        Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection.
        Cell. 2011; 146 (PubMed PMID: 21925319. eng): 980-991
        • Walsh K.B.
        • Teijaro J.R.
        • Wilker P.R.
        • Jatzek A.
        • Fremgen D.M.
        • Das S.C.
        • et al.
        Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus.
        Proc Natl Acad Sci USA. 2011; 108 (PubMed PMID: 21715659. Epub 2011/06/29. eng): 12018-12023
        • Uccelli A.
        • de Rosbo N.K.
        The immunomodulatory function of mesenchymal stem cells: mode of action and pathways.
        Ann NY Acad Sci. 2015; 1351: 114-126
        • Ben-Mordechai T.
        • Palevski D.
        • Glucksam-Galnoy Y.
        • Elron-Gross I.
        • Margalit R.
        • Leor J.
        Targeting macrophage subsets for infarct repair.
        J Cardiovascular Pharmacol Therapeut. 2014; 20 (2015/01/01): 36-51
        • Lee J.W.
        • Fang X.
        • Krasnodembskaya A.
        • Howard J.P.
        • Matthay M.A.
        Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors.
        STEM CELLS. 2011; 29: 913-919
        • K X.
        • H C.
        • Y S.
        • Q N.
        • Y C.
        • S H.
        • et al.
        Management of corona virus disease-19 (COVID-19): the Zhejiang experience.
        Zhejiang da xue xue bao Yi xue ban. 2020; 49 (PubMed PMID: 32096367): 0
        • Zuccari S.
        • Damiani E.
        • Domizi R.
        • Scorcella C.
        • D'Arezzo M.
        • Carsetti A.
        • et al.
        Changes in cytokines, haemodynamics and microcirculation in patients with sepsis/septic shock undergoing continuous renal replacement therapy and blood purification with cytoSorb.
        Blood Purificat. 2020; 49: 107-113
        • Xu Z.
        • Shi L.
        • Wang Y.
        • Zhang J.
        • Huang L.
        • Zhang C.
        • et al.
        Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
        Lancet Respirat Med. 2020; (S2213-600(20)30076-X. PubMed PMID: 32085846. eng)
        • Leuschner F.
        • Courties G.
        • Dutta P.
        • Mortensen L.J.
        • Gorbatov R.
        • Sena B.
        • et al.
        Silencing of CCR2 in myocarditis.
        Eur Heart J. 2015; 36 (PubMed PMID: 24950695. Epub 2014/06/20. eng): 1478-1488
        • Leuschner F.
        • Dutta P.
        • Gorbatov R.
        • Novobrantseva T.I.
        • Donahoe J.S.
        • Courties G.
        • et al.
        Therapeutic siRNA silencing in inflammatory monocytes in mice.
        Nature Biotechnol. 2011; 29 (PubMed PMID: 21983520. eng): 1005-1010
        • London N.R.
        • Zhu W.
        • Bozza F.A.
        • Smith M.C.P.
        • Greif D.M.
        • Sorensen L.K.
        • et al.
        Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza.
        Sci Transl Med. 2010; 2 (23ra19)