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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?</title><author><name sortKey="Liu, Bingwen" sort="Liu, Bingwen" uniqKey="Liu B" first="Bingwen" last="Liu">Bingwen Liu</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Li, Min" sort="Li, Min" uniqKey="Li M" first="Min" last="Li">Min Li</name><affiliation><nlm:aff id="aff3">Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Zhou, Zhiguang" sort="Zhou, Zhiguang" uniqKey="Zhou Z" first="Zhiguang" last="Zhou">Zhiguang Zhou</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Guan, Xuan" sort="Guan, Xuan" uniqKey="Guan X" first="Xuan" last="Guan">Xuan Guan</name><affiliation><nlm:aff id="aff5">Department of Internal Medicine, AdventHealth Orlando, Orlando, USA</nlm:aff></affiliation></author><author><name sortKey="Xiang, Yufei" sort="Xiang, Yufei" uniqKey="Xiang Y" first="Yufei" last="Xiang">Yufei Xiang</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7151347</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151347</idno><idno type="RBID">PMC:7151347</idno><idno type="doi">10.1016/j.jaut.2020.102452</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">001357</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001357</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?</title><author><name sortKey="Liu, Bingwen" sort="Liu, Bingwen" uniqKey="Liu B" first="Bingwen" last="Liu">Bingwen Liu</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Li, Min" sort="Li, Min" uniqKey="Li M" first="Min" last="Li">Min Li</name><affiliation><nlm:aff id="aff3">Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Zhou, Zhiguang" sort="Zhou, Zhiguang" uniqKey="Zhou Z" first="Zhiguang" last="Zhou">Zhiguang Zhou</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author><author><name sortKey="Guan, Xuan" sort="Guan, Xuan" uniqKey="Guan X" first="Xuan" last="Guan">Xuan Guan</name><affiliation><nlm:aff id="aff5">Department of Internal Medicine, AdventHealth Orlando, Orlando, USA</nlm:aff></affiliation></author><author><name sortKey="Xiang, Yufei" sort="Xiang, Yufei" uniqKey="Xiang Y" first="Yufei" last="Xiang">Yufei Xiang</name><affiliation><nlm:aff id="aff1">Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Autoimmunity</title><idno type="ISSN">0896-8411</idno><idno type="eISSN">1095-9157</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The emergent outbreak of coronavirus disease 2019 (COVID-19) <underline>has caused a global pandemic</underline>. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Who" uniqKey="Who">WHO</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, P" uniqKey="Zhou P">P. Zhou</name></author><author><name sortKey="Yang, X L" uniqKey="Yang X">X.L. Yang</name></author><author><name sortKey="Wang, X G" uniqKey="Wang X">X.G. Wang</name></author><author><name sortKey="Hu, B" uniqKey="Hu B">B. Hu</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L. Zhang</name></author><author><name sortKey="Zhang, W" uniqKey="Zhang W">W. Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Turner, A J" uniqKey="Turner A">A.J. Turner</name></author><author><name sortKey="Hiscox, J A" uniqKey="Hiscox J">J.A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Autoimmun</journal-id><journal-id journal-id-type="iso-abbrev">J. Autoimmun</journal-id><journal-title-group><journal-title>Journal of Autoimmunity</journal-title></journal-title-group><issn pub-type="ppub">0896-8411</issn><issn pub-type="epub">1095-9157</issn><publisher><publisher-name>Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7151347</article-id><article-id pub-id-type="publisher-id">S0896-8411(20)30067-6</article-id><article-id pub-id-type="doi">10.1016/j.jaut.2020.102452</article-id><article-id pub-id-type="publisher-id">102452</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Liu</surname><given-names>Bingwen</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Li</surname><given-names>Min</given-names></name><xref rid="aff3" ref-type="aff">c</xref><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Zhou</surname><given-names>Zhiguang</given-names></name><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Guan</surname><given-names>Xuan</given-names></name><email>xuan.guan.md@adventhealth.com</email><xref rid="aff5" ref-type="aff">e</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Xiang</surname><given-names>Yufei</given-names></name><email>yufei.xiang@csu.edu.cn</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="aff2" ref-type="aff">b</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China</aff><aff id="aff2"><label>b</label>Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China</aff><aff id="aff3"><label>c</label>Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China</aff><aff id="aff4"><label>d</label>Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China</aff><aff id="aff5"><label>e</label>Department of Internal Medicine, AdventHealth Orlando, Orlando, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. <email>yufei.xiang@csu.edu.cn</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author. <email>xuan.guan.md@adventhealth.com</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>10</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>10</day><month>4</month><year>2020</year></pub-date><elocation-id>102452</elocation-id><history><date date-type="received"><day>3</day><month>3</month><year>2020</year></date><date date-type="rev-recd"><day>29</day><month>3</month><year>2020</year></date><date date-type="accepted"><day>2</day><month>4</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0010"><p>The emergent outbreak of coronavirus disease 2019 (COVID-19) <underline>has caused a global pandemic</underline>. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.</p></abstract><abstract abstract-type="author-highlights" id="abs0015"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">Cytokine release syndrome (CRS) contributes to life-threatening multiple organ dysfunction in coronavirus disease 2019 (COVID-19) and represents a potential therapeutic target.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">Mechanistic understanding of CRS permits the design of novel immunotherapies.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">Targeting key molecules within the inflammatory cytokine network, such as interleukin-6 (IL-6), is a novel strategy for COVID-19-induced CRS and warrants further investigation.</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">Abstract.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>Coronavirus disease 2019</kwd><kwd>Cytokine release syndrome</kwd><kwd>Interleukin-6</kwd><kwd>Tocilizumab</kwd><kwd>Manuscript</kwd></kwd-group></article-meta></front><body><p id="p0030">The newly emerging coronavirus disease 2019 (COVID-19), first reported in Wuhan, China, has swept across 202 countries with stunning mortality. The World Health Organization (WHO) has declared this deadly outbreak a pandemic, with tremendous ramifications impacting every life. By March 27, 2020, the number of deaths had climbed to 23,495 among 512,701 confirmed cases in WHO reports [<xref rid="bib1" ref-type="bibr">1</xref>]. This strain has been the third most lethal pathogenic human coronavirus, following severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses in 2003 and 2012, respectively. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel beta-coronavirus, has been identified as the pathogen for COVID-19 [<xref rid="bib2" ref-type="bibr">2</xref>]. SARS-CoV-2 targets the lung and likely other organs as well, leading to multiorgan damage by binding to the angiotensin-converting enzyme 2 (ACE2) receptor [<xref rid="bib2" ref-type="bibr">2</xref>], a cell surface protein highly expressed in the lung, heart and kidney [<xref rid="bib3" ref-type="bibr">3</xref>].</p><p id="p0035">Clinical data from Wuhan, China, showed that approximately 17.7–32.0% of patients require intensive care unit (ICU)-level care, with approximately 9.5–12.0 days from symptom onset to multiorgan dysfunctions, namely, acute respiratory distress syndrome (ARDS) (67%), acute kidney injury (29%), acute cardiac injury (23%), and liver dysfunction (29%) [<xref rid="bib4" ref-type="bibr">[4]</xref>, <xref rid="bib5" ref-type="bibr">[5]</xref>, <xref rid="bib6" ref-type="bibr">[6]</xref>]. The mortality of critically ill patients is as high as 49.0–61.5% [<xref rid="bib4" ref-type="bibr">4</xref>,<xref rid="bib5" ref-type="bibr">5</xref>]. Evidence suggests that CRS might play a major role in severe COVID-19. Inflammatory cytokines and chemokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), induced protein 10 (IP10) and monocyte chemoattractant protein-1 (MCP-1), were significantly elevated in COVID-19 patients, and some were more commonly seen in severe patients than in nonsevere patients (<xref rid="tbl1" ref-type="table">Table 1</xref>). In COVID-19 patients with elevated inflammatory cytokines, postmortem pathology has revealed tissue necrosis and interstitial macrophage and monocyte infiltrations in the lung, heart and gastrointestinal mucosa [<xref rid="bib7" ref-type="bibr">7</xref>,<xref rid="bib8" ref-type="bibr">8</xref>]. Moreover, severe lymphopenia with hyperactivated proinflammatory T cells [<xref rid="bib8" ref-type="bibr">8</xref>] and decreased regulatory T cells [<xref rid="bib9" ref-type="bibr">9</xref>] is commonly seen in critically ill patients, suggesting dysregulated immune responses.<table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>The levels of cytokines in patients with COVID-19, SARS and MERS versus those in normal controls.</p></caption><alt-text id="alttext0010">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Cytokines</th><th>COVID-19</th><th>SARS</th><th>MERS</th></tr></thead><tbody><tr><td align="left">IL-6</td><td align="left">↑ in some [<xref rid="bib36" ref-type="bibr">36</xref>,<xref rid="bib58" ref-type="bibr">58</xref>] or in severe cases [<xref rid="bib6" ref-type="bibr">6</xref>,<xref rid="bib34" ref-type="bibr">34</xref>,<xref rid="bib54" ref-type="bibr">54</xref>]</td><td align="left">↑</td><td align="left">Unknown but ↑ in severe than in mild cases</td></tr><tr><td align="left">IL-2</td><td align="left">↑</td><td align="left">↑ or NS</td><td align="left">NS</td></tr><tr><td align="left">IL-1β</td><td align="left">↑</td><td align="left">NS</td><td align="left">Unknown</td></tr><tr><td align="left">IL-8</td><td align="left">↑</td><td align="left">↑</td><td align="left">Unknown</td></tr><tr><td align="left">IL-17</td><td align="left">↑</td><td align="left">Unknown</td><td align="left">↑</td></tr><tr><td align="left">IFN-γ</td><td align="left">↑</td><td align="left">NS</td><td align="left">↑</td></tr><tr><td align="left">TNF-α</td><td align="left">↑</td><td align="left">NS</td><td align="left">↑</td></tr><tr><td align="left">IP10</td><td align="left">↑</td><td align="left"><bold>↑</bold></td><td align="left">Unknown but ↑ in severe than in mild cases</td></tr><tr><td align="left">MCP-1</td><td align="left">↑</td><td align="left">↑ or NS</td><td align="left">Unknown</td></tr><tr><td align="left">IL-10</td><td align="left">↑</td><td align="left">NS or ↑ in convalescent cases</td><td align="left">↑</td></tr><tr><td align="left">IL-4</td><td align="left">↑</td><td align="left">NS or ↓ in convalescent cases</td><td align="left">NS</td></tr><tr><td align="left">Ref</td><td align="left">[<xref rid="bib6" ref-type="bibr">6</xref>,<xref rid="bib33" ref-type="bibr">33</xref>,<xref rid="bib34" ref-type="bibr">34</xref>,<xref rid="bib36" ref-type="bibr">36</xref>,<xref rid="bib54" ref-type="bibr">54</xref>,<xref rid="bib58" ref-type="bibr">58</xref>]</td><td align="left">[<xref rid="bib28" ref-type="bibr">28</xref>,<xref rid="bib59" ref-type="bibr">[59]</xref>, <xref rid="bib60" ref-type="bibr">[60]</xref>, <xref rid="bib61" ref-type="bibr">[61]</xref>]</td><td align="left">[<xref rid="bib62" ref-type="bibr">62</xref>,<xref rid="bib63" ref-type="bibr">63</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Up or down arrows indicate higher or lower levels versus normal controls, respectively. Abbreviations: NS; no significant change versus normal controls, IL: interleukin, IFN-γ: interferon γ, IP: induced protein, MCP: monocyte chemoattractant protein, TNF-α: tumor necrosis factor α.</p></fn></table-wrap-foot></table-wrap></p><p id="p0040">CRS refers to an uncontrolled and overwhelming release of proinflammatory mediators by an overly activated immune system [<xref rid="bib10" ref-type="bibr">10</xref>]. CRS is a common immunopathogenesis underlying many pathological processes, such as ARDS, sepsis, graft-versus-host disease (GvHD), macrophage activation syndrome (MAS) induced by rheumatic diseases, and primary and secondary hemophagocytic lymphohistiocytosis (HLH) [<xref rid="bib11" ref-type="bibr">11</xref>]. Recently, CRS has also been reported to be a complication of immunotherapies, such as chimeric antigen receptor (CAR) T cell therapies [<xref rid="bib12" ref-type="bibr">12</xref>]. Previous experience with SARS and MERS has also revealed florid CRS in critically ill patients (<xref rid="tbl1" ref-type="table">Table 1</xref>). Studies have shown that ARDS occurs in some SARS patients despite a diminishing viral load, suggesting that an exuberant host immune response rather than viral virulence is possibly responsible for tissue pathologies. Therefore, antiviral therapy alone may be inadequate [<xref rid="bib13" ref-type="bibr">13</xref>]. Corticosteroids, one of the most widely utilized anti-inflammatory agents, are still commonly prescribed in treating COVID-19 patients (72.2% in the ICU setting) [<xref rid="bib14" ref-type="bibr">14</xref>]. However, as outlined in the Chinese guidelines of COVID-19 [<xref rid="bib15" ref-type="bibr">15</xref>], physicians need to be cautious of steroid use due to its nebulous benefits in the setting of viral respiratory infection. Several studies even reported inferior outcomes of SARS patients treated with corticosteroids [<xref rid="bib16" ref-type="bibr">16</xref>]. Another concern of corticosteroids is their short- and long-term adverse effects. More than half of SARS patients treated with corticosteroids suffer from joint pain and bone marrow abnormalities [<xref rid="bib17" ref-type="bibr">17</xref>]. Other therapies aiming to dampen excessive serum inflammatory mediators, such as plasmapheresis or continuous renal replacement therapy (CRRT), either require specific equipment or lack documented efficacy [<xref rid="bib18" ref-type="bibr">18</xref>]. Thus, there is still an unmet need for the treatment of COVID-19-induced CRS [<xref rid="bib19" ref-type="bibr">19</xref>]. In the past decade, immunotherapy has made great strides in managing CRS of various etiologies, including autoimmunity, malignancy and CAR T cell therapies (<xref rid="tbl2" ref-type="table">Table 2</xref>). We propose herein that attenuating the detrimental host immune response by immunomodulators may be a beneficial addition to antiviral therapy.<table-wrap position="float" id="tbl2"><label>Table 2</label><caption><p>Summary of candidate therapies for cytokine release syndrome (CRS) and related diseases.</p></caption><alt-text id="alttext0015">Table 2</alt-text><table frame="hsides" rules="groups"><thead><tr><th>Therapy</th><th>Trigger/associated diseases</th><th>Mechanism</th><th>Status for hypercytokinemia</th><th>Approved by U.S. FDA</th><th>Ref</th></tr></thead><tbody><tr><td colspan="6" align="left">Biologic therapy</td></tr><tr><td align="left">Tocilizumab</td><td align="left">MAS, CRS, visceral leishmaniasis-associated HLH, GvHD and sepsis</td><td align="left">Human monoclonal anti-IL-6 receptor antibody</td><td align="left"><list list-type="simple" id="olist0010"><list-item id="o0010"><label>●</label><p id="p0090">Approval for CAR T cell therapy-associated CRS</p></list-item><list-item id="o0015"><label>●</label><p id="p0095">Phase 4 for SARS-CoV-2 (ChiCTR2000029765, NCT04310228, NCT04315480, NCT04317092 …)</p></list-item><list-item id="o0020"><label>●</label><p id="p0100">Phase 2 for GvHD (NCT02206035, NCT04070781, NCT03434730, NCT03699631)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib44" ref-type="bibr">44</xref>,<xref rid="bib45" ref-type="bibr">45</xref>,<xref rid="bib64" ref-type="bibr">[64]</xref>, <xref rid="bib65" ref-type="bibr">[65]</xref>, <xref rid="bib66" ref-type="bibr">[66]</xref>]</td></tr><tr><td align="left">Siltuximab</td><td align="left">CRS</td><td align="left">Anti-IL-6 antibody</td><td align="left"><list list-type="simple" id="olist0015"><list-item id="o0025"><label>●</label><p id="p0105">Preclinical for CRS</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib67" ref-type="bibr">67</xref>]</td></tr><tr><td align="left">Anakinra</td><td align="left">MAS, sepsis, HIV/AIDS-associated HLH and CRS</td><td align="left">IL-1 receptor antagonist blocking IL-1α and IL-1β</td><td align="left"><list list-type="simple" id="olist0020"><list-item id="o0030"><label>●</label><p id="p0110">Phase 1 for MAS (NCT02780583)</p></list-item><list-item id="o0035"><label>●</label><p id="p0115">Phase 2 for MAS and sepsis (NCT03332225)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib68" ref-type="bibr">[68]</xref>, <xref rid="bib69" ref-type="bibr">[69]</xref>, <xref rid="bib70" ref-type="bibr">[70]</xref>]</td></tr><tr><td align="left">Canakinumab</td><td align="left">MAS</td><td align="left">Human monoclonal anti-IL-1β antibody</td><td align="left"><list list-type="simple" id="olist0025"><list-item id="o0040"><label>●</label><p id="p0120">Phase 3 for MAS (NCT00889863, NCT00886769, NCT00891046)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib71" ref-type="bibr">71</xref>,<xref rid="bib72" ref-type="bibr">72</xref>]</td></tr><tr><td align="left">Rilonacep</td><td align="left">MAS</td><td align="left">Neutralizing IL-1α and IL-1β</td><td align="left"><list list-type="simple" id="olist0030"><list-item id="o0045"><label>●</label><p id="p0125">Randomized controlled trial for MAS</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib73" ref-type="bibr">73</xref>]</td></tr><tr><td align="left">Rituximab</td><td align="left">Epstein-Barr virus-induced HLH, GvHD and MAS</td><td align="left">Human monoclonal anti-CD20 antibody to deplete B cells</td><td align="left"><list list-type="simple" id="olist0035"><list-item id="o0050"><label>●</label><p id="p0130">Phase 1–2 for GvHD (NCT04235036, NCT01135641, NCT00350545, NCT01001780 …)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib74" ref-type="bibr">[74]</xref>, <xref rid="bib75" ref-type="bibr">[75]</xref>, <xref rid="bib76" ref-type="bibr">[76]</xref>]</td></tr><tr><td align="left">Alemtuzumab</td><td align="left">HLH, GvHD</td><td align="left">Human monoclonal anti-CD52 antibody</td><td align="left"><list list-type="simple" id="olist0040"><list-item id="o0055"><label>●</label><p id="p0135">Phase 2 for HLH (NCT02472054, NCT02385110)</p></list-item><list-item id="o0060"><label>●</label><p id="p0140">Phase 1–2 for GvHD (NCT00410657, NCT00495755)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib77" ref-type="bibr">77</xref>,<xref rid="bib78" ref-type="bibr">78</xref>]</td></tr><tr><td align="left">Ruxolitinib</td><td align="left">HLH, GvHD and MAS</td><td align="left">Inhibition of JAK/STAT signaling</td><td align="left"><list list-type="simple" id="olist0045"><list-item id="o0065"><label>●</label><p id="p0145">Phase 3 for HLH (NCT04120090, NCT03533790)</p></list-item><list-item id="o0070"><label>●</label><p id="p0150">Phase 4 for GvHD (ChiCTR1900024408)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib66" ref-type="bibr">66</xref>,<xref rid="bib79" ref-type="bibr">79</xref>]</td></tr><tr><td align="left">Tofacitinib</td><td align="left">GvHD</td><td align="left">Selective inhibition of JAK1</td><td align="left"><list list-type="simple" id="olist0050"><list-item id="o0075"><label>●</label><p id="p0155">Preclinical for GvHD</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib80" ref-type="bibr">80</xref>,<xref rid="bib81" ref-type="bibr">81</xref>]</td></tr><tr><td align="left">Tadekinig alfa</td><td align="left">NLRC4-associated MAS</td><td align="left">Recombinant human IL-18-binding protein (rhIL-18BP) to tightly bind IL-18</td><td align="left"><list list-type="simple" id="olist0055"><list-item id="o0080"><label>●</label><p id="p0160">Phase 3 for NLRC4-associated MAS (NCT03512314, NCT03113760)</p></list-item></list></td><td align="left">No</td><td align="left">[<xref rid="bib82" ref-type="bibr">82</xref>]</td></tr><tr><td align="left">Emapalumab</td><td align="left">HLH</td><td align="left">Anti-IFN γ antibody</td><td align="left"><list list-type="simple" id="olist0060"><list-item id="o0085"><label>●</label><p id="p0165">Approval for primary HLH</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib83" ref-type="bibr">83</xref>]</td></tr><tr><td align="left">Infliximab</td><td align="left">HLH, GvHD and sepsis</td><td align="left">Human monoclonal anti-TNFα antibody</td><td align="left"><list list-type="simple" id="olist0065"><list-item id="o0090"><label>●</label><p id="p0170">Phase 1–2 for GvHD (NCT00228839, NCT00228839, NCT00201799)</p></list-item><list-item id="o0095"><label>●</label><p id="p0175">Phase 4 for GvHD in combination with daclizumab (NCT00574470)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib84" ref-type="bibr">[84]</xref>, <xref rid="bib85" ref-type="bibr">[85]</xref>, <xref rid="bib86" ref-type="bibr">[86]</xref>]</td></tr><tr><td align="left">Etanercept</td><td align="left">MAS, GvHD and CRS</td><td align="left">Decoy TNF receptor competitively inhibiting TNF</td><td align="left"><list list-type="simple" id="olist0070"><list-item id="o0100"><label>●</label><p id="p0180">Phase 2–3 for GvHD (NCT00726375, NCT00141739 NCT00141713, NCT00224874, ChiCTR1900024408)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib87" ref-type="bibr">[87]</xref>, <xref rid="bib88" ref-type="bibr">[88]</xref>, <xref rid="bib89" ref-type="bibr">[89]</xref>]</td></tr><tr><td align="left">Ponatinib</td><td align="left">Influenza A</td><td align="left">Inhibiting breakpoint cluster region-Abelson (BCR-ABL) kinase to regulate type I IFNs</td><td align="left"><list list-type="simple" id="olist0075"><list-item id="o0105"><label>●</label><p id="p0185">Preclinical for cytokine storms in influenza</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib90" ref-type="bibr">90</xref>]</td></tr><tr><td colspan="6" align="left"><bold>Alternative therapy: corticosteroids, IVIG, chemotherapeutic agents, blood purification, NSAIDs, cell-based therapy and others</bold></td></tr><tr><td align="left">Corticosteroids</td><td align="left">Widely used for increased levels of cytokines</td><td align="left">Inhibition of HAT and recruitment of HDAC2 activity to the inflammatory gene transcriptional complex to downregulate inflammatory genes</td><td align="left"><list list-type="simple" id="olist0080"><list-item id="u0030"><p id="p0190">Widely used for cytokine storms</p></list-item><list-item id="o0110"><label>●</label><p id="p0195">Phase 4 for SARS-CoV-2 severe pneumonia (NCT04263402, ChiCTR2000029386, ChiCTR2000029656)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib91" ref-type="bibr">91</xref>]</td></tr><tr><td align="left">IVIG</td><td align="left">Widely used for increased levels of cytokines</td><td align="left">Inhibition of complement activation, blockade of Fc-fragments and Fc receptors and neutralization of cytokines</td><td align="left"><list list-type="simple" id="olist0085"><list-item id="u0035"><p id="p0200">Widely used for cytokine storms</p></list-item><list-item id="o0115"><label>●</label><p id="p0205">Phase 2–3 for SARS-CoV-2 (NCT04261426)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib92" ref-type="bibr">92</xref>]</td></tr><tr><td align="left">Etoposide</td><td align="left">Widely used for primary and secondary HLH, but little evidence on HLH induced by influenza or coronavirus</td><td align="left">Selective deletion of activated T cells and efficient suppression of inflammatory cytokine production</td><td align="left"><list list-type="simple" id="olist0090"><list-item id="o0120"><label>●</label><p id="p0210">Widely used for HLH in combination of corticosteroids and cyclosporine A (HLH2004)</p></list-item><list-item id="o0125"><label>●</label><p id="p0215">Preclinical for ARDS</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib79" ref-type="bibr">79</xref>,<xref rid="bib93" ref-type="bibr">93</xref>,<xref rid="bib94" ref-type="bibr">94</xref>]</td></tr><tr><td align="left">Cyclosporine A</td><td align="left">Widely used for primary and secondary HLH, but little evidence on HLH induced by influenza or coronavirus</td><td align="left">Inhibition of the translocation into the nucleus of NF-AT to lower the activity of overactivated T cells</td><td align="left"><list list-type="simple" id="olist0095"><list-item id="o0130"><label>●</label><p id="p0220">Widely used for HLH in combination with corticosteroids and etoposide (HLH2004)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib79" ref-type="bibr">79</xref>,<xref rid="bib93" ref-type="bibr">93</xref>,<xref rid="bib95" ref-type="bibr">95</xref>]</td></tr><tr><td align="left">Cyclophosphamide</td><td align="left">MAS</td><td align="left">A bioprecursor of a nitrogen mustard alkylation agent to disturb DNA and inhibit cell proliferation</td><td align="left"><list list-type="simple" id="olist0100"><list-item id="o0135"><label>●</label><p id="p0225">Phase 3 for HLH in combination with chemotherapies followed by stem cell transplant (NCT00334672)</p></list-item><list-item id="o0140"><label>●</label><p id="p0230">Phase 2 for non-Hodgkin's lymphoma with HLH in combination with rituximab and other chemotherapies (NCT01818908)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib96" ref-type="bibr">96</xref>]</td></tr><tr><td align="left">Mycophenolate mofetil</td><td align="left">MAS and HLH</td><td align="left">Inhibition of inosine monophosphate dehydrogenase to prevent lymphocyte proliferation</td><td align="left"><list list-type="simple" id="olist0105"><list-item id="o0145"><label>●</label><p id="p0235">Phase 3 for HLH in combination with other chemotherapies followed by stem cell transplant (NCT00334672)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib96" ref-type="bibr">96</xref>]</td></tr><tr><td align="left">Plasmapheresis</td><td rowspan="4" align="left">Widely used for increased levels of cytokines</td><td rowspan="4" align="left">Extracorporeal removal of cytokines, endotoxins, and immunocomplexes</td><td align="left"><list list-type="simple" id="olist0110"><list-item id="o0150"><label>●</label><p id="p0240">Randomized single-blind trial for sepsis（NCT01249222）</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib97" ref-type="bibr">97</xref>,<xref rid="bib98" ref-type="bibr">98</xref>]</td></tr><tr><td align="left">Hemofiltration</td><td align="left"><list list-type="simple" id="olist0115"><list-item id="o0155"><label>●</label><p id="p0245">Randomized open-label trial for sepsis (NCT03426943)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib18" ref-type="bibr">18</xref>,<xref rid="bib98" ref-type="bibr">98</xref>]</td></tr><tr><td align="left">Dialysis/hemodialysis</td><td align="left"><list list-type="simple" id="olist0120"><list-item id="o0160"><label>●</label><p id="p0250">Randomized open-label trial for sepsis (NCT00537693)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib99" ref-type="bibr">99</xref>,<xref rid="bib100" ref-type="bibr">100</xref>]</td></tr><tr><td align="left">Hemadsorption</td><td align="left"><list list-type="simple" id="olist0125"><list-item id="o0165"><label>●</label><p id="p0255">Trial for sepsis (NCT00559130, NCT02588794 NCT02288975, NCT04226430)</p></list-item><list-item id="o0170"><label>●</label><p id="p0260">Randomized open-label trial for transplant-associated hypercytokinemia (NCT03145441, NCT04203004）</p></list-item><list-item id="o0175"><label>●</label><p id="p0265">Randomized single-blind trial for CAR T cell-associated CRS (NCT04048434）</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib101" ref-type="bibr">101</xref>]</td></tr><tr><td align="left">Aspirin</td><td align="left">Acute lung injury and ARDS</td><td align="left">Antiplatelet effects to reduce neutrophil recruitment by platelet activation</td><td align="left"><list list-type="simple" id="olist0130"><list-item id="o0180"><label>●</label><p id="p0270">Phase 2 for ARDS (<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01659307" id="intref0010">NCT01659307</ext-link>)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib102" ref-type="bibr">102</xref>]</td></tr><tr><td align="left">Selective COX-2 inhibitors</td><td align="left">Influenza A</td><td align="left">Downregulation of COX-2 to decrease proinflammatory cytokine levels</td><td align="left"><list list-type="simple" id="olist0135"><list-item id="o0185"><label>●</label><p id="p0275">Phase 3 of celecoxib in combination with oseltamivir for influenza A (NCT02108366)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib103" ref-type="bibr">103</xref>]</td></tr><tr><td align="left">Mesenchymal stem/stromal cells (MSCs)</td><td align="left">ARDS, sepsis and GvHD</td><td align="left">Alteration of the behavior of both adaptive and innate immune cells</td><td align="left"><list list-type="simple" id="olist0140"><list-item id="o0190"><label>●</label><p id="p0280">Approval for GvHD in Canada</p></list-item><list-item id="o0195"><label>●</label><p id="p0285">Phase 1–2 for SARS-CoV-2 (NCT04269525, NCT04252118, ChiCTR2000029817, ChiCTR2000029816)</p></list-item><list-item id="o0200"><label>●</label><p id="p0290">Phase 1–2 for ARDS (<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01775774" id="intref0015">NCT 01775774</ext-link>, <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02097641" id="intref0020">NCT 02097641</ext-link>, NCT03818854, <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT01902082" id="intref0025">NCT 01902082</ext-link>)</p></list-item><list-item id="o0205"><label>●</label><p id="p0295">Phase 1–2 for sepsis (NCT03369275, NCT01849237)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib104" ref-type="bibr">104</xref>,<xref rid="bib105" ref-type="bibr">105</xref>]</td></tr><tr><td align="left">Hematopoietic stem cell transplantation</td><td align="left">Primary HLH and refractory HLH</td><td align="left">Replacement with a genetically normal bone marrow</td><td align="left"><list list-type="simple" id="olist0145"><list-item id="o0210"><label>●</label><p id="p0300">Widely used for familial HLH in children</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib93" ref-type="bibr">93</xref>]</td></tr><tr><td align="left">Anti-thymocyte globulin</td><td align="left">Primary HLH, MAS and GvHD</td><td align="left">Selective ablation of T cells</td><td align="left"><list list-type="simple" id="olist0150"><list-item id="o0215"><label>●</label><p id="p0305">Widely used to treat GvHD</p></list-item></list></td><td align="left"><list list-type="simple" id="ulist0015"><list-item id="u0040"><p id="p0310">Yes</p></list-item></list></td><td align="left">[<xref rid="bib106" ref-type="bibr">106</xref>]</td></tr><tr><td align="left">Statin</td><td align="left">Sepsis</td><td align="left">Inhibition of hydroxymethylglutaryl-CoA reductase to reduce proinflammatory cytokine levels</td><td align="left"><list list-type="simple" id="olist0155"><list-item id="o0220"><label>●</label><p id="p0315">Phase 2–3 for sepsis (NCT00676897, NCT00452608)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib107" ref-type="bibr">107</xref>]</td></tr><tr><td align="left">Chloroquine/hydroxychloroquine</td><td align="left">Sepsis and MAS</td><td align="left">Inhibition of Toll-like receptors and high mobility group box 1 (HMBG1) to reduce proinflammatory cytokine levels</td><td align="left"><list list-type="simple" id="olist0160"><list-item id="o0225"><label>●</label><p id="p0320">Preclinical for sepsis</p></list-item><list-item id="o0230"><label>●</label><p id="p0325">Approval for rheumatic diseases and may reduce SLE-induced MAS</p></list-item><list-item id="o0235"><label>●</label><p id="p0330">Phase 3–4 for SARS-CoV-2 (NCT04261517, ChiCTR2000029898 …)</p></list-item></list></td><td align="left">Yes</td><td align="left">[<xref rid="bib108" ref-type="bibr">108</xref>,<xref rid="bib109" ref-type="bibr">109</xref>]</td></tr><tr><td align="left">S1P1 agonist (CYM-5442)</td><td align="left">Influenza A</td><td align="left">S1P1 receptor agonist downregulating inflammatory mediators, possibly by NF-κB signaling</td><td align="left"><list list-type="simple" id="olist0165"><list-item id="o0240"><label>●</label><p id="p0335">Preclinical for cytokine storms in influenza A and GvHD</p></list-item></list></td><td align="left"><list list-type="simple" id="ulist0020"><list-item id="u0045"><p id="p0340">No</p></list-item></list></td><td align="left">[<xref rid="bib110" ref-type="bibr">110</xref>,<xref rid="bib111" ref-type="bibr">111</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: MAS: macrophage activation syndrome, CRS: cytokine release syndrome, HLH: hemophagocytic lymphohistiocytosis, IVIG: intravenous immunoglobulin, CAR: chimeric antigen receptor, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, IL-1: interleukin-1, IL-6: interleukin-6, IL-18: interleukin-18, IFN: interferon. TNF: tumor necrosis factor, JAK/STAT: the Janus kinase/signal transducer and activator of transcription, GvHD: graft-versus-host disease, ARDS: acute respiratory distress syndrome, NSAIDS: nonsteroidal anti-inflammatory drugs, COX-2: cyclo-oxygenase 2; S1P1: sphingosine-1-phosphate receptor 1, NF-κB: nuclear factor kappa-B.</p></fn></table-wrap-foot></table-wrap></p><p id="p0045">A better understanding of the pathogenesis underlying CRS may facilitate the design of novel immunotherapies. The immunologic mechanism of CRS induced by coronaviruses is not fully elucidated, and existing data are largely derived from SARS coronavirus (SARS-CoV), a close counterpart of SARS-CoV-2. It is believed that delayed kinetics of virus clearance are the trigger. The delayed type I interferon (IFN) response plays a pivotal role in the process of SARS. In the initial phase, SARS-CoV evades pattern recognition receptors (PRRs) and antagonizes the type I IFN response by inducing double-membrane vesicles that lack PRRs, mRNA capping and proteins that inhibit PRR downstream cascades [<xref rid="bib20" ref-type="bibr">20</xref>,<xref rid="bib21" ref-type="bibr">21</xref>]. The dampened type I IFN in airway and alveolar epithelial cells results in rapid viral replication. Plasmacytoid dendritic cells (pDCs) and macrophages are exceptions, with a full response to SARS-CoV, launching a delayed but robust type I IFN response and releasing other inflammatory cytokines against SARS-CoV [<xref rid="bib21" ref-type="bibr">21</xref>,<xref rid="bib22" ref-type="bibr">22</xref>]. Consequently, the activation of type I IFN signaling cascades induces extensive IFN-stimulated gene (ISG) expression and attracts inflammatory monocyte-macrophages (IMMs), neutrophils, dendritic cells and natural killer cells to the lung. This process amplifies the innate response, forming a cytokine-driven vicious cycle [<xref rid="bib21" ref-type="bibr">21</xref>]. The virus-specific T cell immune response is indispensable for virus clearance, an essential step in protecting mice from lethal SARS-CoV infection [<xref rid="bib23" ref-type="bibr">23</xref>]. Both regulatory T cells and naïve T cells negatively regulate the activated innate immune responses by cell-cell interactions [<xref rid="bib24" ref-type="bibr">24</xref>]. Exuberant production of cytokines, such as type I IFN, diminishes T cell responses by inducing T cell apoptosis to aggravate CRS and lymphopenia, as observed in SARS patients [<xref rid="bib21" ref-type="bibr">21</xref>,<xref rid="bib25" ref-type="bibr">25</xref>]. The overwhelming proinflammatory cytokines and chemokines cause localized pulmonary injury characterized by diffuse alveolar damage with epithelial and endothelial apoptosis, dysregulated coagulation and pulmonary fibrinolysis. They may also leak into systemic circulation to cause extrapulmonary manifestations and eventually multiple organ dysfunction syndrome [<xref rid="bib26" ref-type="bibr">26</xref>,<xref rid="bib27" ref-type="bibr">27</xref>].</p><p id="p0050">Among the excessive cytokines produced by activated macrophages, IL-6 is one of the key cytokines. Elevated IL-6 levels were observed in patients with SARS and were correlated with disease severity (<xref rid="tbl1" ref-type="table">Table 1</xref>) [<xref rid="bib28" ref-type="bibr">28</xref>]. IL-6 activates its downstream Janus kinase (JAK) signal by binding the transmembrane (<italic>cis</italic>-signaling) or soluble form (<italic>trans</italic>-signaling) of the IL-6 receptor (IL-6R) and interacting with membrane-bound gp130 [<xref rid="bib29" ref-type="bibr">29</xref>]. Excessive IL-6 signaling leads to a myriad of biological effects that contribute to organ damage, such as maturing naïve T cells into effector T cells, inducing vascular endothelial growth factor (VEGF) expression in epithelial cells, increasing vessel permeability [<xref rid="bib30" ref-type="bibr">30</xref>], and reducing myocardium contractility [<xref rid="bib31" ref-type="bibr">31</xref>].</p><p id="p0055">The elevated cytokine levels may also be responsible for the lethal complications of COVID-19. As shown in <xref rid="tbl1" ref-type="table">Table 1</xref>, patients with COVID-19, SARS or MERS presented distinct cytokine profiles. Patients with COVID-19 presented elevated T helper 2 cytokines (interleukin-4) in addition to T helper 1 cytokines compared to those in patients with SARS or MERS. There are many potential therapies targeting the host immune system that may be effective for COVID-19, such as inflammatory cytokine blockade (IL-6, IL-1, and IFN), stem cell therapy, immune cell depletion, transfusion of convalescent plasma and artificial extracorporeal liver support [<xref rid="bib32" ref-type="bibr">32</xref>], among which we believe IL-6 blockade is a promising strategy for COVID-induced CRS<underline>.</underline> We noticed that elevated IL-6 levels were consistently reported in several studies of COVID-19 [<xref rid="bib33" ref-type="bibr">[33]</xref>, <xref rid="bib34" ref-type="bibr">[34]</xref>, <xref rid="bib35" ref-type="bibr">[35]</xref>, <xref rid="bib36" ref-type="bibr">[36]</xref>] and might serve as a predictive biomarker for disease severity [<xref rid="bib37" ref-type="bibr">37</xref>]. A large retrospective cohort study found that IL-6 levels were correlated with mortality in patients with COVID-19 [<xref rid="bib6" ref-type="bibr">6</xref>]. Mechanistically, IL-6 is essential for the generation of T helper 17 (Th17) cells in the dendritic cell-T cell interaction [<xref rid="bib30" ref-type="bibr">30</xref>]. The excessive IL-6 may explain the overly activated Th17 cells observed in COVID-19 patients, as reported by Xu et al. [<xref rid="bib8" ref-type="bibr">8</xref>]. Although clinical data of IL-6 blockade in virus infection-related CRS are unavailable, animal studies of SARS-CoV have demonstrated that inhibiting nuclear factor kappa-B (NF-κB), a key transcription factor of IL-6, or infecting animals with SARS-CoV lacking the coronavirus envelope (E) protein, a strong stimulus to NF-κB signaling, increased animal survival, with reduced IL-6 levels [<xref rid="bib38" ref-type="bibr">38</xref>]. Interestingly, we noticed that the E proteins of SARS-CoV-2 (Ref sequence QHD43418.1) and SARS-CoV (Ref sequence NP_828854.1) share 95% homology. Since the E protein is the determinant of virulence and mediates the host immune reaction to coronavirus [<xref rid="bib39" ref-type="bibr">39</xref>,<xref rid="bib40" ref-type="bibr">40</xref>], it is reasonable to speculate that both viruses elicit a similar immune response. Hence, targeting IL-6 may be effective for COVID-induced CRS.</p><p id="p0060">Tocilizumab is a recombinant humanized monoclonal anti-IL‐6R antibody. It binds both soluble and membrane‐bound IL‐6R to inhibit IL‐6‐mediated cis- and trans-signaling [<xref rid="bib41" ref-type="bibr">41</xref>]. Tocilizumab has been approved by the U.S. Food and Drug Administration for the treatment of severe CAR T cell‐induced CRS (<xref rid="tbl2" ref-type="table">Table 2</xref>) [<xref rid="bib12" ref-type="bibr">12</xref>]. As mentioned earlier, CRS is the most severe adverse effect induced by CAR T cell therapy, with an incidence of 50–100% [<xref rid="bib41" ref-type="bibr">41</xref>]. It is believed that binding of the CAR T cell receptor to its antigen induces the activation of bystander cells to release massive amounts of interferon γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which further activate innate immune cells, including macrophages and endothelial cells, to secrete IL-6 and other inflammatory mediators [<xref rid="bib42" ref-type="bibr">42</xref>]. IL-6 is a central mediator of toxicity in CRS, and its level correlates with the severity of CAR T cell‐induced CRS [<xref rid="bib12" ref-type="bibr">12</xref>,<xref rid="bib43" ref-type="bibr">43</xref>]. Clinically, severe cases of CAR-T induced CRS present with fever, hypoxia, acute renal failure, hypotension, and cardiac arrhythmia that often warrants ICU admission [<xref rid="bib12" ref-type="bibr">12</xref>]. Tocilizumab showed promising efficacy in severe CRS. After one or two doses of tocilizumab, 69% of patients responded within 14 days, for whom fever and hypotension resolved within hours, and vasopressors could be weaned quickly in several days [<xref rid="bib10" ref-type="bibr">10</xref>,<xref rid="bib41" ref-type="bibr">41</xref>]. The effect of tocilizumab has also been reported in CRS related to several other conditions, such as sepsis, GvHD and MAS [<xref rid="bib44" ref-type="bibr">[44]</xref>, <xref rid="bib45" ref-type="bibr">[45]</xref>, <xref rid="bib46" ref-type="bibr">[46]</xref>]. Moreover, tocilizumab is safe for both pediatric and adult patients, as no adverse reactions have been reported in a retrospective analysis of patients with CAR T cell-induced CRS [<xref rid="bib41" ref-type="bibr">41</xref>]. The most common serious adverse effect is infections in patients with rheumatoid arthritis, in which chronic therapy is maintained for a longer period of time (3.11–3.47/100 person-years with 8 mg/kg tocilizumab every 4 weeks) [<xref rid="bib47" ref-type="bibr">47</xref>]. Moreover, a possible correlation between tocilizumab and medication-related osteonecrosis of the jaws was reported in patients with osteoporosis [<xref rid="bib48" ref-type="bibr">48</xref>]<underline>.</underline></p><p id="p0065">Given the efficacy of tocilizumab in CRS and the pivotal role of IL-6 in COVID-19, we propose to repurpose tocilizumab to treat severe cases of COVID-19. Regarding its clinical use, we suggest taking the following factors into consideration and hope that future clinical trials will be able to address them. 1) Diagnosis criteria. There is currently no consensus in diagnosing CRS in COVID-19. Early diagnosis of CRS in COVID-19 patients and prompt initiation of immunomodulatory treatment may be beneficial, as suggested by the experience in HLH [<xref rid="bib49" ref-type="bibr">49</xref>]. Prompt screening of COVID-19 patients with Hscore, a diagnostic score for HLH, may help to discriminate patients with CRS [<xref rid="bib50" ref-type="bibr">50</xref>]<underline>.</underline>2) Disease severity grading system. Experience with immunotherapy-triggered CRS suggests that tocilizumab is indicated only for severe cases, while the risk benefit assessment favors symptomatic management for mild cases [<xref rid="bib10" ref-type="bibr">10</xref>]. This approach is rationalized by the worry that aggressive antiinflammation therapy may negate the effect of therapeutic biologicals, such as CAR T cells. This principle is not shared in viral infections, such as COVID-19, in which timely intervention in mild or moderate patients may prevent progression. A disease severity grading system may provide an objective tool to assess the most appropriate timing to initiate tocilizumab treatment. Currently, the Chinese guidelines for COVID-19 grade patients into mild, moderate, severe and critical by vital signs, radiographic findings and complications [<xref rid="bib51" ref-type="bibr">51</xref>]. It is currently unclear which population may benefit the most from the treatment. 3) Combined antiviral treatment. Based on experience with corticosteroids, immunosuppressive agents may delay virus clearance. Combining immunomodulators with antiviral agents may add further benefit. Preliminary results from clinical trials of several antiviral treatments are expected to be available soon (remdesivir [NCT04252664, NCT04257656], favipiravir [ChiCTR2000029600, NCT04310228] and chloroquine [ChiCTR2000029609, NCT04286503]). 4) Secondary infection. Infection is a common adverse effect associated with immunomodulators such as tocilizumab. Critically ill COVID-19 patients are susceptible to secondary infection and may have an increased risk of comorbid chronic infections, such as hepatitis B and tuberculosis [<xref rid="bib5" ref-type="bibr">5</xref>]. It is unclear to what degree tocilizumab contributes to secondary infection. Hence, the goal of treatment is to prevent or attenuate life-threatening inflammation while minimizing the potential of secondary infection. For this reason, prophylactic antibiotics may be indicated, and bacteriologic and fungal assessments are of great importance. For patients with secondary infection or coexisting chronic infection, the utilization of tocilizumab should be cautious. 5) Cytokine measurement. Cytokine levels may serve as biomarkers for risk stratification and prognosis. A previous cohort study suggested that IL-6 levels were significantly elevated in COVID-19 patients but varied considerably among both ICU and non-ICU patients [<xref rid="bib34" ref-type="bibr">34</xref>]. This observation raises the question of whether IL-6 blockade is effective only in patients with elevated serum IL-6 levels. If so, IL-6 measurement may be an indispensable part of the grading system. Moreover, the IL-6 level alone may not be sufficient to reflect its functional downstream effects [<xref rid="bib52" ref-type="bibr">52</xref>]. An assay that distinguishes functional IL-6 from total IL-6 may provide a refined approach to guide therapeutic decisions. C-reactive protein (CRP), an acute-phase inflammatory protein synthesized by IL-6-dependent hepatic biosynthesis, is a reliable marker of IL-6 bioactivity and is used to predict CRS severity and monitor IL-6 blockade efficacy for patients with CAR T cell-induced CRS [<xref rid="bib10" ref-type="bibr">10</xref>,<xref rid="bib12" ref-type="bibr">12</xref>]. The CRP level in virus-induced CRS remains to be determined. Most studies suggested that elevated CRP levels were associated with severe COVID-19 [<xref rid="bib37" ref-type="bibr">37</xref>,<xref rid="bib53" ref-type="bibr">53</xref>,<xref rid="bib54" ref-type="bibr">54</xref>], with a few exceptions [<xref rid="bib35" ref-type="bibr">35</xref>]. Nevertheless, future studies on biomarkers are needed for the purpose of risk stratification and therapeutic effect monitoring. There is also a battery of biological agents available that target various critical molecules in the inflammatory network (<xref rid="tbl2" ref-type="table">Table 2</xref>), such as IL-1, IL-18, TNF, and IFN, or Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. These agents may also be beneficial, and if so, routine inflammatory cytokine measurement is warranted.</p><p id="p0070">Notably, SARS-CoV, MERS-CoV and SARS-CoV-2 were all considered to have originated in bats, a nature reservoir of various coronavirus species with high genomic diversity [<xref rid="bib55" ref-type="bibr">55</xref>,<xref rid="bib56" ref-type="bibr">56</xref>]. It is unclear how many bat coronaviruses are directly or indirectly transmissible to humans and how many have the potential to cause disease, especially for those that share the viral spike sequence and are capable of using the human ACE2 receptor for entry [<xref rid="bib55" ref-type="bibr">55</xref>]. Thus, it is highly likely that a novel bat coronavirus could cause future epidemics. For future epidemic preparedness and to reduce mortality in COVID-19 patients, global effort is needed to promote novel therapy to treat virus-induced CRS during the COVID-19 outbreak. Potential therapies available for CRS are summarized in <xref rid="tbl2" ref-type="table">Table 2</xref>. We hope that this assessment will spur future clinical trials on COVID-19-induced CRS. Utilizing biologicals such as tocilizumab to treat virus-induced CRS is a new field. Many other therapeutic options, including hydroxychloroquine combined with azithromycin (NCT04322123, NCT04321278) [<xref rid="bib57" ref-type="bibr">57</xref>], mesenchymal stem cell therapy (NCT04269525, NCT04252118) and convalescent plasma (NCT04292340), have moved into clinical trials for COVID-19. We look forward to seeing additional exciting progress and clinical evidence in this area.</p><sec id="sec1"><title>Fundings</title><p id="p0075">Dr. Yufei Xiang was supported by Shenghua Yuying talented program from <funding-source id="gs5">Central South University</funding-source> and <funding-source id="gs8">European Foundation for Diabetes Study</funding-source> (EFSD) fellowship. Prof. Zhiguang Zhou was supported by the <funding-source id="gs7">National Natural Science Foundation of China</funding-source> (81820108007, 81600649), Science and <funding-source id="gs6">Technology Major Project of Hunan Province</funding-source> (2017SK1020).</p></sec><sec id="sec2"><title>Author contributions</title><p id="p0080">B.L searched literatures, B.L, Y.X and X.G drafted the manuscript, Y.X, X.G, M.L and Z.Z. discussed and revised the manuscript.</p></sec><sec sec-type="COI-statement"><title>Declaration of competing interest</title><p id="p0085">No potential conflicts of interest relevant to this review were reported.</p></sec></body><back><ref-list id="cebib0010"><title>References</title><ref id="bib1"><label>1</label><element-citation publication-type="book" id="sref1"><person-group person-group-type="author"><name><surname>WHO</surname></name></person-group><chapter-title>Coronavirus Disease 2019 (COVID-19) Situation Report – 67</chapter-title><year>2020</year></element-citation></ref><ref id="bib2"><label>2</label><element-citation publication-type="journal" id="sref2"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>P.</given-names></name><name><surname>Yang</surname><given-names>X.L.</given-names></name><name><surname>Wang</surname><given-names>X.G.</given-names></name><name><surname>Hu</surname><given-names>B.</given-names></name><name><surname>Zhang</surname><given-names>L.</given-names></name><name><surname>Zhang</surname><given-names>W.</given-names></name></person-group><article-title>A pneumonia outbreak associated with a new coronavirus of probable bat origin</article-title><source>Nature</source><year>2020</year></element-citation></ref><ref id="bib3"><label>3</label><element-citation publication-type="journal" id="sref3"><person-group person-group-type="author"><name><surname>Turner</surname><given-names>A.J.</given-names></name><name><surname>Hiscox</surname><given-names>J.A.</given-names></name><name><surname>Hooper</surname><given-names>N.M.</given-names></name></person-group><article-title>ACE2: from vasopeptidase to SARS virus receptor</article-title><source>Trends Pharmacol. 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