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. 2020 Nov 9;21(1):24. doi: 10.3892/etm.2020.9456

Interleukin-6 signaling blockade treatment for cytokine release syndrome in COVID-19 (Review)

Jia-Jie Chen 1,*, Li-Na Zhang 1,*, Hu Hou 2, Lingqing Xu 3,, Kunmei Ji 1
PMCID: PMC7690237  PMID: 33262810

Abstract

A severe immune response in patients with coronavirus disease 2019 (COVID-19) can cause a potentially lethal unconstrained inflammatory cytokine storm, known as cytokine release syndrome (CRS). The present study provides an overview of the biology underlying CRS and how targeted inhibition of interleukin (IL)-6 signaling may improve outcomes and the survival of patients suffering from COVID-19. Preliminary clinical results have indicated that antagonism of the IL-6 receptor (IL-6R), including with the FDA-approved humanized monoclonal antibody tocilizumab, can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile. The available clinical data support the expansion of clinical trials using IL-6R targeting inhibitors for severe and critical COVID-19 treatment.

Keywords: coronavirus disease 2019, cytokine release syndrome, interleukin-6 signaling, Tocilizumab, clinical trials

1. Introduction

As of May 2020, 300,000 people had died of coronavirus disease 2019 (COVID-19) worldwide, with cases still on the rise in a number of countries (1-3). The 2019 novel coronavirus, subsequently designated assevere acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), identified in samples of bronchoalveolar lavage fluid from patients with COVID-19, was confirmed as the cause of the COVID-19 pandemic (2). The analysis of genome sequencing indicated that SARS-CoV-2 is a betacoronavirus 2b lineage associated with human SARS and Middle East respiratory syndrome (MERS) (2). The fast spread of the COVID-19 suggests that SARS-COV-2 is highly contagious (3). Commonly, patients with COVID-19 experience fever, cough, myalgia and fatigue. Although the majority patients recover from COVID-19, as many as 20% develop serious complications, including acute respiratory distress syndrome, which may quickly deteriorate into respiratory failure, or even multiple organ dysfunction syndrome, and may need to be transferred to an intensive care unit (ICU) (1). At present, there are no effective therapies or vaccines for COVID-19(3). There remains an urgent requirement to identify effective treatment strategies for COVID-19 that can reduce mortality risk in affected patients.

2. The peril of cytokine storms in COVID-19

Although the factors underlying COVID-19 presentation variability are still being elucidated, it is believed that disease severity is related to a virus-induced cytopathic effect and whether there is viral escape of the host immune response (4). A severe host immune response can cause lethal tissue lesions and an unconstrained inflammatory cytokine storm, known as cytokine release syndrome (CRS), as has been seen in patients infected with other coronaviruses, such as those identified as the pathogens that cause SARS and MERS (5).

Patients with COVID-19, especially those requiring ICU admission, have been reported to exhibit increased plasma levels of inflammatory cytokines, including interleukin (IL)-6, IL-2, IL-7, IL-10, granulocyte colony-stimulating factor, interferon-γ inducible protein, monocyte chemoattractant protein, macrophage inflammatory protein 1α and tumor necrosis factor α (6). Histology of biopsy samples obtained from patients who suffered mortality due to COVID-19 has revealed bilateral diffuse alveolar injury accompanied by cell-fibromyxoid exudates with inflammatory infiltration of interstitial mononuclear cells, predominantly lymphocytes (7). Given the histological observations that evidence CRS in critical and lethal COVID-19, it can be suggested that therapeutic interventions that dampen inflammatory cytokine signaling may alleviate inflammation and reduce mortality in COVID-19.

3. IL-6 signaling and inflammatory storms

Elevated IL-6 is a pronounced and causative factor of CRS in patients, including CRS in patients with SARS or MERS (8). Serum IL-6 levels have been related associated with CRS severity in patients with SARS. In one report, serum IL-6 levels were indicated to reach 517±796 pg/ml in patients suffering severe SARS, and then to decrease gradually down to 68.8±25.9 pg/ml as patients recovered (9). In addition, in a study using a mouse model of CRS and CRS-induced neurotoxicity, monocyte-derived IL-6 was demonstrated to be required for the development of CRS and associated neurotoxicity during the administration of chimeric antigen receptor T-cell immunotherapy (10). Specifically, suppression of serum IL-6 levels was associated with an alleviation of CRS and neurotoxicity in the CRS model mice (10).

IL-6 activates downstream pathways primarily via a classic cis-signaling and trans-signaling pathway (11). In the cis-signaling pathway, a complex of IL-6 with the widely expressed gp130 protein binds the membrane-bound IL-6 receptor (mIL-6R), which is expressed selectively on immune cells. This triggers transduction via a Janus kinase (JAK) and STAT3 protein mediated signaling pathway (12). Activation of the IL-6 cis-signaling pathway has multiple effects on both the acquired (B and T cells) and innate (neutrophils, macrophages and natural killer cells) immune systems, which may contribute to the development of CRS (13). In the trans-signaling pathway, high levels of IL-6 bind soluble IL-6Rs, forminga complex with gp130 dimers on cell surfaces and thereby inducing downstream JAK-STAT3 signaling in a variety of cell types, including endothelial cells (14). Activation of this IL-6 trans-signaling pathway can lead directly to a systemic cytokine storm, including the secretion of VEGF (vascular endothelial growth factor), monocyte chemoattractant protein-1, IL-8 and IL-6, while also causing an increase in the expression of E-cadherin (15). VEGF and E-cadherin increase vascular permeability and leakage, leading to pathophysiological processes that underlie lung dysfunction in lower respiratory disease (15).

4. Inhibition of IL-6 signaling

There are two main types of IL-6 signaling inhibitors available, those that target IL-6 and those that target IL-6R (Fig. 1). IL-6 signaling can be targeted using monoclonal antibodies, including siltuximab, sirukumab, olokizumab, clazakizumab and satralizumab (16,17). Siltuximab was approved by the US FDA in 2014 as a humanized antibody drug for the treatment of multicentric Castleman disease (16). Although other IL-6 targeting antibodies have been indicated to inhibit IL-6 associated inflammation in clinical studies, their safety remains undetermined (16). For example, in a phase 3 clinical trial of sirukumabfor the treatment of arthritis (registration no. NCT01856309), an increased number of deaths occurred in the sirukumab treatment group compared with the placebo group, most often due to a major cardiovascular adverse event. This outcome led the US FDA not approving the clinical use of sirukumab for arthritis. Similarly, a trial of the clazakizumab was also terminated due to adverse events in aphase 2 clinical trial for the treatment of arthritis (registration no. NCT02015520). Olokizumab is currently being examined in a phase 3 clinical trial for the treatment of arthritis (registration no. NCT02760433), and a phase 3 clinical trial of satralizumab for the treatment of optic neuromyelitis spectrum disorder has yielded positive results (registration no. NCT02028884) (17).

Figure 1.

Figure 1

Actions of IL-6 and IL-6R inhibiting monoclonal antibodies on cytokine release-mediated inflammatory storms. The US FDA status of investigational drugs are shown with a green (approval) or red (rejection) box. The inhibitors suppress IL-6 signaling by impeding gp130 mediated activation of JAK and STAT3 signaling, thereby inhibiting cytokine-mediated inflammation and alleviating CRS. IL, interleukin; JAK, Janus kinase; sIL, soluble interleukin; glycoprotein 130, gp130.

IL-6 signaling has diverse biological functions, including the mediation of a protective feedback effect on tissue damage (18). In an experimental acute respiratory distress syndrome model of primary direct viral lung infection (as opposed to infection outside of the lungs), IL-6 blockers have been demonstrated to increase mortality, mainly due to reduced autophagy and increased pulmonary fibrosis (19). In addition, loss of IL-6 can lead to systemic insulin resistance in mice (20). Therefore, due to the fact IL-6 targeting inhibitors may cause an adverse reaction, translation of such agents into clinical applications requires close attention and thorough investigation.

The IL-6R targeting humanized monoclonal antibodies tocilizumab and sarilumab have been approved by the US FDA for the treatment of rheumatoid arthritis (21). Additionally, owing to its pronounced inflammation inhibiting effects, tocilizumab has been approved for use in chimeric antigen receptor T-cell therapy for systemic juvenile idiopathic arthritis and B-precursor acute lymphoblastic leukemia-associated CRS (22). Tocilizumab acts as a competitive antagonist for soluble and membrane-bound forms of IL-6R, thereby inhibiting both cis- and trans-signaling pathways and, consequently, reducing inflammatory activity (23). Compared with IL-6 inhibitors, IL-6R inhibitors have been demonstrated to exhibit a high level of safety in clinical studies (24-26). Long-term animal toxicity testing has indicated that tocilizumab is well tolerated by body systems, with no obvious abnormalities being observed in opportunistic histopathology (24-26). Potential uses of tocilizumab in ovarian (27), pancreatic (28) and colorectal cancer (29) are also being examined. A combination of tocilizumab with carboplatin and/or doxorubicin has indicated good feasibility and safety in a phase 1 clinal trial for the treatment of ovarian cancer (30). Therefore, it is reasonable to examine whether the IL-6R targeting inhibitor tocilizumab may be used to inhibit CRS and alleviate disease severity in patients with COVID-19.

5. Clinical trials of tocilizumab treatment for COVID-19

With respect to the development of CRS in patients with COVID-19, Zhou et al (31) reported that serum IL-6 levels in patients with COVID-19 (n=33) were increased due to significantly increased proportions and numbers of inflammatory CD14+ CD16+ monocytes. As aforementioned, histology of autopsy samples from patients who have succumbed to COVID-19 revealed bilateral diffuse alveolar injury and cellular fibromyxoid exudates that are consistent with CRS (6). A total of 26 clinical investigations of tocilizumab treatment (commonly, 8 mg/kg intravenously) for COVID-19 were registered between January to May 2020 (ClinicalTrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn), including 23 intervention trials and 3 observation trials (Table I). Some trials have only included patients with very high serum IL-6 levels, such as >7 or 40 pg/ml (32-36). Xu et al (32) reported an encouraging alleviation of clinical symptoms of COVID-19. In the aforementioned study, a total of 21 patients with COVID-19 (including 17 with severe disease and 4 with critical disease) who presented with fever as their first symptom (mean body temperature, 38.8±0.6˚C), and whose symptoms did not improve in response conventional treatment, exhibited encouraging responses to tocilizumab treatment. The patients exhibited varying degrees of deterioration, persistent fever, hypoxemia and pulmonary lesion worsened while receiving conventional treatment (mean time, 5.6 days), but within 1 day of starting tocilizumab treatment, all exhibited some alleviation of fever, with some patients returning to a normal body temperature, and the majority of patients experiencing an improvement in respiratory function and chest tightness. Within 5 days of starting the tocilizumab treatment, inflammation indicators (for example, peripheral blood lymphocyte counts and C-reactive protein levels) had mostly recovered and 15/20 patients required less oxygen support to sustain their oxygen saturation (1 patient refused oxygen support), including 2 patients who were withdrawn from mechanical ventilation (32). All 21 patients recovered and were discharged from the hospital an average of 15.1 days after beginning tocilizumab therapy, with no incidences of adverse drug reactions or secondary lung infections (32).

Table I.

Clinical trials of tocilizumab (Toc) for patients with COVID-19 from January to May of 2020.

Identifier Study type Intervention model Intervention Phase IL-6 level N Location
ChiCTR2000029765 Interventional Randomized, parallel asnmt Toc 4-8 mg/kg IV 4 >7 pg/ml 94 China
NCT04377750 Interventional Randomized, parallel asnmt Toc 8 mg/kg IV 4 - 500 Israel
NCT04345445 Interventional Randomized, crossover asnmt Toc 8 mg/kg IV 3 - 310 Malaysia
NCT04320615 Interventional Randomized, DB, multicenter, parallel asnmt Toc 8 mg/kg IV 3 - 330 USA
NCT04372186 Interventional Randomized, DB, multicenter, parallel asnmt Toc 8 mg/kg IV 3 - 379 -
NCT04361032 Interventional Randomized, multicenter, parallel asnmt Toc 8 mg/kg IV 3 - 260 Tunisia
NCT04356937 Interventional Randomized, DB, single-center, parallel asnmt Toc 8 mg/kg IV 3 - 300 USA
NCT04361552 Interventional Randomized, parallel asnmt Toc IV 3 - 180 USA
NCT04317092 Interventional Multicenter, single group asnmt Toc 8 mg/kg IV/12 h 2 - 400 Italy
NCT04377659 Interventional Randomized, parallel asnmt Toc 8 mg/kg IV 2 ≥80 pg/ml 40 USA
NCT04331795 Interventional Non-randomized, single group asnmt Toc 200 mg 2 - 50 USA
NCT04335071 Interventional Randomized, DB, multicenter, parallel asnmt Toc 8 mg/kg IV 2 - 100 USA
NCT04346355 Interventional Randomized, multicenter, parallel asnmt Toc 8 mg/kg IV/12 h 2 - 398 Italy
NCT04363736 Interventional Randomized, multicenter, parallel asnmt Toc 8 mg/kg IV 2 - 100 -
NCT04377503 Interventional Randomized, crossover asnmt Toc 8 mg/kg IV per 12 h 2 >7 pg/ml 40 -
NCT04363853 Interventional DB, single group asnmt Toc 2 - 200 Mexico
NCT04370834 Interventional Single group asnmt Toc IV 2 - 200 -
NCT04315480 Interventional Single group asnmt Toc 8 mg/kg IV 2 - 38 Italy
NCT04333914 Interventional Randomized, multicenter, parallel asnmt Toc 400 mg IV 2 - 273 France
NCT04331808 Interventional Randomized, parallel asnmt Toc 8 mg/kg IV 2 - 228 France
NCT04332094 Interventional Randomized, multicenter, parallel asnmt Toc 162 mg sc 2x 12 h interval 2 - 276 Spain
NCT04310228 Interventional Randomized, multicenter, parallel asnmt Toc 4-8 mg/kg IV - >7 pg/ml 150 China
ChiCTR2000030442 Interventional Non-randomized asnmt Toc - - 100 China
NCT04359667 Observational Case-only study Toc 8 mg/kg IV - - 30 Croatia
NCT04332913 Observational Cohort study Toc 400 mg IV - >40 pg/ml 30 Italy
NCT04306705 Observational Cohort study Toc 8 mg/kg IV - ≥3x normal UL 120  

Information from ClinicalTrials.gov registration (website: https://clinicaltrials.gov) and Chinese Clinical Trial Registry (ChiCTR, website: https://www.chictr.org.cn).. Asnmt, assignment; DB, double-blinded; Toc, tocilizumab; IV, intravenous injection; sc, subcutaneous; UL, upper limit; N, numbers.

A number of studies have demonstrated that tocilizumab treatment is effective in patients with COVID-19. In a retrospective study conducted through a chart review, 239 patients with COVID-19, including 135 with non-severe disease and 104 with severe disease, who at some point in the course of their disease developed signs of CRS, were treated with tocilizumab (33). Among patients treated with tocilizumab and required mechanical ventilation, the survival rate was 75% (33). After commencement of tocilizumab treatment, very few adverse reactions occurred, which included increased high-sensitivity C-reactive protein levels and oxygen requirements, and the patients' oxygenation and inflammation biomarkers consistently improved (33). The survival rate among patients treated with tocilizumab and with severe disease (83%) was statistically similar to that of patients with non-severe disease (91%) (33). A single-center study of a prospective series of 100 patients diagnosed with COVID-19 pneumonia reported that 32 of 43 patients in ICU exhibited rapid and sustained clinical improvement in response to tocilizumab treatment (34). Additionally, tocilizumab was demonstrated to shorten clinical improvement time in a retrospective cohort study (35). Another retrospective cohort study indicated that tocilizumab administration was associated with reduced duration of hospitalization, ICU admission and mechanical ventilation inpatients with COVID-19(36). Additionally, tocilizumab has been demonstrated to be well tolerated and to be free of clinically significant adverse events while prohibiting disease progression in hospitalized patients with moderate COVID-19 and excessive inflammation (37).

Although limited in scope, these data suggest that tocilizumab can improve the prognosis of severe and critical patients with COVID-19, including reducing mortality. Follow-up studies are currently examining the effectiveness of tocilizumab for COVID-19, including clinical trials in Italy and France (38). Based on encouraging data and observations with tocilizumab, the National Health Commission of the People's Republic of China has declared officially that tocilizumab can be provided to patients with COVID-19 who exhibit extensive bilateral lung lesions opacity and to those in severe or critical condition with increased serum IL-6 levels (39).

6. Conclusion

In the context of an ongoing urgent requirement for an effective COVID-19 treatment, a promising strategy of controlling CRS has emerged. Preliminary clinical results have indicated that antagonism of IL-6R with tocilizumab can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile. The data obtained so far supports the expansion of clinical trials of IL-6R targeting inhibitors, such as tocilizumab, for severe and critical COVID-19 treatment.

Acknowledgements

Not applicable.

Funding

The present study was supported in part by research funding from Shenzhen City (grant nos. JSGG20200102165803939 and JSGG20200225151806035), the Shenzhen University Top Ranking Project (grant no. 86000000210) and the Qingyuan People's Hospital Medical Scientific Research Fund Project (grant no. 20190209).

Availability of data and materials

Not applicable.

Authors' contributions

JJC and KJ conceived and designed the study. JJC and LNZ performed the literature review. JJC and LNZ wrote the manuscript. HH, LX and KJ revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  • 1.Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020;395:470–473. doi: 10.1016/S0140-6736(20)30185-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–1069. doi: 10.1001/jama.2020.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38:1–9. doi: 10.12932/AP-200220-0772. [DOI] [PubMed] [Google Scholar]
  • 5.Channappanavar R, Perlman S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39:529–539. doi: 10.1007/s00281-017-0629-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol. 2020;92:568–576. doi: 10.1002/jmv.25748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422. doi: 10.1016/S2213-2600(20)30076-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–679. doi: 10.1158/2159-8290.CD-16-0040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Zhang Y, Li J, Zhan Y, Wu L, Yu X, Zhang W, Ye L, Xu S, Sun R, Wang Y, Lou J. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun. 2004;72:4410–4415. doi: 10.1128/IAI.72.8.4410-4415.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–748. doi: 10.1038/s41591-018-0036-4. [DOI] [PubMed] [Google Scholar]
  • 11.Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016;64:1403–1415. doi: 10.1016/j.jhep.2016.02.004. [DOI] [PubMed] [Google Scholar]
  • 12.Baran P, Hansen S, Waetzig GH, Akbarzadeh M, Lamertz L, Huber HJ, Ahmadian MR, Moll JM, Scheller J. The balance of interleukin (IL)-6, IL-6.soluble IL-6 receptor (sIL-6R), and IL-6.sIL-6R.sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem. 2018;293:6762–6775. doi: 10.1074/jbc.RA117.001163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8:1237–1247. doi: 10.7150/ijbs.4989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 2016;138:2570–2578. doi: 10.1002/ijc.29923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–248. doi: 10.1038/nrclinonc.2018.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Deisseroth A, Ko CW, Nie L, Zirkelbach JF, Zhao L, Bullock J, Mehrotra N, Del Valle P, Saber H, Sheth C, et al. FDA approval: Siltuximab for the treatment of patients with multicentric castleman disease. Clin Cancer Res. 2015;21:950–954. doi: 10.1158/1078-0432.CCR-14-1678. [DOI] [PubMed] [Google Scholar]
  • 17.Yamamura T, Kleiter I, Fujihara K, Palace J, Greenberg B, Zakrzewska-Pniewska B, Patti F, Tsai CP, Saiz A, Yamazaki H, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381:2114–2124. doi: 10.1056/NEJMoa1901747. [DOI] [PubMed] [Google Scholar]
  • 18.Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(a016295) doi: 10.1101/cshperspect.a016295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020;19(102537) doi: 10.1016/j.autrev.2020.102537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Matthews VB, Allen TL, Risis S, Chan MH, Henstridge DC, Watson N, Zaffino LA, Babb JR, Boon J, Meikle PJ, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010;53:2431–2441. doi: 10.1007/s00125-010-1865-y. [DOI] [PubMed] [Google Scholar]
  • 21.Navarro G, Taroumian S, Barroso N, Duan L, Furst D. Tocilizumab in rheumatoid arthritis: A meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum. 2014;43:458–469. doi: 10.1016/j.semarthrit.2013.08.001. [DOI] [PubMed] [Google Scholar]
  • 22.Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, Pazdur R. FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943–947. doi: 10.1634/theoncologist.2018-0028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Jones SA, Richards PJ, Scheller J, Rose-John S. IL-6 transsignaling: The in vivo consequences. J Interferon Cytokine Res. 2005;25:241–253. doi: 10.1089/jir.2005.25.241. [DOI] [PubMed] [Google Scholar]
  • 24.Kaly L, Rosner I. Tocilizumab-a novel therapy for non-organ-specific autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26:157–165. doi: 10.1016/j.berh.2012.01.001. [DOI] [PubMed] [Google Scholar]
  • 25.Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: A randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371:998–1006. doi: 10.1016/S0140-6736(08)60454-7. [DOI] [PubMed] [Google Scholar]
  • 26.Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381:1541–1550. doi: 10.1016/S0140-6736(13)60250-0. [DOI] [PubMed] [Google Scholar]
  • 27.Yanaihara N, Hirata Y, Yamaguchi N, Noguchi Y, Saito M, Nagata C, Takakura S, Yamada K, Okamoto A. Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary. Mol Carcinog. 2016;55:832–841. doi: 10.1002/mc.22325. [DOI] [PubMed] [Google Scholar]
  • 28.Goumas FA, Holmer R, Egberts JH, Gontarewicz A, Heneweer C, Geisen U, Hauser C, Mende MM, Legler K, Röcken C, et al. Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Int J Cancer. 2015;137:1035–1046. doi: 10.1002/ijc.29445. [DOI] [PubMed] [Google Scholar]
  • 29.Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–113. doi: 10.1016/j.ccr.2009.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Dijkgraaf EM, Santegoets SJ, Reyners AK, Goedemans R, Wouters MC, Kenter GG, van Erkel AR, van Poelgeest MI, Nijman HW, van der Hoeven JJ, et al. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patients with recurrent epithelial ovarian cancer. Ann Oncol. 2015;26:2141–2149. doi: 10.1093/annonc/mdv309. [DOI] [PubMed] [Google Scholar]
  • 31.Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, Sun R, Tian Z, Xu X, Wei H. doi: 10.1101/2020.02.12.945576. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. Feb 20, 2020 doi: [DOI] [Google Scholar]
  • 32.Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA. 2020;117:10970–10975. doi: 10.1073/pnas.2005615117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, Azar MM, Mcmanus D, Chen SC, Gleeson SE, et al. doi: 10.1016/j.chest.2020.06.006. Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: Survival and clinical outcomes. Chest: 15 Jun, 2020 doi: 10.1016/j.chest.2020.06.006 (Epub ahead for print). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airò P, Bazzani C, Beindorf EA, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020;19(102568) doi: 10.1016/j.autrev.2020.102568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kewan T, Covut F, Al-Jaghbeer MJ, Rose L, Gopalakrishna KV, Akbik B. Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study. EClinicalMedicine. 2020;24(100418) doi: 10.1016/j.eclinm.2020.100418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Eimer J, Vesterbacka J, Svensson AK, Stojanovic B, Wagrell C, Sonnerborg A, Nowak P. doi: 10.1111/joim.13162. Tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe COVID-19: A retrospective cohort study. J Intern Med: Aug 3, 2020 doi: 10.1111/joim.13162 (Epub ahead for print). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Potere N, Di Nisio M, Rizzo G, La Vella M, Polilli E, Agostinone A, Spacone A, Di Carlo S, Costantini A, Abbate A, et al. doi: 10.1016/j.ijid.2020.07.078. Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation. Int J Infect Dis: Aug 5, 2020 doi: 10.1016/j.ijid.2020.07.078 (Epub ahead for print). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Arthritis drug shows ‘significant’ promise in severe COVID-19 cases: Study (2020, April 28) https://medicalxpress.com/news/2020-04-arthritis-drug-significant-severe-covid-.html. Accessed 30 May 2020. [Google Scholar]
  • 39. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (7th Interim edition). China NHCOTPSRO. http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989/files/ce3e6945832a438eaae415350a8ce964.pdf. Accessed 30 May 2020. [Google Scholar]

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Data Availability Statement

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