Prompt Reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1 and a Relatively Low Basal Ratio of Ferritin/CRP Is Possibly Associated With the Efficacy of Tocilizumab Monotherapy in Severely to Critically Ill Patients With COVID-19

  1. Shoji Hashimoto
  2. Kazuyuki Yoshizaki
  3. Kazuko Uno
  4. Heita Kitajima
  5. Tsuyoshi Arai
  6. Yoshitaka Tamura
  7. Hiroshi Morishita
  8. Hiroto Matsuoka
  9. Yuki Han
  10. Seijiro Minamoto
  11. Tomonori Hirashima
  12. Tomoki Yamada
  13. Yozo Kashiwa
  14. Makoto Kameda
  15. Seiji Yamaguchi
  16. Yasunari Tsuchihashi
  17. Mitsuhiro Iwahashi
  18. Emi Nakayama
  19. Tatsuo Shioda
  20. Takayuki Nagai
  21. Toshio Tanaka

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Abstract

Background and Aim: Tocilizumab, a humanized anti-IL-6 receptor antibody, has been used to treat severely to critically ill patients with COVID-19. A living systematic review with meta-analysis of recent RCTs indicates that the combination therapy of corticosteroids and tocilizumab produce better outcomes, while previous observational studies suggest that tocilizumab monotherapy is beneficial for substantial numbers of patients. However, what patients could respond to tocilizumab monotherapy remained unknown.

Methods: In this retrospective study we evaluated the effects of tocilizumab monotherapy on the clinical characteristics, serum biomediator levels, viral elimination, and specific IgG antibody induction in 13 severely to critically ill patients and compared with those of dexamethasone monotherapy and dexamethasone plus tocilizumab.

Results: A single tocilizumab administration led to a rapid improvement in clinical characteristics, inflammatory findings, and oxygen supply in 7 of 11 patients with severe COVID-19, and could recover from mechanical ventilation management (MVM) in 2 patients with critically ill COVID-19. Four patients exhibited rapidly worsening even after tocilizumab administration and required MVM and additional methylprednisolone treatment. Tocilizumab did not delay viral elimination or inhibit IgG production specific for the virus, whereas dexamethasone inhibited IgG induction. A multiplex cytokine array system revealed a significant increase in the serum expression of 54 out of 80 biomediators in patients with COVID-19 compared with that in healthy controls. Compared with those who promptly recovered in response to tocilizumab, patients requiring MVM showed a significantly higher ratio of basal level of ferritin/CRP and a persistent increase in the levels of CRP and specific cytokines and chemokines including IL-6, IFN-γ, IP-10, and MCP-1. The basal high ratio of ferritin/CRP was also associated with clinical deterioration even in patients treated with dexamethasone and tocilizumab.

Conclusion: Tocilizumab as monotherapy has substantial beneficial effects in some patients with severe COVID-19, who showed a relatively low level of the ratio of ferritin/CRP and prompt reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1. The high ratio of ferritin/CRP is associated with rapid worsening of pneumonia. Further evaluation is warranted to clarify whether tocilizumab monotherapy or its combination with corticosteroid is preferred for severely to critically ill patients with COVID-19.

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  1. Version published to 10.3389/fmed.2021.734838
  2. ScreenIT

    SciScore for 10.1101/2020.06.24.20134288: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: All patients provided written informed consent, and the off-label compassionate use of tocilizumab was approved by the Ethics Committee of Osaka Habikino Medical Center (Approved ID: 150-7).
    IRB: All patients provided written informed consent, and the off-label compassionate use of tocilizumab was approved by the Ethics Committee of Osaka Habikino Medical Center (Approved ID: 150-7).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Detection of specific antibody against SARS-CoV-2: The serum levels of IgM and IgG class antibodies specific for SARS-CoV-2 were determined by using the Corona Virus COVID-19 Antibody Rapid Detection kit according to the manufacturer’s instructions (Healgen Scientific Ltd.).17 The test samples in an individual patient included all of the sera collected before and 1-2 and 3-4 weeks after tocilizumab injection, or in some cases at 4-5 weeks after injection, depending on the availability.
    IgG class
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This report has several limitations. The sample size was small, and the data were analyzed retrospectively. Moreover, the treatment protocol involved combination therapy of tocilizumab with anti-viral drugs, so the direct effect of tocilizumab could not be evaluated. Further evaluation using a randomized controlled trial design is essential.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.06.24.20134288v1 on medRxiv