Temporal Clinical and Laboratory Response to Interleukin-6 Receptor Blockade With Tocilizumab in 89 Hospitalized Patients With COVID-19 Pneumonia

  1. Daria Fomina
  2. Mar’yana A. Lysenko
  3. Irina P. Beloglazova
  4. Zinaida Yu. Mutovina
  5. Nataliya G. Poteshkina
  6. Inna V. Samsonova
  7. Tat’yana S. Kruglova
  8. Anton A. Chernov
  9. Alexander V. Karaulov

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Abstract

Background: Pandemic COVID-19 pneumonia due to SARS-2 is an important cause of morbidity and mortality. Emerging evidence links poor outcomes to an inflammatory cytokine storm.Methods: We treated 89 hospitalized patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) with an infusion of tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor.Results: Clinical and laboratory evidence of improvement was evident when baseline and 1-2-day post-infusion indices were compared. Among the 72 patients receiving supplemental oxygen without mechanical ventilation, severity of condition on the NEWS2 scale scores fell from 5 to 2 (P<0.001), C reactive protein levels fell from 95 to 14 mg/L (P<0.001), and lymphocyte counts rose from 900 to 1000/uL (P=0.036). Sixty-three of 72 patients were discharged from the hospital, one patient died, and eight patients remained in the hospital at the time of this writing. Among the 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (P=0.014) and early improvements in NEWS2 scores in 10 of 17 patients, 10 patients ultimately died and the other seven remain in the hospital at the time of this writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration.Conclusions: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of tocilizumab, an anti-IL-6 receptor antibody, is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

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  1. Version published to 10.20411/pai.v5i1.392
  2. ScreenIT

    SciScore for 10.1101/2020.06.12.20122374: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Patients and Intervention: Off-label administration of Tocilizumab was approved by the Local Ethics Committee of the 52nd Moscow City Clinical Hospital for treatment of COVID-19 complicated by cytokine storm.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical data processing was carried out using the application program “IBM SPSS STATISTICS V-22” software.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    Although our results suggest that TCZ therapy is beneficial for hospitalized patients with COVID-19, this report has important limitations. First, this was a retrospective study conducted in a heterogeneous group of patients. Interpretation of this study is also limited by the absence of a control group that did not receive TCZ. Nonetheless the temporal improvement in clinical and laboratory scores suggest that these are related to TCZ administration. Controlled studies are needed to determine whether cytokine blockade and in particular, blockade of IL-6 confers benefit to persons with COVID-19. Such studies are ongoing and their findings are eagerly awaited. Our data suggest that for COVID-19 patients requiring mechanical ventilation, IL-6 blockade alone may be insufficient; other interventions are necessary.

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.06.12.20122374 on medRxiv