Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 ‘Cytokine Storm’: A Retrospective Observational Cohort Study

  1. Sonali Narain
  2. Dimitre G. Stefanov
  3. Alice S. Chau
  4. Andrew G. Weber
  5. Galina Marder
  6. Blanka Kaplan
  7. Prashant Malhotra
  8. Ona Bloom
  9. Audrey Liu
  10. Martin L. Lesser
  11. Negin Hajizadeh
  12. Northwell COVID-19 Research Consortium

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Abstract

Background

Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes.

Methods

We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020 and April 15, 2020, were included. Cytokine storm was defined by inflammatory markers: ferritin >700ng/mL, C-reactive protein >30mg/dL, or lactate dehydrogenase >300U/L. Patients were subdivided into six groups -no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-interleukin 6 (IL-6) antibody (tocilizumab) or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality.

Results

There were 3,098 patients who met inclusion criteria. The most common comorbidities were hypertension (40-56%), diabetes (32-43%) and cardiovascular disease (2-15%). Patients most frequently met criteria with high lactate dehydrogenase (74.8%) alone, or in combination, followed by ferritin (71.4%) and C-reactive protein (9.4%). More than 80% of patients had an elevated D-dimer. Patients treated with a combination of tocilizumab and corticosteroids (Hazard Ratio [HR]: 0.459, 95% Confidence Interval [CI]: 0.295-0.714; p<0.0001) or corticosteroids alone (HR: 0.696, 95% CI: 0.512-0.946; p=0.01) had improved hospital survival compared to standard of care. Corticosteroids and tocilizumab was associated with increased survival when compared to corticosteroids and anakinra (HR: 0.612, 95% CI: 0.391-0.958; p-value=0.02).

Conclusions

When compared to standard of care, corticosteroid and tocilizumab used in combination, or corticosteroids alone, was associated with reduced hospital mortality for patients with COVID-19 cytokine storm.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.16.20126714: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The Institutional Review Board for the Feinstein Institutes of Medical Research at Northwell Health approved this study as minimal-risk research and waived the requirement for informed consent.
    Consent: The Institutional Review Board for the Feinstein Institutes of Medical Research at Northwell Health approved this study as minimal-risk research and waived the requirement for informed consent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    SAS 9.4 (SAS Institute, Cary, NC) was used for the statistical analysis.
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    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 we were rigorous in our approach to the study design and data analysis, there are intrinsic limitations that preclude definitive conclusions in retrospective studies. The effect of systematic practice variability across the health system could not be evaluated. The use of electronic health record database limited our ability to measure other potential confounders which could have influenced provider decision making about treatments, and outcomes. Further analysis of our data is needed to evaluate the effects of immunomodulatory treatments on disease progression, including rates of thrombosis and infections. Despite these limitations, our study is the largest to date reporting outcomes comparing the use of corticosteroids, tocilizumab, anakinra and standard of care without immunomodulatory treatment in COVID-19 CCS. Our findings suggest that, when compared to standard of care, tocilizumab and corticosteroids used together, or corticosteroids used alone, was associated with lower hospital mortality. Further investigation into the effects of differential immunomodulatory dosing, and head-to-head comparison of tocilizumab plus corticosteroids versus corticosteroids alone is warranted.

    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.

  2. Version published to 10.1101/2020.06.16.20126714v1 on medRxiv