Skip to main content

Efficacy of tocilizumab treatment in severely ill COVID-19 patients

The current coronavirus disease 2019 (COVID-19) pandemic induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused a global increase in hospitalizations and deaths. Unfortunately, effective medicines to fight this disease, especially in the severely ill patients, are still lacking [1]. Tocilizumab, a humanized monoclonal antibody used in rheumatoid arthritis treatment, might also be effective in treating severe COVID-19 as it could selectively target the interleukin-6 (IL-6) receptor [2]. Considering the uncertain efficacy of tocilizumab treatment in severe COVID-19, we conducted a systematic review and meta-analysis to clarify this added effect of tocilizumab.

We performed a systematic search of PubMed, Embase, Medline, Cochrane, and CNKI database through 25 July 2020, using the following search terms alone or in combination: (1) “COVID-19,” (2) “coronavirus,” (3) “SARS-CoV-2,” (4) “COVID,” (5) “anti-interleukin-6 receptor antibodies,” (6) “anti-IL-6 receptor antibodies,” (7) “anti-IL-6,” (8) “tocilizumab,” (9)“sarilumab,” and (10) “siltuximab.” Clinical trials regarding tocilizumab as a therapeutic intervention were selected. Two independent investigators selected eligible trials and extracted data from articles. Discrepancies in screening/data extraction were addressed by group discussion. Proportional variables were measured by odds ratio (OR) and corresponding 95% confidence intervals (CI). P values < 0.05 were considered statistically significant. Significant heterogeneity (P < 0.10 or I2 ≥ 50%) was evaluated by chi-square and I2 tests in a fixed-effect model. The comparison of the outcome between tocilizumab and control was conducted by using Review Manager 5.4 (Revman, The Cochrane Collaboration, Oxford, UK).

Finally, 10 studies involving 1675 severe COVID-19 patients were included, among which only one trial was a randomized controlled trial, while the rest were all retrospective cohort studies. These studies included COVID-19 patients who were older/elderly (mean/median age ≥ 52 years) in America, Europe, and India, among whom 675 patients received tocilizumab, while 1000 patients underwent standard care. Severe COVID-19 patients received tocilizumab via intravenous or subcutaneous formulation, while doses and administration time points varied. Standard care included hydroxychloroquine, lopinavir/ritonavir, remdesivir, azithromycin, low weight heparin, and/or methylprednisolone, among others (Table 1). Our meta-analysis result revealed a significant difference in mortality between tocilizumab group (132/675, 19.5%) and control group (283/1000, 28.3%) in the fixed-effect model (OR, 0.47; 95%Cl, 0.36–0.60; P < 0.00001), suggesting efficacy of tocilizumab treatment for severe COVID-19. However, high heterogeneity was also observed (I2 = 74%, P < 0.0001) as shown in Fig. 1. SARS-CoV-2 infection might cause a hyperimmune response associated with acute respiratory distress (ARDS), the latteris a leading cause of death for severe COVID-19 [3]. Uncontrolled immune activation would result in cytokine storm, also known as cytokine release syndrome (CRS), appearing as overproduction of pro-inflammatory cytokines and chemokines [4]. Severe COVID-19 patients always present elevated inflammatory markers, among which the elevation of IL-6 is associated with severity of COVID-19 [5]. Besides, the upregulated expression of IL-6 receptor (IL-6R) was also detected in COVID-19 patients [6]. Therefore, IL-6/IL6R might serve as a messenger not only for transmitting inflammatory signals throughout the lung and other organs but also by activating cellular signal pathway, thus causing ARDS and multiple organ dysfunction. It is reasonable to speculate that IL-6 blockade is beneficial for avoiding poor prognosis.

Table 1 Study characteristics and demographics of included severely ill coronavirus disease 2019 (COVID-19) patients
Fig. 1
figure1

Forest plot of pooled mortality of severely ill coronavirus disease 2019 (COVID-19) patients from included studies

Our meta-analysis had several limitations: (1) most included studies were retrospective analysis of cases, resulting in poor quality of the included studies; (2) the uniformity of the diagnostic criteria for severe COVID-19 needs to be improved, and the extraction of related factors is limited; and (3) extraction of the original data is incomplete, and some data cannot be converted due to the lack of relevant data.

In summary, this is the first meta-analysis demonstrating the efficacy of tocilizumab treatment in severely ill COVID-19 patients.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

ACEI:

Angiotension converting enzyme inhibitors

ARB:

Angiotension receptors blockers

ARDS:

Acute respiratory distress syndrome

COVID-19:

Coronavirus disease 2019

CI:

Confidence intervals

CRS:

Cytokine release syndrome

FiO2 :

Fraction of inspired oxygen

ICU:

Intensive care unit

IL-6:

Interleukin-6

IMV:

Invasive mechanical ventilation

NSAID:

Non-steroidal anti-inflammatory drugs

NIV:

Non- invasive Ventilation

OR:

Odds ratio

PaO2 :

Partial pressure of oxygen

SaO2 :

Oxygen saturation

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

References

  1. 1.

    Reddy SG. Population health, economics and ethics in the age of COVID-19. BMJ Glob Health. 2020;5. https://doi.org/10.1136/bmjgh-2020-003259.

  2. 2.

    Cully M. Immune status could determine efficacy of COVID-19 therapies. Nat Rev Drug Discov. 2020;19:431–4. https://doi.org/10.1038/d41573-020-00110-3.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020. https://doi.org/10.1001/jama.2020.12839.

  4. 4.

    Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000.e3. https://doi.org/10.1016/j.chom.2020.04.009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Koutsakos M, Kedzierska K. A race to determine what drives COVID-19 severity. Nature. 2020;583:366–8. https://doi.org/10.1038/d41586-020-01915-3.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Zhu LN, Yang PH, Zhao YZ, et al. Single-cell sequencing of peripheral blood mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients. Immunity. 2020. https://doi.org/10.1016/j.immuni.2020.07.009.

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the Zhejiang Provinicial Natural Science Foundation of China (LY20H010002) and the Medical and Health Research Program of Zhejiang Province (2019RC181) to TBP.

Author information

Affiliations

Authors

Contributions

TBP contributed the conception and design of this review; ZJ wrote the paper. TBP and CW revised and edited this manuscript. All authors reviewed the draft and approved the final manuscript for submission.

Corresponding author

Correspondence to Bao-ping Tian.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhao, J., Cui, W. & Tian, B. Efficacy of tocilizumab treatment in severely ill COVID-19 patients. Crit Care 24, 524 (2020). https://doi.org/10.1186/s13054-020-03224-7

Download citation

Keywords

  • Tocilizumab
  • COVID-19
  • Efficacy
  • Meta-analysis