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
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Fig. 1
figure 1

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

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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.