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Infectious Diseases and Therapy logoLink to Infectious Diseases and Therapy
. 2021 Jul 9;10(3):1677–1698. doi: 10.1007/s40121-021-00483-x

Efficacy and Safety of Tocilizumab Treatment COVID-19 Patients: A Case-Control Study and Meta-Analysis

Weijun Jiang 1, Weiwei Li 1, Qiuyue Wu 1, Ying Han 1, Jing Zhang 1, Tao Luo 1, Yanju Guo 1, Yang Yang 1, Peiran Zhu 1, Xinyi Xia 1,2,3,✉
PMCID: PMC8269405  PMID: 34244956

Abstract

Introduction

As the pandemic progresses, the pathophysiology of COVID-19 is becoming more apparent, and the potential for tocilizumab is increasing. However, the clinical efficacy and safety of tocilizumab in the treatment of COVID-19 patients remain unclear.

Methods

To assess the efficacy and safety of tocilizumab treatment in COVID-19 patients, we performed a retrospective case-control study. The study was conducted, including 95 patients treated with tocilizumab plus standard treatment and matched controls with 95 patients treated with standard treatment therapy by propensity score from February to April 2020. We searched some databases using the search terms for studies published from January 1, 2020, to June 1, 2021.

Results

Our case-control study found a lower mortality rate in the tocilizumab treatment group than in the standard treatment group (9.47% versus 16.84%, P = 0.134), but the results were not statistically significant. We also found that the mortality rate in tocilizumab treatment groups was significantly lower than in the standard treatment group in the stratified ICU analysis (OR 0.52, 95% CI 0.44–0.61, P = 0.048 and OR 0.31, 95% CI 0.10–0.99, P = 0.044). We selected 49 studies (including 6568 cases and 11,660 controls) that met the inclusion criteria in the meta-analysis. In the overall analysis, we performed a meta-analysis that showed significantly decreased mortality after patients received tocilizumab (OR 0.81, 95% CI 0.69–0.95, P = 0.008). We also revealed significant associations within some subgroups. The sequential trial analysis showed a true-positive result. No significant associations were observed between tocilizumab and elevated secondary infection risk, discharge, adverse events, and mechanical ventilation in the overall analysis.

Conclusion

Tocilizumab significantly decreased mortality in COVID-19 patients with no increased discharge, secondary infection risk, adverse events, and mechanical ventilation in a meta-analysis. Our data suggest that clinicians should pay attention to tocilizumab therapy as an effective and safe treatment for COVID-19 patients.

Keywords: COVID-19, Efficacy, Meta-analysis, Safety, Tocilizumab

Key Summary Points

Why carry out this study?
As the pandemic progresses, the pathophysiology of COVID-19 is becoming more apparent, and the potential for tocilizumab is increasing.
However, the clinical efficacy and safety of tocilizumab in the treatment of COVID-19 patients remain unclear.
What was learned from the study?
The study was conducted, including 95 patients treated with tocilizumab plus standard treatment and matched controls with 95 patients treated with standard treatment therapy by propensity score from February to April 2020. We searched some databases using the search terms for studies published from January 1, 2020, to June 1, 2021.
Our case-control study found a lower mortality rate in the tocilizumab treatment group than in the standard treatment group (9.47% versus 16.84%, P = 0.134), but the results were not statistically significant.
We selected 49 studies (including 6568 cases and 11,660 controls) that met the inclusion criteria in the meta-analysis. In the overall analysis, we performed a meta-analysis that showed significantly decreased mortality after patients received tocilizumab (OR 0.81, 95% CI 0.69–0.95, P = 0.008). We also revealed significant associations within some subgroups. The sequential trial analysis showed a true-positive result.
No significant associations were observed between tocilizumab and elevated secondary infection risk, discharge, adverse events, and mechanical ventilation in the overall analysis.
Our data suggests that clinicians should pay attention to tocilizumab therapy as an effective and safe treatment for COVID-19 patients.
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Digital Features

This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to 10.6084/m9.figshare.14785560.

Introduction

Coronavirus disease 2019 (COVID-19) may be associated with a dysregulated immune response and hyperinflammation, which can lead to or exacerbate acute respiratory distress syndrome (ARDS) and multiple organ failure [1–3]. As the pandemic progressed, there was an unfounded enthusiasm surrounding the use of tocilizumab. However, the clinical efficacy and safety of tocilizumab treatment of COVID-19 patients have been controversial.

Epidemiologic studies and earlier recent retrospective studies have demonstrated that patients infected with SARS-CoV-2 exhibited high plasma levels of circulating interleukin 6 (IL-6), IL-1Ra, IL-1β, IL-10, IL-17, IL-18, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF), suggesting a rapid activation of the innate immune response [4–11]. Several studies have shown that plasma IL-6 levels are elevated in COVID-19 patients in the intensive care unit (ICU), and they appear to be positively correlated with mortality [12–17]. In an observational study, tocilizumab, an anti-IL-6 receptor monoclonal antibody, has been approved for the treatment of various inflammatory diseases and appeared to improve outcomes in COVID-19 patients in several countries [2]. Some recent studies have suggested that tocilizumab may be intensively related to a lower risk of intubation or death in severe and critically ill patients with COVID-19 pneumonia. Since the clinical severity of COVID-19 patients appears to be associated with a cytokines storm and an overproduction of soluble inflammatory mediators, tocilizumab is currently under investigation. Still, the results were inconsistent [18–25].

Amid the shortage of robust evidence regarding the use of tocilizumab in COVID-19 patients, we aimed to evaluate the efficacy and safety of tocilizumab treatment for COVID-19 patients in a case-control study and meta-analysis, which will help inform clinical management of COVID-19 patients.

Methods

Patients

The retrospective case-control study was performed between February to April 2020 and was conducted in Wuhan, China. All participants were admitted to the Huoshenshan Hospital and were confirmed COVID-19 cases according to quantitative real-time polymerase chain reaction (qRT-PCR). We received approval from the ethics committee of Huoshenshan Hospital and conducted the study following the tenets of the Declaration of Helsinki and its amendments.

All participants voluntarily provided written informed consent for sample collection and their subsequent analysis. Intravenous tocilizumab was administered at a dose of 8 mg/kg body weight (up to 800 mg), up to twice, 12 h apart. Matched control patients were retrospectively identified within the electronic information database of Huoshenshan Hospital. The primary endpoint was 60 days’ mortality, improvement, and discharge, and critical secondary endpoints were hospital stay, secondary infection, and mechanical ventilation. All participants received standard treatment, including hydroxychloroquine and antiviral therapy, including lopinavir/ritonavir, antimicrobial agents, and corticosteroids.

Study Selection

We searched PubMed, Web of Science, and MedRxiv using the search terms severe acute respiratory syndrome coronavirus 2, COVID-19, SARS-CoV-2, 2019-nCoV interleukin-6 inhibitors, tocilizumab, and coronavirus for studies published from January 1, 2020, to June 1, 2021 (Fig. 1).

Fig. 1.

Fig. 1

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Flow diagram of the study selection process

Data Extraction and Verification

The inclusion criteria of the meta-analysis were: (1) research focus on tocilizumab and COVID-19; (2) studies on humans; (3) the number of cases and controls; (4) papers with full text available. The exclusion criteria of the meta-analysis were: (1) review, (2) case report; (3) animal study; (4) incomplete data and unclear outcome effects; (5) repeat of the report.

Specific information about the included studies is listed in Table 3, including (1) the author’s last name and country, (2) publication and online time, (3) 3thnicity or race, (4) severity of disease, (5) dose of tocilizumab, (6) study design, (7) journal, (8) case size, (9) number of cases and controls, (10) number of discharges in cases and controls, (11) number of deaths in cases and controls, (12) number of secondary infections in cases and controls, and (13) number of mechanical ventilations in cases and controls. First, three authors (Weijun Jiang, Weiwei Li, and Ying Han) independently screened the studies that met inclusion and exclusion criteria and extracted all data. If two or three of the three agreed, the study was included in the meta-analysis. Next, each of the three authors pulled the data, while the other two cross-checked the data. Disagreements were resolved through review and discussion.

Table 3.

Characteristics of all studies describing tocilizumab treatment COVID-19 patients in the meta-analysis

Author (country) Time Race Disease severity Dose Study type Journal Case size Case/control Discharge case/control Mortality case/control Adverses events case/control Secondary infection case/control MV case/control
Roumier (France) [31] 20200420 Caucasian Severe 8 mg/kg Retrospective Observational study Unpublished < 100 30/29 3/9 10/16
Colaneri (Italy) [32] 20200509 Caucasian Critical 8 mg/kg Case-control study Published < 100 21/91 5/19 0/0
Capra (Italy) [14] 20200513 Caucasian Severe ≤ 400 mg Retrospective observational study Published < 100 62/23 57/10 2/11 0/0 5/4
Wadud (USA) [33] 20200513 Mix Severe ≤ 400 mg Case-control study Unpublished < 100 44/50 17/26
Ramaswamy (USA) [34] 20200514 Mix Mix 8 mg/kg Case-control study Unpublished < 100 21/65 3/8 13/10
Kimmig (USA) [24] 20200515 Mix Critical ≤ 400 mg Retrospective observational study Published < 100 54/57 18/34 19/11 29/16
Quartuccio (Italy) [26] 20200515 Caucasian Severe ≤ 400 mg Case-control study Published < 100 42/69 30/21 7/0 17/0 26/0
Ip (USA) [35] 20200521 Mix Critical ≤ 400 mg Multicenter cohort study Published > 100 134/413 62/231 18/44
Campochiaro (Italy) [6] 20200522 Caucasian Severe ≤ 400 mg Cohort study Published < 100 32/33 20/16 5/11 8/9 4/4 4/2
Moreno-Garcia (Spain) [36] 20200605 Caucasian Mix NA Cohort study Unpublished < 100 77/94 65/71 8/17 3/14
Martinez-Sanz (Spain) [37] 20200608 Caucasian Mix 400–800 mg Multicenter cohort study Unpublished > 100 260/969 61/120
Kewan (USA) [23] 20200620 Mix Severe 8 mg/kg Cohort study Published < 100 28/23 11/13 3/2 5/5 5/5 21/11
Guaraldi (Italy) [21] 20200624 Caucasian Severe 8 mg/kg Multicenter cohort study Published > 100 179/365 13/73 1/1 24/14 33/57
Canziani (Italy) [13] 20200708 Caucasian Mix 8 mg/kg Case-control study Published < 100 64/64 17/24 20/25 9/29
Potere (Italy) [25] 20200709 Caucasian Severe ≤ 400 mg Case-control study Published < 100 40/40 2/11 0/0 1/3
Somers (USA) [28] 20200711 Mix Severe 8 mg/kg Cohort study Published < 100 78/76 44/30 7/20 42/20 31/43
Carvalho (Brazil) [38] 20200715 Caucasian Critical ≤ 400 mg Case-control study Unpublished < 100 29/24 5/4 11/4 15/7
Gokhale (India) [39] 20200716 Caucasian Severe ≤ 400 mg Cohort study Published < 100 70/91 26/30 33/61 19/9
De Rossi (Italy) [15] 20200717 Caucasian Severe ≤ 400 mg Cohort study Published < 100 90/68 7/34 0/0 6/4 13/6
Rojas-Marte (USA) [19] 20200801 Mix Severe NA Case-control study Published < 100 96/97 43/55 16/26 1/0
Eimer (Sweden) [40] 20200803 Caucasian Severe 8 mg/kg Cohort study Published < 100 51/80 10/26 0/0 9/20 42/74
Patel (USA) [41] 20200803 Mix Mix NA Cohort study Published < 100 42/41 23/11 11/12
Potere (Italy) [18] 20200805 Caucasian Moderate ≤ 400 mg Case-control study Published < 100 10/10 0/0 0/0 0/0 0/1
Pettit (USA) [42] 20200813 Mix NA ≤ 400 mg Retrospective observational study Published < 100 74/74 29/17 17/6 25/23
Rodríguez-Bano (Spain) [27] 20200826 Caucasian NA 400–800 mg Multicenter cohort study Published < 100 88/339 2/41 11/36
Roomi (USA [43]) 20200901 Mix NA NA Cohort study Published < 100 32/144 25/38 6/13 47/31
Albertini (France) [4] 20200910 Caucasian Severe 8 mg/kg Cohort study Published < 100 22/22 10/10 3/2 0/0 0/0 2/6
Galvan-Roman (Spain) [16] 20200930 Caucasian Severe 8 mg/kg Cohort study Published < 100 58/88 14/16 3/7
Zheng (China) [44] 20201008 Asian Mix 400–800 mg Retrospective Observational study Published < 100 92/89 83/88 9/1 0/0 0/0
Holt (USA) [45] 20201013 Mix NA ≤ 400 mg Cohort study Published < 100 32/31 10/9
Guisado-Vasco (Spain) [46] 20201015 Caucasian Severe 8 mg/kg Cohort study Published > 100 132/475 44/97
Klopfenstein (France) [47] 20201016 Caucasian Severe 8 mg/kg Case-control study Published < 100 30/176 16/82 8/66 0/39
Rossi (France) [48] 20201017 Caucasian Severe 8 mg/kg Case-control study Published > 100 106/140 23/63
Gupta (USA) [22] 20201020 Mix Critical NA Multicenter cohort study Published > 100 433/3491 125/1419 140/1085
Hermine (France) [8] 20201020 Caucasian Mix 8 mg/kg RCT Published < 100 63/67 7/8 28/36 2/14 5/14
Salvarani (Italy) [11] 20201020 Caucasian NA 8 mg/kg RCT Published < 100 60/66 54/58 2/1 1/4
Stone (USA) [12] 20201021 Mix Mix 8 mg/kg RCT Published > 100 161/82 147/72 9/3 2/2 13/14 11/8
Tsai (USA) [20] 20201105 Mix Severe 400–800 mg Cohort study Published < 100 66/66 18/18 4/4
Hill (USA) [17] 20201117 Mix Severe ≤ 400 mg Cohort study Published < 100 43/45 26/27 9/15 4/2 9/18
Ruiz-Antora'n (Spain) [29] 20201206 Caucasian Severe 400–800 mg Multicenter cohort study Published > 100 268/238 45/75 124/72
Tian (China) [30] 20201209 Asian Severe 400–800 mg Multicenter cohort study Published < 100 65/130 14/42 18/41
Rosas (USA) [49] 20201212 Mix Severe 8 mg/kg RCT Unpublished > 100 294/144 58/28 113/58
Salama (USA) [1] 20201217 Mix NA 8 mg/kg RCT Published > 100 249/128 26/11 38/25 25/16
Veiga (Brazil) [50] 20210120 Mix Mix 8 mg/kg RCT Published < 100 65/64 35/31 14/6 29/21 10/10 11/10
Kumar (India)[51] 20210316 Caucasian Mix ≤ 400 mg RCT Published < 100 20/10 16/6 0/3 18/4 1/3
Peter W Horby (UK) [52] 20210211 Mix Severe 400–800 mg RCT Unpublished > 100 2022/2094 1093/999 596/694
Arvinder (India) [53] 20210504 Caucasian Mix 8 mg/kg RCT Published < 100 91/88 11/15 30/22 5/5 14/13
Gordon (UK) [54] 20210225 Mix Critical 8 mg/kg RCT Published > 100 353/402 163/218 87/134 9/11 1/0 104/121
Jiang (China) 20210701 Asian Mix 8 mg/kg Case-control study Unpublished < 100 95/95 86/79 9/16 16/2
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The mix of severity, symptoms of the disease include moderate, severe, and critical; mix of race, including Asian, Caucasian, African, and so on; ICU, intensive care unit; NA, no appearance

Statistical Analysis

Categorical variables were summarized as counts and percentages (%). For the continuous measurement, we used the Kolmogorov-Smirnov test to evaluate the distribution type. We also used mean ± standard deviation (SD) to express the customarily distributed data and otherwise used median and interquartile ranges (IQR) to describe the continuous variables. Continuous variables of different groups of data were compared using independent sample double-tailed t-test and Mann-Whitney test. Chi-square and Fisher’s exact test was used to compare the frequencies of categorical variables. We used a 1:1 propensity score matching (PSM) analysis to reach patients who underwent tocilizumab with those who did not. We used SPSS (v.20.0; SPSS Inc., Chicago, IL, USA) to perform statistical analysis.

We used the DerSimonian and Laird method data in the random-effects model and used the Mantel-Haenszel method in the fixed-effects model. Z-test was used to determine the pooled odds ratio (OR) statistical significance, with P values < 0.05 being considered statistically significant. When the P value for heterogeneity was ≤ 0.10 or I2 ≥ 50%, there was heterogeneity between comparative studies. Conversely, if I2 < 50% and the P value for heterogeneity was > 0.10, this indicated that there was no heterogeneity between comparative studies. We used funnel plots and Egger’s linear regression test to evaluate publication bias. We used STATA version 11.0 (Stata Corp., College Station, TX, USA) to carry statistical analyses. Similarly, we used novel statistical analysis software, known as trial sequence analysis (TSA), to examine the reliability and conclusiveness of the existing evidence.

Results

Basic Characteristics and Demographics

We analyzed a total of 190 participants who were determined to have COVID-19 in the clinical study. Ninety-five patients received standard treatment alone, and 95 received treatment with tocilizumab in addition to standard treatment. Of all patients, 63 (66.32%) cases and 56 (58.95%) controls had coexisting conditions, including hypertension, hyperlipidemia, hyperuricemia, diabetes, chronic cardiac disease, cancer, etc.

Interestingly, we found that both hospital stay and secondary infection risk in the case group were significantly higher than in the control group (P < 0.001). However, the rate of mortality in the tocilizumab treatment group was lower than that in the standard treatment group, but no statistically significant difference was found. We also found that the mortality rate in tocilizumab treatment groups was significantly lower than in the standard treatment group in the stratified ICU analysis (OR 0.52, 95% CI 0.44–0.61, P = 0.048 and OR 0.31, 95% CI 0.10–0.99, P = 0.044). In the subgroup without secondary infection, the tocilizumab treatment group's mortality rate was significantly lower than that in the standard treatment group (OR 0.35, 95% CI 0.12–1.00, P = 0.040).

However, no significant differences in age, disease severity, rate of cure, and basic disease between the tocilizumab group and standard treatment group were found. Our results showed that tocilizumab treatment did not significantly reduce the rate of COVID-19 mortality and the increased secondary infection risk. Clinicians are advised to use this therapy with caution. The clinical characteristics and demographic data of all participants are shown in Tables 1 and 2.

Table 1.

Clinical characteristics of all COVID-19 patients

Characteristics All (N = 190) Case (N = 95) Control (N = 95) P value
Age (mean ± SD) years 67.27 ± 34.51 68.55 ± 11.50 66 ± 13.64 0.183
Hospital stay (mean ± SD) days 24.13 ± 12.67 12.75 ± 27.68 11.55 ± 20.58 0.000
ICU no. (%) 0.163
No 139 (71.16%) 66 (69.47%) 73 (76.84%)
Yes 51 (36.84%) 29 (30.53%) 22 (23.16%)
Gender group no. (%) 0.765
Male 120 (61.16%) 59 (62.11%) 61 (64.21%)
Female 70 (36.84%) 36 (37.89%) 34 (35.79%)
Basic disease no. (%) 0.296
No 71 (37.37%) 32 (33.68%) 39 (41.05%)
Yes 119 (62.63%) 63 (66.32%) 56 (58.95%)
Outcome no. (%) 0.134
Cure 165 (86.84%) 86 (90.53%) 79 (83.16%)
Death 25 (13.16%) 9 (9.47%) 16 (16.84%)
Disease severity no. (%) 0.789
Moderate 25 (13.16%) 13 (13.68%) 12 (12.63%)
Severe 108 (56.84%) 52 (54.74%) 56 (58.95%)
Critical 57 (30.00%) 30 (31.58%) 27 (28.42%)
Secondary infection no. (%)
No 172 (90.53%) 79 (83.16%) 93 (97.89%) 0.000
Yes 18 (9.47%) 16 (16.84%) 2 (2.11%)
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Bold values indicate statistically significant results

SD, standard deviation; ICU, intensive care unit

Table 2.

Outcome of tocilizumab treatment COVID-19 patients in stratified analysis

Outcome Tocilizumab adjOR 95% CIs P
Case (N = 95) Control (N = 95)
Disease
No Cure 29 35 0.91 0.19–4.38 0.901
Death 3 4
Yes Cure 57 44 0.39 0.13–1.11 0.069
Death 6 12
Severity
Moderate Cure 13 12 -
Death 0 0
Severe Cure 52 54 0.103
Death 0 2
Critical Cure 21 13 0.40 0.13–1.18 0.092
Death 9 14
ICU
No Cure 66 70 0.52 0.44–0.61 0.048
Death 0 3
Yes Cure 20 9 0.31 0.10–0.99 0.044
Death 9 13
Gender
Female Cure 32 30 0.94 0.22–4.09 0.932
Death 4 4
Male Cure 54 49 0.38 0.12–1.12 0.075
Death 5 12
Secondary infection
No Cure 74 78 0.35 0.12–1.00 0.040
Death 5 15
Yes Cure 12 1 0.33 0.02–6.65 0.478
Death 4 1
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Bold values indicate statistically significant results

ICU, intensive care unit; Ph, P value of heterogeneity, P value of Q-test for the heterogeneity test; OR, odds ratio; CI, confidence interval

Study Selection and Characteristics

The combination of search terms produced all the related articles. A preliminary review of titles and abstracts found 157 articles that required a full manuscript review. According to the inclusion criteria, we selected 49 papers with potential relevance through literature retrieval and screening (Fig. 1). In our meta-analysis, a total of 49 studies, including 6568 cases and 11,660 controls, met the inclusion criteria. Table 3 summarizes the characteristics of the selected studies.

Mortality

In the overall analysis, we performed a meta-analysis of 49 studies (6568 tolcizumab plus standard treatment COVID-19 patients and 11,660 standard treatment COVID-19 patients) that reported that significantly decreased mortality after patients received tocilizumab (OR 0.81, 95% CI 0.69–0.95, P = 0.008). We also revealed significant associations within the mix of race subgroup (OR 0.86, 95% CI 0.79–0.94, P = 0.001), Caucasian subgroup (OR 0.64, 95% CI 0.45–0.89, P = 0.008), severe subgroup (OR 0.65, 95% CI 0.52–0.82, P = 0.001), critical subgroup (OR 0.77, 95% CI 0.66–0.89, P < 0.001), dose of 800 mg subgroup (OR 0.81, 95% CI 0.70–0.94, P = 0.006), no specific dose subgroup (OR 0.74, 95% CI 0.62–0.89, P = 0.001), case-control study subgroup (OR 0.72, 95% CI 0.56–0.91, P = 0.006), journal of published subgroup (OR 0.78, 95% CI 0.64–0.94, P = 0.011), and case size of < 100 subgroup (OR 0.77, 95% CI 0.61–0.98, P = 0.030), but not the remaining subgroups. In addition, there was an edge effect in dose of the ≤ 400 mg subgroup (OR 0.66, 95% CI 0.42–1.03, P = 0.067) and the multicenter case-control subgroup (OR 0.69, 95% CI 0.45–1.05, P = 0.081). For mortality, the number of patients did not reach the optimal information size. However, the blue cumulative Z curve crossed both the traditional boundary and the TSA boundary showing that no more tests are needed to reach a positive conclusion in advance. Specific data are summarized in Figs. 2, 3 and Table 4.

Fig. 2.

Fig. 2

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Forest plot of mortality and tocilizumab treatment COVID-19 patients

Fig. 3.

Fig. 3

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Trial sequential analysis of mortality and tocilizumab treatment COVID-19 patients

Table 4.

The mortality and risk of infection of tocilizumab treatment COVID-19 patients

Mortality OR (95% CI) P Ph I2% Pb Secondary infection risk OR (95% CI) P Ph I2% Pb
Total 0.81 (0.69–0.95) 0.008  < 0.001 63.2 0.767 Total 1.16 (0.94–1.45) 0.170 0.001 48.4 0.880
Race Race
MIX 0.86 (0.79–0.94) 0.001 0.155 24.5 Caucasian 1.14 (0.76–1.70) 0.530 0.006 51.5
Asian 0.97 (0.34–2.76) 0.952 0.048 67.2 MIX 1.07 (0.92–1.23) 0.378 0.102 34.1
Caucasian 0.64 (0.45–0.89) 0.008  < 0.001 75.1 Asian 5.50 (1.59–19.09) 0.007 0.188 42.3
Severity Severity
MIX 1.03 (0.68–1.56) 0.886 0.009 56.3 Severe 1.23 (0.87–1.74) 0.248 0.008 51.9
Severe 0.65 (0.52–0.82)  < 0.001  < 0.001 67.4 Critical 1.12 (0.93–1.34) 0.226 0.319 15.0
Critical 0.77 (0.66–0.89) 0.001 0.346 10.9 MIX 0.97 (0.48–1.97) 0.934 0.010 62.3
NA 1.11 (0.77–1.60) 0.586 0.103 45.5 Moderate 1.00 (0.05–18.30) 1.000 - -
NA 1.13 (0.75–1.72) 0.559 0.115 49.5
Dose Dose
8 mg/kg 0.81 (0.70–0.94) 0.006 0.100 45.8 8 mg/kg 0.98 (0.67–1.44) 0.932 0.001 60.9
400–800 mg 0.90 (0.58–1.40) 0.633 < 0.001 82.8 400–800 mg 1.43 (1.06–1.92) 0.018 0.561 0.0
≤ 400 mg 0.66 (0.42–1.03) 0.067 < 0.001 71.4 ≤ 400 mg 1.92 (1.40–2.63) < 0.001 0.228 21.9
NA 0.74 (0.62–0.89) 0.001 0.346 10.5 NA 1.00 (0.82–1.21) 0.973 0.157 50.0
Study type Study type
Retrospective observational study 0.89 (0.27–2.95) 0.845 < 0.001 81.5 Retrospective observational study 2.00 (1.15–3.47) 0.013 0.545 0.0
Case-control study 0.72 (0.56–0.91) 0.006 0.247 20.7 Case-control 1.98 (1.14–3.45) 0.016 0.001 73.1
Multicenter cohort study 0.69 (0.45–1.05) 0.081 < 0.001 85.3 Cohort study 1.22 (0.85–1.77) 0.285 0.663 0.0
Cohort study 0.78 (0.54–1.11) 0.167 0.001 62.0 Multicenter cohort 1.67 (0.63–4.41) 0.302 0.010 69.8
RCT 0.89 (0.80–0.99) 0.032 0.372 7.6 RCT 0.79 (0.61–1.03) 0.079 0.173 30.6
Journal Journal
Unpublished 0.93 (0.66–1.29) 0.642 0.004 64.7 Unpublished 2.21 (0.64–7.64) 0.212 0.013 77.1
Published 0.78 (0.64–0.94) 0.011 < 0.001 60.9 Published 1.12 (0.89–1.41) 0.322 0.003 45.7
Case size Case size
< 100 0.77 (0.61–0.98) 0.030 < 0.001 51.3 < 100 1.18 (0.86–1.62) 0.314 0.015 41.4
> 100 0.86 (0.69–1.08) 0.200 < 0.001 79.8 > 100 1.15 (0.84–1.56) 0.384 0.003 67.3
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Bold values indicate statistically significant results

The mix of severity, symptoms of the disease include moderate, severe and critical; mix of race, including Asian, Caucasian, African, and so on; ICU, intensive care unit; NA, no appearance; OR, odds ratio; CI, confidence interval; Ph, P value of heterogeneity, P value of Q-test for the heterogeneity test; I2, 0–25, no heterogeneity; 25–50, modest heterogeneity; 50, high heterogeneity

Secondary Infection Risk

No significant associations were observed between tocilizumab and an elevated secondary infection risk in the overall analysis. However, we found significantly increased secondary infection risk after COVID-19 patients received tocilizumab in the dose of 400–800 mg subgroup (OR 1.43, 95% CI 1.06–1.92, P = 0.018), dose of ≤ 400 mg subgroup (OR 1.92, 95% CI 1.40–2.63, P < 0.001), retrospective observational study subgroup (OR 2.00, 95% CI 1.15–3.47, P = 0.013), and case-control study subgroup (OR 1.98, 95% CI 1.14–3.45, P = 0.016). In addition, there was an edge effect in the RCT subgroup (OR 0.79, 95% CI 0.61–1.03, P = 0.079). Figure 4 and Table 4 summarize the data associated with tocilizumab and secondary infection risk.

Fig. 4.

Fig. 4

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Forest plot of safety of tocilizumab treatment COVID-19 patients. a Forest plot of tocilizumab and secondary infection risk in COVID-19 patients. b Forest plot of tocilizumab and discharge in COVID-19 patients. c Forest plot of tocilizumab and adverse events in COVID-19 patients. d Forest plot of tocilizumab and mechanical ventilation in COVID-19 patients

Discharge

We also failed to find significantly increased discharge after COVID-19 patients received tocilizumab in the overall analysis (OR 1.13, 95% CI 0.98–1.32, P = 0.100). We revealed significantly increased discharge in tocilizumab treatment COVID-19 patients in the cohort study subgroup (OR 1.32, 95% CI 1.06–1.65, P = 0.014). We revealed significantly decreased discharge in tocilizumab treatment COVID-19 patients in the dose of 400–800 mg subgroup (OR 0.88, 95% CI 0.80–0.98, P = 0.018). However, we also found an edge effect in Caucasian subgroup analysis (OR 1.24, 95% CI 1.00–1.55, P = 0.051), the no specific dose subgroup (OR 1.82, 95% CI 0.95–3.47, P = 0.069), case-control study subgroup (OR 1.37, 95% CI 1.00–1.89, P = 0.051), journal of unpublished subgroup (OR 0.91, 95% CI 0.0.82–1.00, P = 0.055), journal of published subgroup (OR 1.18, 95% CI 0.99–1.41, P = 0.060), and case size of < 100 subgroup (OR 1.19, 95% CI 0.99–1.44, P = 0.060). Specific data are summarized in Fig. 4 and Table 5.

Table 5.

The rate of discharge, adverse events and mechanical ventilation of tocilizumab treatment COVID-19 patients

Discharge OR (95% CI) P Ph I2% Pb Adverse event OR (95% CI) P Ph I2% Pb Mechanical ventilation OR (95% CI) P Ph I2% Pb
Total 1.13 (0.98–1.32) 0.100 0.011 46.4 0.367 Total 1.26 (0.97–1.62) 0.078 0.999 0.0 0.075 Total 1.03 (0.72–1.47) 0.866 < 0.001 73.4 0.657
Race Race Race
Caucasian 1.24 (1.00–1.55) 0.051 0.564 0.0 Caucasian 1.27 (0.88–1.81) 0.197 0.976 0.0 Caucasian 0.85 (0.55–1.32) 0.472 < 0.001 63.3
MIX 1.11 (0.88–1.39) 0.397 0.003 64.3 MIX 1.25 (0.87–1.79) 0.226 0.953 0.0 MIX 1.40 (0.71–2.76) 0.327 < 0.001 82.6
Asian 1.03 (0.77–1.40) 0.824 0.393 0.0 Asian 1.03 (0.06–16.78) 0.981 – – Asian 0.88 (0.47–1.65) 0.685 – –
Severity Severity Severity
Severe 0.94 (0.86–1.04) 0.228 0.069 43.5 Severe 1.04 (0.52–2.08) 0.920 0.998 0.0 Severe 1.01 (0.70–1.45) 0.968 0.008 53.4
Critical 0.87 (0.43–1.78) 0.701 0.045 75.2 Critical 0.84 (0.36–1.96) 0.679 0.353 0.0 Critical 1.77 (0.62–5.06) 0.284 – –
MIX 1.07 (0.88–1.29) 0.514 0.707 0.0 Moderate 1.00 (0.05–18.30) 1.000 – – MIX 0.71 (0.36–1.40) 0.326 0.002 71.3
NA 1.71 (0.60–4.84) 0.312 0.010 84.7 MIX 1.40 (0.99–1.96) 0.054 0.969 0.0 Moderate 0.33 (0.01–9.16) 0.516 – –
NA 1.28 (0.74–2.21) 0.377 – – NA 2.74 (0.45–16.58) 0.273 < 0.001 94.0
Dose Dose Dose
8 mg/kg 1.12 (0.96–1.30) 0.163 0.953 0.0 8 mg/kg 1.24 (0.95–1.63) 0.118 0.981 0.0 8 mg/kg 0.82 (0.57–1.16) 0.256 0.007 55.7
400–800 mg 0.88 (0.80–0.98) 0.018 0.880 0.0 400–800 mg 1.03 (0.06–16.78) 0.981 – – 400–800 mg 0.88 (0.47–1.65) 0.685 – –
≤ 400 mg 1.19 (0.81–1.76) 0.380 0.079 47.0 ≤ 400 mg 1.38 (0.67–2.88) 0.385 0.937 0.0 ≤ 400 mg 1.41 (0.74–2.70) 0.295 0.007 62.1
NA 1.82 (0.95–3.47) 0.069 0.041 68.6 NA 1.71 (0.13–22.61) 0.684 < 0.001 90.7
Study type Study type Study type
Retrospective observational study 0.98 (0.52–1.83) 0.950 0.051 66.5 Retrospective Observational study 1.03 (0.06–16.78) 0.981 – – Retrospective Observational study 0.83 (0.50–1.36) 0.462 0.415 0.0
Case-control study 1.37 (1.00–1.89) 0.051 0.210 36.0 Case-control study 0.65 (0.13–3.34) 0.603 0.706 0.0 Case-control study 1.43 (0.36–5.65) 0.611 < 0.001 80.7
Cohort study 1.32 (1.06–1.65) 0.014 0.221 25.1 Cohort study 1.09 (0.52–2.31) 0.813 0.996 0.0 Cohort study 1.18 (0.61–2.26) 0.625 < 0.001 82.9
RCT 0.93 (0.85–1.02) 0.116 0.424 0.0 Multicenter cohort study 0.49 (0.03–7.89) 0.615 – – Multicenter cohort study 1.06 (0.73–1.54) 0.755 0.458 0.0
RCT 1.32 (1.00–1.74) 0.049 0.954 0.0 RCT 0.73 (0.46–1.16) 0.183 0.551 0.0
Journal Journal
Unpublished 0.91 (0.82–1.00) 0.055 0.281 21.1 Unpublished 1.07 (0.34–3.35) 0.905 0.003 78.9
Published 1.18 (0.99–1.41) 0.060 0.081 33.8 Published 1.02 (0.69–1.50) 0.921 < 0.001 73.7
Case size Case size Case size
< 100 1.19 (0.99–1.44) 0.060 0.087 32.9 < 100 1.30 (0.95–1.76) 0.099 0.997 0.0  < 100 1.04 (0.69–1.56) 0.851 < 0.001 75.3
> 100 0.99 (0.81–1.22) 0.953 0.097 57.1 > 100 1.18 (0.75–1.84) 0.480 0.803 0.0 > 100 1.07 (0.70–1.63) 0.758 0.333 0.0
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Bold values indicate statistically significant results

The mix of severity, symptoms of the disease include moderate, severe and critical; mix of race, including Asian, Caucasian, African, and so on; ICU, intensive care unit; NA, no appearance; OR, odds ratio; CI, confidence interval; Ph, P value of heterogeneity, P value of Q-test for the heterogeneity test; I2, 0–25, no heterogeneity; 25–50, modest heterogeneity; 50, high heterogeneity

Adverse Events and Mechanical Ventilation

No significant association was found between tocilizumab and adverse events and mechanical ventilation in COVID-19 patients in the overall analysis. We found significantly increased adverse events risk in tocilizumab treatment COVID-19 patients in the RCT subgroup (OR 1.32, 95% CI 1.00–1.74, P = 0.049). Subgroup analyses were performed to clarify the effects of potential ethnicity, disease severity, drug dose, study type, and case size and whether the article is officially published. There was no significant association between tocilizumab treatment and estimated risk of adverse events and mechanical ventilation, as shown in Fig. 4 and Table 5.

Publication Bias and Sensitivity Analysis

We performed Egger's test and Begg's funnel plot to assess the publication bias of the meta-analysis. We also conducted sensitivity analysis by omitting one study at a time when calculating summary results. Although the size of the sample of cases in all included studies varied, corresponding pooled ORs and 95%CIs did not qualitatively change with or without studies on small pieces.

Discussion

The World Health Organization (WHO) announced COVID-19 may progress to a pandemic associated with substantial morbidity and mortality and is a public health emergency of globalized concern as of 1 February 2020 [1, 3, 12]. At the time of this writing, over 174 million laboratory-diagnosed COVID-19 patients had been reported spanning 212 countries and regions and contributing to > 3,730,000 death.

SARS-CoV-2 brings about a broad spectrum of clinical manifestations, ranging from asymptomatic or paucisymptomatic forms (with malaise, myalgia, dry cough, and fever) to full-blown viral pneumonia ARDS, multiorgan failure, and death [2, 25]. The serum cytokine profiles of some moderate to severe COVID-19 patients overlap with secondary hemophagocytic lymphocytosis (sHLH) and macrophage activation syndrome (MAS). Viruses are known as solid triggers of MAS/sHLH, and serum ferritin levels are associated with mortality in MAS and COVID-19 patients. Endogenous IL-1 is a proinflammatory cytokine that induces the production of IL-6 by macrophages and monocytes and is elevated in MAS, COVID-19 disease, and other diseases, such as severe chimerical antigen receptor T-cell (CAR-T)-mediated cytokine release syndrome (CRS) [2, 26–28].

IL-6 inhibitors or their receptor inhibitors have been successfully treated with other cytokine storm syndromes or CRS secondary to CAR T-cell therapies. We already have several drug options available, including IL-6 inhibitors (siltuximab, sirukumab, clazakizumab) and IL-6 receptor inhibitors (tocilizumab, sarilumab). It is noteworthy that tocilizumab has been officially included in the National Health Commission of the People's Republic of China COVID-19 Guidelines for diagnosis and treatment program (7th edition) since March 2020: "Tocilizumab can be used in COVID-19 patients with extensive ground-glass lesions opacity in bilateral lungs or critically ill COVID-19 patients, who have elevated laboratory detected serum IL-6 levels" [2]. The Infectious Diseases Society of America (IDSA) has also recently published guidelines and suggested that tocilizumab should only be used in clinical trials of hospitalized COVID-19 patients because of the lack of reliable clinical treatment data [2].

The Infectious Diseases Society of America (IDSA) has also recently published guidelines and suggested that tocilizumab should only be used in clinical trials of hospitalized COVID-19 patients because of the lack of reliable clinical treatment data [1, 11, 12]. However, several retrospective observational studies have found that, in addition to standard treatment, tocilizumab is a safe and promising treatment to prevent disease progression in hospitalized COVID-19 patients with moderate and hyper-inflammation [13–16, 28–30]. Our case-control study also found a lower mortality rate in the tocilizumab treatment group than in the standard treatment group (9.47% versus 16.84%), but the results were not statistically significant. However, we found that tocilizumab significantly decreased mortality and increased discharge in COVID-19 patients but no increased secondary infection risk, adverse event, and mechanical ventilation in a meta-analysis of 49 studies (6568 cases and 11,660 controls). We additionally found similar results in several subgroups. Therefore, our data suggest that clinicians should pay attention to tocilizumab therapy as an effective and safe treatment for COVID-19 patients.

Some limitations of the study need to be noted. First, in the absence of clinical test data of every patient, it is not clear which patients with high clinical indicators will benefit most when treated with tocilizumab. Second, subgroup analyses involved relatively small groups, which may not provide sufficient statistical power to explore accurate correlations. Third, every doctor has a different treatment for clinical diagnostics, which would allow for adjustment by other factors. Finally, the inclusion of zero-event trials can sometimes reduce effect size estimates and narrow confidence intervals.

Conclusion

To our knowledge, it is the systematic review and meta-analysis to investigate the efficacy and safety of tocilizumab treatment in COVID-19 patients in the the biggest sample size. Tocilizumab significantly decreased mortality in COVID-19 patients but no increased discharge, secondary infection risk, adverse event, and mechanical ventilation in a meta-analysis. Our data suggest that clinicians should pay attention to tocilizumab therapy as an effective and safe treatment for COVID-19 patients.

Acknowledgements

I am very grateful to my wife for her help and support. We also appreciate the valuable comments from other members of our laboratory.

Funding

Our work was supported by the Key Foundation of Wuhan Huoshenshan Hospital (2020[18]), Scientific Research Project of Jiangsu Commission of Health (H2019065), Medical Innovation Project of Logistics Service (18JS005), and Key Research & Development Program of Jiangsu Province (BE2018713). The Journal’s Rapid Service Fee was funded by the authors.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship contributions

All authors reviewed and approved the final manuscript. Weijun Jiang wrote and revised the paper. Weijun Jiang, Qiuyue Wu, and Xinyi Xia conceived and designed the experiments. Weijun Jiang, Ying Han, and Weiwei Li performed publication searches and selection. Weijun Jiang and Peiran Zhu contributed materials/analysis tools. Weijun Jiang, Yang Yang, and Yanju Guo prepared the figures. Weijun Jiang, Jing Zhang, and Tao Luo analyzed the data.

Disclosures

All authors declare that they have no competing interests in the work.

Compliance with Ethics Guidelines

All participants voluntarily provided written informed consent for sample collection and their subsequent analysis. We have the approval of the ethics committee of Huoshenshan Hospital and have conducted it following the tenets of the Declaration of Helsinki and its amendments.

Data Availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

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