key: cord-1017836-k1mf8vfy
authors: Zhao, Meng; Lu, Jieyu; Tang, Yihu; Dai, Yawei; Zhou, Jingxin; Wu, Yanhu
title: Tocilizumab for treating COVID-19: a systemic review and meta-analysis of retrospective studies
date: 2020-10-13
journal: Eur J Clin Pharmacol
DOI: 10.1007/s00228-020-03017-5
sha: a5eb3e0e8b01fbf5a6a56a6071838767d08dd9c6
doc_id: 1017836
cord_uid: k1mf8vfy

OBJECTIVES: COVID-19 has become a global epidemic, and effective therapies have not been discovered up to now. We conducted this study to explore the effectiveness and safety of tocilizumab recently used for treating COVID-19. METHOD: A comprehensive search was conducted (up to September 27, 2020), and 19 eligible records were identified according to the inclusion and exclusion criteria. The data of the studies were extracted by 2 independent reviewers and were analyzed to evaluate the safety and availability of tocilizumab for treating COVID-19. RESULTS: Thirteen retrospective case-control studies (n = 2285 patients) and 6 retrospective single-armed studies (n = 208) were retrieved in this study. In the comparison of tocilizumab treatment group (TCZ) and standard treatment group (ST), significant associations with a lower risk of admission to ICU, use of ventilation, and mortality (OR, 95% CI: 0.53, 0.26~1.09; 0.66, 0.46~0.94; 0.44, 0.36~0.55) were found in the tocilizumab treatment group. What is more, patients treated with tocilizumab had better clinical improvement compared with the patients treated with ST (OR, 1.24; 95% CI, 0.96~1.62). After taking tocilizumab, the patients had lower C-reactive protein (CRP), white blood cell count (WBC), aspartate aminotransferase (AST) (WMD, 95% CI: − 99.66, − 156.24~− 43.09; − 0.95, − 1.8~− 0.11; − 12.58, − 18.88~−6.29) but higher troponin (WMD, 7.61; 95% CI, 3.06~12.15) than before. In addition, tocilizumab did not have significant influence on patients’ neutrophil count (Neut), lymphocyte count (Lymp), platelet count (Plt), alanine aminotransferase (ALT), and creatine (WMD, 95% CI: − 0.29, − 2.91~2.33; 0.42, − 0.23~1.07; 5.2, − 2.85~13.25; 22.49, − 2.73~47.7; − 44.78, − 93.37~3.81). CONCLUSION: Tocilizumab may have potential effectiveness to treat COVID-19 according to the results of this study. However, more large-scale studies are needed for more accurate conclusions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00228-020-03017-5) contains supplementary material, which is available to authorized users.

Since December 2019, the global epidemic of novel coronavirus disease 2019 (COVID-19) had infected over 30,000,000 people worldwide up to September 27, 2020. COVID-19 can result in interstitial pneumonia with respiratory failure, which is the principal cause of death [1] . There is no widely approved medicine for treating this deadly infectious disease as yet.

In recent months, several case reports or case series [2] [3] [4] [5] indicated that interleukin-6 receptor antagonist tocilizumab successfully improved the clinical manifestations of sever patients infected by COVID-19. There were also several retrospective case-control and single-armed studies that reported the outcomes of using tocilizumab for treating COVID-19. However, the results of those studies have not been systemically reviewed and analyzed. Thus, we collected and summarized those studies to explore the effectiveness and safety of tocilizumab recently used for treating COVID-19.

A comprehensive search using (tocilizumab) OR (anti-IL-6 monoclonal antibody) OR (IL-6 blockade) OR (IL-6 receptor antagonist) AND (COVID-19) OR (novel coronavirus disease) OR (SARS-CoV-2) was conducted by 2 authors using PubMed, Embase, Medline, and Cochrane (up to September 27, 2020) , and the language was limited to English.

The studies searched in three databases were included by the following criteria: (1) patients had a definite diagnosis of COVID-19 infection; (2) patients received tocilizumab treatment; and (3) sufficient data were provided for clinical outcomes. Additionally, unqualified studies were excluded by the following criteria: (1) case reports, reviews, editorials, and letters; (2) duplicate records; and (3) studies with insufficient data.

Two authors extracted necessary information from each included study: first author, publication year, sample size, gender, clinical outcomes of TCZ group, ST group, and pre-TCZ and post-TCZ. The quality of each study was not assessed because of the extremely insufficiency of data of the included studies.

In the retrospective case-control studies, odds ratios (ORs) of admission to ICU, use of ventilation, mortality, and clinical improvement were calculated to compare the effectiveness between tocilizumab treatment and standard treatment.

In the retrospective single-armed studies, weighted mean differences (WMDs) of CRP, procalcitonin, WBC count, AST, troponin, Neut count, Lymp count, Plt count, ALT, and creatine were compared between pre-TCZ and post-TCZ to assess the safety of tocilizumab on the blood system, inflammatory reaction, heart, liver, and kidney.

Formula SD ≈ Norm IQR = (P 75-− P 25 ) × 0.7413 [6] was used to calculate the SD of the outcomes.

The heterogeneity of the results was estimated using the Q test and I 2 statistics. The fixed pooling model was used when I 2 ≤ 50%; otherwise, the random pooling model was selected.

WMD < 0 suggested a decrease in indicator after taking tocilizumab. OR < 1 indicated favorable outcomes of admission to ICU, use of ventilation, and mortality but poor clinical improvement in TCZ group. These calculations were completed using Stata v. 16 .

The procedures used to screen eligible studies are shown in Fig. 1 . Nineteen articles with 2493 patients were included. The details of the 19 included studies are summarized in Table 1 , and all the calculated outcomes are shown in Table 2 .

Thirteen studies and 2285 patients were included to compare the outcomes between TCZ and ST groups. The ORs for admission to ICU, use of ventilation, mortality, and clinical improvement between TCZ and ST were shown in Fig. 2 and Fig. 3 . Lower rate of admission to ICU, use of ventilation, and mortality and higher rate of clinical improvement were identified in the TCZ group.

After taking tocilizumab, the value of CRP significantly decreased (Fig. 4 ). In the blood system, the WBC count, Neut count, Lymp count, and Plt count were not obviously influenced by tocilizumab (Fig. 5 ). In addition, Fig. 6 showed that the value of AST significantly decreased and troponin increased after taking tocilizumab. However, the level of ALT and creatine were not significantly affected.

Sensitivity analysis of the OR for mortality between the TCZ and ST groups was calculated to evaluate the robustness of the results. Figure 7 indicates that the results would not be obviously changed by deleting any included study.

Pneumonia is the most common clinical manifestation of COVID-19 infection, and 6-10% of the patients can evolve into respiratory failure, requiring mechanical ventilation or positive airway pressure therapy [26] . Dawei Wang [27] reported that the acute respiratory distress syndrome (ARDS) caused by COVID-19 may have associations with cytokine storm syndrome. Fei Zhou [28] also reported that higher IL-6 was associated with more frequency mortality. Therefore, tocilizumab, as the IL-6 receptor antagonist, is used for treating COVID-19 in more and more therapeutic centers. Until now, studies Therefore, we reviewed and summarized these studies for more accurate conclusions. TCZ group have more favorable clinical outcomes compared with the ST group. Lower rate of admission to ICU, use of ventilation, and mortality and higher rate of clinical improvement were identified in this study, which is consistent with the conclusions from the case reports and case series [2] [3] [4] [5] . By binding to human IL-6 receptor, tocilizumab competitively inhibits IL-6 signaling [29] and prevents the cytokine storm of patients infected COVID-19. After taking tocilizumab, the serum CRP significantly decreased, which is consistent with the outcomes of treating rheumatoid arthritis, Castleman disease, and Crohn disease [29] .

In the blood system, tocilizumab does not have obvious influence on the neutrophil count, lymphocyte count, and platelet count. Despite a significant decrease of WBC was identified after taking tocilizumab, we cannot conclude that tocilizumab has effect on reducing WBC count because of the rarity of high WBC count in patients with COVID-19.

AST was apparently lower than before taking tocilizumab, and ALT was similar with before. A meta-analysis conducted by Mark C. Genovese indicated that transaminase elevations with tocilizumab were frequent [30] , which is not consistent with the result of our study. More studies are needed to investigate the effect of tocilizumab on hepatic function. In addition, tocilizumab did not have significant influence on patients' creatine according to the result obtained from this study. Cardiac injure is common (19.7%) among hospitalized patients with COVID-19 [31] , and cardiac troponin I levels were significantly higher in those with severe COVID-19 infection compared with those with non-severe disease [32] . In this meta-analysis, troponin significantly increased after taking tocilizumab. Whether tocilizumab or the progression of the Fig. 5 Forest plot of WMDs for WBC count, Neut count, Lymp count, and Plt count between pre-TCZ and post-TCZ. WBC, white blood cell; Neut, neutrophil; Lymp, lymphocyte; Plt, platelet; WMD, weighted mean differences; CI, confidence interval Fig. 6 Forest plot of WMDs for ALT, AST, troponin, and creatine between pre-TCZ and post-TCZ. ALT, alanine aminotransferase; AST, aspartate aminotransferase; WMD, weighted mean differences; CI, confidence interval disease caused the elevated troponin remains unclear. More RCTs focused on the comparison of troponin between taking tocilizumab group and no-taking group are needed to figure out whether tocilizumab has cardiac toxicity.

No adverse events after taking tocilizumab were reported in the included studies. But toxic erythema, eosinophilia, and hypertriglyceridemia [33, 34] were reported by two case reports after taking tocilizumab. What is more, intestinal perforation should be noticed when using tocilizumab to treat COVID-19 [35] .

First, the sample size of this study was extremely small, which results in the high heterogeneities of several observational indicators, low robustness of the results, and low reliability of the conclusion. Second, all the included studies were retrospective observational studies. In retrospective case-control study, it is impossible to match the baseline characteristics of TCZ and ST groups, which may result in severe selection bias. In retrospective singlearmed study, it is difficult to conclude that the improvement or deterioration of the laboratory indexes were caused by the effect of tocilizumab or the progression of the disease itself because of the absence of the control group. Third, in the situation of COVID-19 pandemic with no specific therapy drug available, studies with positive conclusions are more easily to be published, which may result in obvious publication bias. Although publication bias was not assessed because of the limited number of included studies, it does not mean there is no publication bias in this meta-analysis. Fourth, the data of each included study is insufficient.

Tocilizumab may have potential effectiveness to treat COVID-19 according to the results of this study. However, more large-scale studies are needed for more accurate conclusions because of the limited sample size of this study. 

China Medical Treatment Expert Group for Covid-19 (2020) Clinical characteristics of coronavirus disease 2019 in China

Rapid and severe Covid-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with tocilizumab

Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: a case report

Successful recovery from severe COVID-19 pneumonia after kidney transplantation: The interplay between immunosuppression and novel therapy including tocilizumab

Transpl Infect Dis:e13334

Dramatic improvement after tocilizumab of severe COVID-19 in a child with sickle cell disease and acute chest syndrome

Remote ischemic preconditioning reduces cardiac troponin I release in cardiac surgery: a meta-analysis

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia

Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian centre study on tocilizumab versus standard of care

Tocilizumab for treatment of severe COVID-19 patients: preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms

Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients

Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: a prospective cohort study

Observational study on off-label use of tocilizumab in patients with severe COVID-19

Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study

Humanitas and Gavazzeni / Castelli COVID-19 Task Forces. Interleukin-6 receptor blocking with intravenous tocilizumab in COVID-19 severe acute respiratory distress syndrome: a retrospective case-control survival analysis of 128 patients

Tocilizumab improves survival in patients with persistent hypoxia in severe COVID-19 pneumonia

Montichiari COVID-19 Study Group. Early use of low dose tocilizumab in patients with COVID-19: A retrospective cohort study with a complete follow-up

Effective treatment of severe COVID-19 patients with tocilizumab

Feasibility of Tocilizumab in ICU patients with COVID-19

Tocilizumab for the treatment of severe coronavirus disease

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center

Tocilizumab challenge: a series of cytokine storm therapy experiences in hospitalized COVID-19 pneumonia patients

Outcome of COVID-19 patients with use of tocilizumab: a single center experience

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease

Transaminase levels and hepatic events during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in rheumatoid arthritis

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan

Sanchis-Gomar F (2020) Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis

Toxic erythema' and eosinophilia associated with tocilizumab therapy in a COVID-19 patient

Acute hypertriglyceridemia in patients with COVID-19 receiving tocilizumab

Tocilizumab in COVID-19: beware the risk of intestinal perforation

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Acknowledgments The authors thank Dr. Zhong Yuan and Huang Haobin for the assistance with this study.Authors' contributions MZ and JYL collected and analyzed the data and wrote the paper; YHT and YWD collected and analyzed the data; JXZ and YHW revised the whole paper. All authors reviewed the final paper. All authors read and approved the final manuscript.Funding This work was financially supported by projects of the National Youth Foundation of China (NSFC, grant nos. 81700340).

Conflict of interest The authors declare that they have no conflict of interest.