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Efficacy and Safety of IL-6 Inhibitors in Patients with COVID-19 Pneumonia: A Systematic Review and Meta-Analysis of Multicentre, Randomised Trials

Introduction: The novel coronavirus disease 2019 (COVID-19) is frequently characterized by dysregulated host immune response with hyperinflammation and self-induced host inflammatory damage that results in severe respiratory failure and frequently death. Interleukin-6 (IL-6) appeared among the key cytokines involved in COVID-19 associated cytokine storm. Therefore, several trials investigated whether IL-6 inhibition with tocilizumab or sarilumab could improve symptoms and outcome of COVID-19 patients. We performed a meta-analysis of randomized trials to test this hypothesis. 
 
Methods: PubMed, Scopus, Cochrane central register and medRxiv were searched by two independent investigators up to February 23rd, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab, COVID-19 pneumonia, randomized controlled trials. Studies in setting other than adult human COVID-19 were excluded. The primary outcome was mortality at the longest follow-up available. Secondary outcomes included need for intubation and incidence of adverse events. Two independent investigators examined and extracted data from eligible trials. 
 
Results: A total of 371 studies were assessed, with a total of 10 studies (6,465 patients) finally included in the meta-analysis. All the trials were multicentre and the majority were open-label vs standard treatment. IL-6 inhibitors use was associated with reduced all-cause mortality at the longest follow-up available (823/3,310 [24·9%] in the IL-6 inhibitors group versus 902/3,038 [29·7%] in the control group, RR = 0·89; 95% CI 0·82 to 0·96; p for effect = 0·003, I2 = 6%, with eight studies included). Use of IL-6 inhibitors was associated with a significant reduction in need for intubation, while we found no difference in rate of adverse events and secondary infections. 
 
Conclusion: Administration of IL-6 inhibitors may reduce all-cause longest follow-up mortality and need for intubation in COVID-19 patients, without increasing risk of adverse events. However, these findings need to be confirmed in high-quality randomized controlled trials. 
 
Funding Statement: None. 
 
Declaration of Interests: None.