Efficacy and safety of IL-6 inhibitors in patients with COVID-19 pneumonia: a systematic review and meta-analysis of multicentre, randomized trials

Abstract

Purpose COVID-19 is characterized by dysregulated immune response, respiratory failure and a relevant mortality rate among hospitalized patients. Interleukin-6 (IL-6) is involved in COVID-19-associated cytokine storm, and several trials investigated whether its inhibition could improve patients’ outcome. We performed a meta-analysis of randomized trials (RCT) to test this hypothesis. Materials and methods Two independent investigators searched PubMed, Scopus, ClnicalTrials.gov and medRxiv up to September 1st, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab; COVID-19 adult patients with pneumonia; and being a RCT. Primary outcome was mortality at the longest follow-up. Secondary outcomes included intubation rate and incidence of adverse events. Two independent investigators extracted data from eligible trials. Results Of the 763 studies assessed, 15 RCTs were included (9,320 patients), all were multicentre, and the majority open-label vs standard treatment. IL-6 inhibitors were associated with reduced all-cause mortality at the longest follow-up (1315/5,380 [24.4%] in the IL-6 inhibitors group versus 1080/3,814 [28.3%] in the control group, RR = 0.90; 95% CI 0.84 to 0.96; p for effect = 0.003, I2 = 0%, with 13 studies included), with reduction in 28/30-day mortality and intubation rates, and with no increase in adverse events and secondary infections. Conclusion IL-6 inhibitors reduced longest follow-up mortality and intubation in COVID-19 patients. Findings need to be confirmed in high-quality RCTs.

The Association between TNF-α, IL-6, and Vitamin D Levels and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis

“…Additionally, IL-6 was also reported as an independent predictor of ICU admission [95]. The results of this meta-analysis were also in line with a previous meta-analysis of RCTs that presented a reduction in the incidence of intubation in COVID-19 patients receiving IL-6 inhibitors [96].…”

“…Another study recorded that the mean IL-6 levels were 2.9 times higher in complicated COVID-19 patients compared with uncomplicated COVID-19 patients [97]. A meta-analysis of RCTs reported a decreased incidence of death in COVID-19 patients receiving IL-6 inhibitors [96].…”

Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis

“…Studies suggest that tocilizumab improves treatment outcomes in enrolled patients about 10 days after symptoms onset and within 48 h from hospital admission, with a moderate to severe illness [ 16 , 17 , 19 ]. A recent meta-analysis also suggested that administration of tocilizumab within 10 days after symptom onset could reduce mortality and the need for intubation [ 33 ].…”

Clinical update on COVID-19 for the emergency and critical care clinician: Medical management

“…These are humanized monoclonal antibodies approved by the United States Food and Drug Administration (FDA) for use in rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome [ 9 , 10 , 45 , 46 ]. Multiple trials have evaluated IL-6 antagonists for treatment of COVID-19, finding an overall reduction in 28-day mortality [ [45] , [46] , [47] , [48] , [49] , [50] , [51] ]. The REMAP-CAP study evaluated tocilizumab or sarilumab versus standard of care within the first 24 h of ICU admission for COVID-19 patients requiring either respiratory support (invasive and non-invasive mechanical ventilation including HFNC >30 L/min and FiO2 > 0.4) or cardiovascular support (vasopressor or inotrope infusion) [ 51 ].…”

“…There are concerns of superinfection, hepatotoxicity, thrombocytopenia, and leukopenia with IL-6 antagonists, but current data suggest no significant difference in adverse events when compared with placebo or standard care [ 9 , 10 , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] ]. The WHO recommends patients with severe or critical COVID-19 infections should be given both steroids and IL-6 antagonists simultaneously [ 9 ].…”