A recent systematic review by Cortegiani et al.1 reviewed the evidence and appraised the quality of evidence concerning the use of tocilizumab in patients with coronavirus disease 2019 (COVID-19). Despite a thorough appraisal of a large number of clinical studies (n = 28) on tocilizumab in patients with COVID-19, Cortegiani et al.1 concluded that there is still insufficient evidence on its clinical efficacy in patients with COVID-19 because these studies are associated with a high risk of bias and poor quality. We would like to complement the discussion on the evidence of tocilizumab use in patients with COVID-19.

Interleukin (IL)-6 blocking agents such as tocilizumab have been touted as the potential treatment for COVID-19 since the recognition of the cytokine storm associated with a severe course of COVID-19, which involves increased levels of several cytokines where one of them is IL-6. However, a more pressing question is “Do increased concentrations of an IL-6 imply that its neutralisation will be effective in COVID-19?” While a recent observational study2, not included in the systematic review, demonstrated mortality benefits associated with the use of COVID-19, the two recent randomized controlled trials3,4 did not replicate the findings. The randomized, double-blinded, placebo-controlled COVACTA trial3 among hospitalized patients with COVID-19 reported no difference in 28-day mortality between the tocilizumab arm and placebo arm (19.7% and 19.4%, respectively). Furthermore, based on the results released on September 18, 2020, from the randomized, double-blind, placebo-controlled EMPACTA trial4, there was no statistical difference in 28-day mortality between patients who received tocilizumab and patients who received a placebo (10.4% and 8.6%, respectively).

The findings from randomized controlled trials have proved that the use of tocilizumab in COVID-19 did not live up to the hype, where the increased concentration of IL-6 does not imply that its neutralization will be effective in COVID-19. There is a possibility that the wrong cytokine was targeted to dampen the cytokine storm in COVID-19. A recent prospective study by Blot et al.5 compared the concentrations of IL-6 between 27 patients with COVID-19 pneumonia and 36 patients with non-COVID-19 pneumonia. It was reported that the plasma concentrations of IL-6 were significantly lower in the patients with COVID-19 pneumonia compared to the patients with pneumonia other than COVID-19 (121.0 pg/mL versus 460.4 pg/mL).

The findings of this prospective study, coupled with the findings from two randomized controlled trials that failed to detect mortality benefits with tocilizumab, suggest that IL-6 may not be the cytokine that drives the progression of COVID-19. The use of tocilizumab is not harmless since it may predispose patients to the development of secondary infections. We suggest a shift in focus and to target other mediators of hyperinflammatory state in patients with COVID-19.