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Letter to the Editor
DOI: 10.1016/j.pulmoe.2020.10.004
Open Access
Available online 4 November 2020
Interleukin-6 blockade with tocilizumab in COVID-19: Does it live up to its hype?
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C.S. Kowa,
Corresponding author
chiasiang_93@hotmail.com

Corresponding author.
, S.S. Hasanb,c
a School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
b Department of Pharmacy, University of Huddersfield, Huddersfield, United Kingdom
c School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan, Australia
Received 02 October 2020
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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.

Conflicts of interest

The authors have no conflicts of interest.

References
[1]
A. Cortegiani, M. Ippolito, M. Greco, V. Granone, A. Protti, C. Gregoretti, et al.
Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review.
[2]
N. Biran, A. Ip, J. Ahn, R.C. Go, S. Wang, S. Mathura, et al.
Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study.
Lancet Rheumatol, 2 (2020), pp. e603-12
[3]
I. Rosas, N. Bräu, M. Waters, R.C. Go, B.D. Hunter, S. Bhagani, et al.
Tocilizumab in hospitalized patients with COVID-19 pneumonia. Preprint.
medRxiv, (2020),
[4]
Roche. Roche’s phase III EMPACTA study showed Actemra/RoActemra reduced the likelihood of needing mechanical ventilation in hospitalised patients with COVID-19 associated pneumonia. [Accessed 24 September 2020]. https://www.roche.com/media/releases/med-cor-2020-09-18.htm.
[5]
M. Blot, A. Bourredjem, C. Binquet, L. Piroth, LYMPHONIE Study Group.
Is interleukin 6 the right target in COVID-19 severe pneumonia?.
Am J Respir Crit Care Med, (2020),
Copyright © 2020. Sociedade Portuguesa de Pneumologia
Pulmonology

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