Severe COVID-19 and interleukin-6 receptor antagonist tocilizumab: Some notes of concern.

We read with great interest the article by McCarthy et al., regarding the favourable use of tocilizumab in a series of patients presenting with cytokine storm related to coronavirus disease 2019 (COVID‐19) infection. The promising role of tocilizumab has been highlighted in recent reports of critically ill patients with COVID‐19 pneumonia, showing encouraging results. However, data remain conflicting and anti‐inflammatory intervention does not go without critical thought or cost.

One has to bear into mind the increased risk of bacterial superinfections, following viral pneumonia in these patients. Reducing short‐term mortality from cytokine release syndrome may come at the expense of long‐term fatality rate, due to secondary healthcare or ventilator‐associated bacterial or fungal infections, especially in critically ill patients with increased length of hospitalization in intensive care units (ICU). In view of long‐term immunosuppression, need for prophylaxis against latent tuberculosis, herpes complex or hepatitis B virus re‐activation before administration is still open to discussion. Compromised mucosal integrity in these patients due to hypoperfusion could further promote bacterial translocation and lead to fatal sepsis or bowel perforation. In this context, perhaps early rather than late administration in COVID‐19 ward patients could be of certain value, before the need of intensive care and at the very beginning of inflammatory cascade, based on specific diagnostic criteria that need to be clearly established.

The best dosing scheme is still to be defined. Although one can argue that a single dose of tocilizumab has negligible long‐term impact on immune responses, the exact number of doses and determination of specific criteria for need of more than one dose remains to be clarified. Current protocols recommend administration of 5–8 mg/kg followed by an extra dose 12–24 h later depending on clinical response. What the adequate clinical response would be, given the cost and risk of adverse events of such regimen needs to be strictly defined. These would be clinical, laboratory or imaging? And if so, at what time following initial administration would re‐assessment be wise to be performed? Experience with rheumatoid arthritis patients dictates at least 2 weeks of watchful wait regarding clinical response, while even in the series of COVID‐19 critically ill patients that tocilizumab was eventually used, no data on interleukin (IL)‐6 levels have in the end been recorded.

Lastly, pharmacoeconomically speaking, increased cost cannot be ignored. In the absence of another efficient therapeutic or preventive regimen, use seems justifiable. However, in view of a second epidemic wave and a healthcare system facing mass number of cases, stringent budgets and allocation of financial resources to alternative equally necessary measures (e.g. ventilator machines) and long‐term administration of such regimen to a vast amount of patients will not be viable.

All that said, we believe that at this point of the pandemic use of tocilizumab is promising and in certain cases necessary to increase chances of better outcomes, in failure or absence of other means. However, further larger clinical trials are needed to justify and clearly define its use, as wide administration will not be sustainable.