Reply.

We thank Dr Akinosoglou and Dr Gogos for their valuable comments regarding our recent report on real‐world experience in the use of tocilizumab for treatment of coronavirus disease 2019 (COVID‐19) with hyperinflammatory state. As they state, data on the potential benefit of treatment with interleukin‐6 receptor antagonists (IL‐6RA) in COVID‐19 remains inconsistent and they highlight potential concerns for adverse outcomes arising from blockade of IL‐6 receptor in those who are critically ill. However, observational studies demonstrate favourable outcomes regarding mortality and risk of proceeding to endotracheal intubation when IL‐6RA are used in a pre‐critical (pre‐intensive care unit (ICU)) setting, such as that described in our report, before the onset of severe respiratory failure. Apart from optimal timing of drug administration, there also remains uncertainty regarding the optimal dosing of tocilizumab in this clinical setting. It has been suggested that some individuals might need higher or repeated doses of tocilizumab, due to persistently high levels of IL‐6 post‐treatment, which have been associated with worse clinical outcomes in some reports.

While the potential risk of bacterial infections represents a concern, a recently published rapid review and meta‐analysis including 28 studies showed that bacterial co‐infections and superinfections were reported in only 3.5% and 15.5% of patients with COVID‐19, respectively. However, more than 70% of patients were treated with antibiotics, mostly empirically, which raises the concern that patients with COVID‐19 might receive unnecessary antibiotic treatment. On the other hand, the risk of bacterial infection may be higher in the ICU setting, where more frequent use of vascular and other indwelling devices represent a risk for bloodstream infections (BSI), which are also often reported in patients with COVID‐19. Moreover, the use of anti‐inflammatory agents in the ICU setting, including tocilizumab, was associated with a higher risk of developing BSI, especially when used in combination with methylprednisolone. Considering the lack of convincing evidence on the clinical improvement of critically ill patients treated with IL‐6RA, the risks might outweigh the benefits in the critical setting.

Hence, optimal dosing and timing of such agents is essential and likely the administration in the pre‐ICU setting, prior to the establishment of end organ damage or acute respiratory distress syndrome (ARDS), may be of most benefit. To address these questions, our group has designed a phase 2, open‐label, two‐stage, multi‐centre, randomized trial comparing different doses of single‐dose administration of tocilizumab in adults with severe, non‐critical, COVID‐19 with evidence of hyperinflammatory state. This study is limited to patients in a pre‐ICU setting, with specific exclusion criteria (such as history of immunosuppression, active malignancies, diverticulitis or intestinal perforation). In the first stage, standard of care (SOC) will be compared to SOC plus a single infusion of tocilizumab (8 mg/kg). (Fig. 1). On the basis of the findings from stage 1, the study will progress to stage 2, where patients will be randomized to a single dose of either standard dose (8 mg/kg) or a lower dose (4 mg/kg) of tocilizumab plus SOC. This and other ongoing trials on the use of IL‐6RA in patients with COVID‐19 will hopefully produce the much needed, high‐quality evidence on the efficacy and safety of treatment with immune modulatory agents in patients with severe COVID‐19.

Figure 1

Clinical trial plan. Brief description of patient population (top left). Description of the two stages of the clinical trial (stage 1 and stage 2), with definition of the two study arms for each stage.