Reply to Yang et al.: Tocilizumab treatment in COVID-19 patients needs the assessment of the disease severity and timely intervention

We appreciate that Yang et al. (1) are concerned about the safety concerns regarding the use of tocilizumab and the combination usage with glucocorticoids in COVID-19 patients. We propose that tocilizumab can effectively treat severe COVID-19 patients (2); such effectiveness has also been confirmed by many other groups (3, 4).

Whether glucocorticoids usage is suitable for COVID-19 has been controversial for a long time. Some researchers do not recommend it to treat severe acute respiratory syndrome coronavirus 2-induced lung injury or shock (5). But a clinical trial from Oxford University reported that dexamethasone could reduce the 28-d mortality of COVID-19 patients with invasive mechanical ventilation or oxygen, but not of patients without respiratory support (6). This corticosteroid study further confirmed that blocking inflammatory cytokines storm is effective in COVID-19 if such treatments are given when the disease is dominated by immunopathology, with active virus replication playing a secondary role. Besides tocilizumab, all of the 21 patients in our study received glucocorticoid for a short period of time, range 3 d to 5 d, as appropriate, at a dose not exceeding the equivalent of 1 mg⋅kg⁻¹⋅d⁻¹ to 2 mg⋅kg⁻¹⋅d⁻¹ of methylprednisolone according to “Diagnosis and treatment protocol for novel coronavirus pneumonia (seventh interim edition)” (7). No adverse events were reported. In Luo et al.’s (8) study, three of eight patients who received tocilizumab combined with methylprednisolone died, and two experienced aggravation. It should be considered that four of these five poor-treatment results patients were critical patients. The analysis of the correlation of clinical outcomes is complex and diverse, especially in critical cases, such as age, comorbidities, vasoconstrictors, ventilators, etc. Therefore, it is too early to make any conclusion. Basically, glucocorticoids should be used strictly following the treatment protocol of China or the World Health Organization, and could be beneficial if you choose the right dose, at the right time, and in the right patients.

The critical consideration is that real-time assessment of disease severity and timely intervention are critical in tocilizumab treatment. In the two tocilizumab treatment articles that Yang et al. (1) mention (8, 9), most patients were already in the critical stage when they started to be treated with tocilizumab, and some of them already had organ failure. We recommend that timely use of tocilizumab in conditions when patients are moderate or progressing to severe cases would achieve better results. For critical patients with extensive and severe irreversible damage to the lungs and even other organ failure, tocilizumab intervention beginning at this stage can hardly reverse the situation. We suggest that IL-6 concentrations can be detected if fever persists for more than 3 d. Tocilizumab can be used if serum IL-6 content is five times beyond the normal level. In our PNAS research (2), we find that the IL-6 levels are temporarily increased after tocilizumab, because IL-6 receptors have been blocked by tocilizumab. Similar conditions can be observed in another multicenter study (3). Together, tocilizumab treatment is recommended to reduce the mortality of COVID-19. Both the Infectious Diseases Society of America and the American Thoracic Society suggest using tocilizumab in clinical trials is worthwhile (10, 11).