Reply

From the Authors: We appreciate the important questions raised by Dr Niu and colleagues regarding the role of IL-6 antagonists in paediatric patients with COVID-19 pneumonia and multisystem inflammatory syndrome in children (MIS-C). Until 30 November 2021, in a total of 6,325,000 COVID-19 cases in patients under 18 years in the United States, 5973 cases resulting in 52 deaths fulfilled the MIS-C criteria. Paediatric patients with COVID-19 pneumonia have markedly elevated serum IL-6 levels compared to healthy controls (32 [13– 146] vs. 8 [2–14.7] pg/ml; p = 0.004), while plasma IL-6 is elevated in critically ill MIS-C patients, however, at levels lower than those of sepsis (156 [36–579] vs. 1432 [122– 6886] ng/dl; p < 0.001). The utility of IL-6 levels in MIS-C is still ambiguous, probably due to the heterogeneity of the disease and our poor understanding of the involved molecular pathophysiological pathways. Elevated serum IL-6 levels make anti-IL-6 treatments potential candidates for the cytokine storm in severely or critically ill patients with COVID-19. The fact that tocilizumab has been approved for use in active systemic juvenile idiopathic arthritis and chimeric antigen receptor T-cell-induced severe or life-threatening cytokine release syndrome in adults and paediatric patients of 2 years of age and older provides some reassurance regarding the safety for the use of tocilizumab in patients with severe COVID-19. However, it is of utmost importance to differentiate between critically ill COVID-19 and septic paediatric patients as the drug could be proven harmful to the latter. Moreover, the possible deterioration of coronary artery aneurysms is a significant concern in children with Kawasaki disease associated with SARS-CoV-2 infection treated with tocilizumab. In a meta-analysis of 97 studies/case series with 8243 paediatric patients, Panda et al. reported the use of tocilizumab in 1.5% of the patients with severe COVID-19, while it was administered in 27% of children with MIS-C. In the recent update of its guidelines, the American College of Rheumatology recommended the use of tocilizumab in combination with glucocorticoids in children with COVID19 requiring supplemental oxygen or respiratory support, acknowledging a potential higher risk for bacterial and fungal infections. Similarly, the Australian National COVID-19 Clinical Evidence Taskforce has recently formulated a conditional recommendation supporting the use of tocilizumab in children and adolescents requiring supplemental oxygen, especially when features of hyperinflammation are evident, and in children with MIS-C who do not respond to intravenous immunoglobulin and/or corticosteroids. Larger prospective randomized controlled trials are needed to assess the efficacy and safety of tocilizumab in children and adolescents with COVID-19. Until these results are available, the use of tocilizumab may be considered in carefully selected cases of severe or critically ill COVID-19 paediatric patients, particularly in the presence of MIS-C; however, with the caution that before its administration, physicians should make every effort to exclude the existence or coexistence of infection and sepsis.