Dear Editor


The narrative review reported by Plocque and colleagues [1] elegantly discussed if interleukin-6 (IL-6) receptor inhibitors should be used in the management of coronavirus disease 2019 (COVID-19). Undeniably, as discussed by the authors, the interruption of the IL-6 pathway by administering IL-6 receptor inhibitors, especially tocilizumab, could reduce the risk of mortality in patients with COVID-19 who are high-flow oxygen-dependent as well as patients with COVID-19 who have recently been admitted to the intensive care unit. In fact, the mortality reduction has previously been reported in the prospective meta-analysis [2] conducted by The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Nevertheless, despite their mortality benefits, the potential risks associated with IL-6 receptor inhibitors during the management of COVID-19 are still unclear. In their review, the authors have discussed the potential increased risk of nosocomial infections [1]. We intend to complement their discussion by raising another perspective that should be considered while using IL-6 receptor inhibitors in patients with COVID-19.

Three years into the COVID-19 pandemic, we are learning about various post-acute sequelae in patients who acquire COVID-19, with many investigations underway to discover the pathophysiology of long COVID. Interestingly, IL-6 has been associated with the development of long COVID, where the blood profiling of patients with long COVID revealed chronic elevation of the plasma level of IL-6 [3]. Indeed, a recent systematic review and meta-analysis [4] of 22 studies observed that increased IL-6 level correlates significantly with long COVID.

These observations should again raise attention concerning the appropriateness of using IL-6 receptor inhibitors in patients with COVID-19, given that these agents would raise the serum level of IL-6, which can predispose to the development of long COVID [5]. Our hypothesis is supported by a recent study [6] investigating the subsequent development of depression and anxiety, and quality of life in patients with moderate to severe COVID-19 treated with tocilizumab versus no tocilizumab. It was observed that patients in the tocilizumab group had significantly more depressive and anxiety symptoms, and a worse quality of life than the controls at a 3-month follow-up. The increased systemic IL-6 level from the administration of tocilizumab may be the culprit, as previous cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 reported that inflammatory mediators reach the CSF from the systemic circulation, instead of being produced per se within the central nervous system [7]. The excess unbound peripheral IL-6 due to the blockade of peripheral receptors by tocilizumab may be available to exert its action centrally.

While the evidence is very much preliminary, we believe it is imperative to investigate the long-term outcomes of patients with COVID-19 treated with tocilizumab and possibly other IL-6 receptor inhibitors. The monoclonal IL-6 antibodies, such as sirukumab and siltuximab, which target IL-6 itself rather than IL-6 receptors, could theoretically avoid the aforementioned risk of long COVID. Nonetheless, owing to relatively scarce evidence, it is still unclear whether monoclonal IL-6 antibodies reduce mortality in patients with COVID-19, similar to the IL-6 receptor inhibitors. Therefore, large-scale randomised trials should also be conducted to establish the role of monoclonal IL-6 antibodies in the treatment of COVID-19.