Tocilizumab in COVID-19 therapy: who benefits, and how?

Abstract

The RECOVERY Collaborative Group reported statistically significant improvement in survival of patients with COVID-19 who were receiving tocilizumab interleukin (IL)-6 inhibitor, albeit with very modest reduction of mortality (31% vs 35% with usual care, p=0·0028).1RECOVERY Collaborative GroupTocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645Summary Full Text Full Text PDF PubMed Scopus (801) Google Scholar This result adds to a number of studies with tocilizumab and other IL-6 antagonists, such as sarilumab, which showed only minor, or no, reduction in mortality.2Lescure FX Honda H Fowler RA et al.Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 522-532Summary Full Text Full Text PDF PubMed Scopus (131) Google Scholar Given that IL-6 is associated with COVID-19 severity and mortality,3Del Valle DM Kim-Schulze S Huang HH et al.An inflammatory cytokine signature predicts COVID-19 severity and survival.Nat Med. 2020; 26: 1636-1643Crossref PubMed Scopus (1056) Google Scholar the question arises as to why IL-6 antagonist therapy does not substantially improve survival. In April, 2021, we showed that IL-6 serum concentrations are indeed associated with COVID-19 severity (appendix); however, a better classification of severity is obtained when IL-6 is combined with other cytokine concentrations.4Dorgham K Quentric P Goekkaya M et al.Distinct cytokine profiles associated with COVID-19 severity and mortality.J Allergy Clin Immunol. 2021; 147: 2098-2107Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar Moreover, within each respiratory severity group, IL-6 is not significantly associated with mortality (appendix). It is rather distinct combinations of interferon α, inteferon β, IL-10, and tumour necrosis factor α that are better predictors of mortality in different severity groups.4Dorgham K Quentric P Goekkaya M et al.Distinct cytokine profiles associated with COVID-19 severity and mortality.J Allergy Clin Immunol. 2021; 147: 2098-2107Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar Nevertheless, mortality in the low IL-6 group of patients is significantly lower than in the high IL-6 group of patients (appendix), suggesting that IL-6 inhibitors should be given only to patients with high IL-6. Indeed, a retrospective analysis of tocilizumab therapy as a function of baseline IL-6 concentrations showed a large reduction in mortality (from 36% to 16%) in patients with high-baseline IL-6, but no reduction in mortality in low-baseline IL-6 patients.5Galvan-Roman JM Rodriguez-Garcia SC Roy-Vallejo E et al.IL-6 serum levels predict severity and response to tocilizumab in COVID-19: an observational study.J Allergy Clin Immunol. 2020; 147: 72-80Summary Full Text Full Text PDF PubMed Scopus (95) Google Scholar In conclusion, clinical trials of IL-6 antagonist therapy, such as RECOVERY1RECOVERY Collaborative GroupTocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645Summary Full Text Full Text PDF PubMed Scopus (801) Google Scholar and sarilumab COVID-19 global studies,2Lescure FX Honda H Fowler RA et al.Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 522-532Summary Full Text Full Text PDF PubMed Scopus (131) Google Scholar should consider reanalysis of their results as a function of IL-6 baseline concentrations. More generally, clinical trials of personalised precision medicine, based on cytokine profiling, are needed for optimisation of COVID-19 therapy. We declare no competing interests. Download .pdf (.15 MB) Help with pdf files Supplementary appendix Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trialIn hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Full-Text PDF Open AccessTocilizumab in COVID-19 therapy: who benefits, and how?The randomised controlled RECOVERY trial1 has met its primary endpoint of reduced 28-day mortality. We congratulate the RECOVERY Collaborative Group for this excellent study. However, the mortality at day 28 was up to 31% in the tocilizumab group and was higher than the results of other published randomised controlled trials.2 The pathophysiology underlying COVID-19 is characterised by SARS-CoV-2 viral infection-induced inflammatory response, cell death, and microvascular thrombosis. Thrombosis appears to be common in patients with COVID-19 pneumonia and could also be responsible for multiorgan failure in patients who are critically ill. Full-Text PDF Tocilizumab in COVID-19 therapy: who benefits, and how? – Authors' replyWe thank Chengliang Yang and Hedi Zhao for their interest in the thrombotic event rate in the RECOVERY trial of tocilizumab in patients hospitalised with COVID-19.1 Data on thrombotic events were only collected on follow-up forms from Nov 1, 2020, so these data are only available for about 60% of participants. Nevertheless, we observed no difference in the thrombotic event rate between patients allocated to tocilizumab or usual care alone (appendix). Full-Text PDF