key: cord-0865720-2wpg8gqi
authors: Man Niu, Man; Cao, Yue; Li, Rui Xue; Fan, Guo Zhen; Hu, Peng
title: Outcome heterogeneity in COVID-19 patients receiving tocilizumab
date: 2021-09-17
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab816
sha: 26f37b2749747450a41aa9101d6088d8198120ca
doc_id: 865720
cord_uid: 2wpg8gqi

nan

A c c e p t e d M a n u s c r i p t

In a recent meta-analysis published in Clinical Infectious Diseases, Malgie et al. [1] analyzed 10 observational studies encompassing 1358 coronavirus disease-2019 (COVID-19) patients and revealed that a 12% lower mortality rate was observed among patients receiving tocilizumab treatment compared with untreated controls, and the number needed to treat to save a life may be as low as 11. Paradoxically, Tleyjeh et al. [2] conducted a meta-analysis of 24 COVID-19 studies and found that tocilizumab reduced the risk of mechanical ventilation in hospitalized patients with COVID-19, with no definitive evidence of a reduction in short-term mortality or an increased risk of infection. An editorial comment by Moehring et al. [3] showed that illness severity and immunotherapy programmes accounted for the outcome heterogeneity after tocilizumab treatment. In addition, the other 2 items should also be considered.

Interleukin (IL)-6 stimulates desirable antibody production by immune cells that express membranous IL-6 receptors, but also initiates series of undesirable proinflammatory processes by cells that lack IL-6 receptors. IL-6 transsignaling to cells that lack IL-6 receptors requires dimerization of shed soluble IL-6 receptors with another membrane protein, glycoprotein 130 encoded by IL6ST [4] . Two variants of IL6ST, p.Ile454Thr (rs2228046) and p.Gly148Arg (rs2228044), have been documented as the possible explanations for the variable efficacy of tocilizumab. According to data from UK Biobank, the sorting intolerant from tolerant scores of p.Ile454Thr (rs2228046) and p.Gly148Arg (rs2228044) are 0.004 and 0.01 respectively, and associated with deleterious outcomes of COVID-19. The higher frequencies of risk alleles in both loci may contribute to a higher mortality from COVID-19 in African (rs2228046: 42%, rs2228044: 60%), compared with European (rs2228046: 0.08%, rs2228044: 11%) [5] .

After undergoing almost 2-year prevalence worldwide, multiple SARS-CoV-2 variants have been characterized. B.1.617.2, also named as Delta variant, is a representative of the highly pathogenic SARS-CoV-2 variants and mainly A c c e p t e d M a n u s c r i p t causes the second wave of extensive COVID-19 [6] . Wall et al. [7] carried out an initial analysis of the Legacy study to track serological responses to vaccination and identified a reduction of 5.8-fold in neutralising activity against B.1.617.2 relative to wild-type. In addition, a retrospective study from Singapore also indicated that patients infected with B.1.617.2 were more susceptible to hypoxia, intensive care unit admission, or even death than those who had wild-type SARS-CoV-2 infection (adjusted odds ratio for composite outcomes: 4.9) [8] . Despite limited direct evidence on the efficacy of tocilizumab among COVID-19 patients with diverse variants, the current knowledge of virology demonstrates that the therapeutic response to tocilizumab may be distinctive in patients infected with B.1.617.2.

In summary, a significant heterogeneity for the composite outcomes exists in available studies on COVID-19 patients receiving tocilizumab treatment, which is mainly associated with 4 influential factors including but not limited to, illness severity, immunotherapy programmes, IL6ST polymorphism and SARS-CoV-2 variants.

Decreased mortality in coronavirus disease 2019 patients treated with tocilizumab: a rapid systematic review and meta-analysis of observational studies

Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review an meta-analysis

Compiling observational research during a pandemic: a necessary bridge

Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor trans-signaling responses

Interleukin-6 receptor antagonists in critically ill patients with COVID-19

Neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants induced by natural infection or vaccination: a systematic review and pooled analysis

Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination

Clinical and virological features of SARS-CoV-2 variants of concern: a retrospective cohort study comparing B.1.1.7 (Alpha), B.1.315 (Beta), and B.1.617.2 (Delta)

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