Beneficial and harmful outcomes of tocilizumab in severe COVID‐19: A systematic review and meta‐analysis

Abstract

Introduction:The results of studies of tocilizumab (TCZ) in COVID-19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID-19. Methods:We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms ("COVID-19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]).Results: Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID-19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random-effects model, the hospital-wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID-19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56-0.93). The pooled hospital-wide mortality OR was 1.25 (95% CI = 0.74-2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59-0.76) in patients admitted to the ICU. The pooled OR of hospitalwide mortality (including ICU) of COVID-19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54-0.84). The pooled in-hospital mortality OR was 0.71 (95% CI = 0.35-1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48-1.45) for late administration (>10 days from symptom onset). The meta-analysis did not find significantly higher risk for secondary infections in COVID-19 patients treated with TCZ.Conclusions: TCZ prevented mortality in patients hospitalized for COVID-19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset.

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

“…We show here that blocking IL-6 signalling in pulmonary microvascular endothelial cells with Tocilizumab led to reduced LRG1 levels thus attenuating the production of a significant angiopathic factor. Studies and meta-analyses on the use of Tocilizumab in the clinics to treat severe and critically ill COVID-19 patients have reported beneficial outcomes, although critics had initially questioned the efficiency of identifying the right COVID-19 positive populations to treat with Tocilizumab 76 , 77 . If LRG1 is angiopathic in COVID-19 patients, then inhibition of IL-6 may not be sufficient to stop LRG1 as IL-1β and TNFα, both prevalent in COVID-19 infected lungs 50 , are also capable of LRG1 induction 4 .…”

Mouse models of COVID-19 recapitulate inflammatory pathways rather than gene expression

“…To dissect this apparent incongruity, the IL-6 receptor signaling network (IL-6R network) was examined in detail. The IL-6 was consistently identified as a USR with positive z-scores (Figure 4A,B), with excessive IL-6 levels also associated with COVID-19 ARDS (49). An IL-6R network, comprising 546 genes, was generated in IPA (Supplemental Table 7A).…”

“…A series of human clinical trials have shown the benefit of anti-inflammatory treatments for COVID-19 ARDS such as corticosteroids (e.g. dexamethasone) (48) and anti-IL-6-receptor (tocilizumab) (49). When IPA Chemical Drug USRs were compared, a highly significant correlation emerged, with dexamethasone appearing with the expected negative z-score in both mice and human data sets (Figure 4C, Chemical drug).…”

Clusters of inflammation in COVID-19: descriptive analysis and prognosis on more than 15,000 patients from the Spanish SEMI-COVID-19 Registry

“…Of all the treatments tested in COVID-19, it is the immunosuppressants/immunomodulators (corticosteroids and tocilizumab) that have demonstrated the greatest effectiveness to date [16][17][18][19][20][21][22][23][24][25]. They are especially indicated in those patients with analytical parameters of inflammation such as the patients included in the present study.…”