key: cord-0817727-fakwtvbp
authors: Christou, Miss Sabina; Mohamed, Miss Siham; Tsigarides, Jordan
title: Tocilizumab – A beacon of hope in the management of severe COVID‐19?
date: 2020-08-28
journal: J Med Virol
DOI: 10.1002/jmv.26466
sha: d3f7d4198cc2f08bc91c7e7cf41cc3fe54211522
doc_id: 817727
cord_uid: fakwtvbp

We read with interest the article entitled “Early use of tocilizumab in the prevention of adult respiratory failure in SARS‐CoV‐2 infections and the utilization of interleukin‐6 levels in the management” by Antony et al.(1) This article is protected by copyright. All rights reserved.

We read with interest the article entitled "Early use of tocilizumab in the prevention of adult respiratory failure in SARS-CoV-2 infections and the utilization of interleukin-6 levels in the management" by Antony et al. 1 A major pathological hallmark underlying Coronavirus disease 2019 (COVID-19) is the activation of a cytokine release syndrome (CRS). 2 As Interleukin-6 (IL-6) seems to be the main chemokine driving the CRS in COVID-19, investigating the role of tocilizumab (TCZ), an IL-6 receptor antagonist, has attracted much attention. The authors have suggested that early use of TCZ may reduce the requirement for mechanical ventilation (MV) and the associated increased morbidity and mortality. However, we feel it is important to highlight the study's deficiencies that influence the interpretation of the results.

A total of 80 out of 112 COVID-19 patients were included, which constitutes a relatively small sample size and limits study power. Although partially explained by the short timeframe of the study, the lack of a reported power calculation hampers determination of the significance of the results. A combined primary endpoint could have also been used to minimize the impact of the limited sample size. The sample selection process was also poorly described with very little mention of recruitment procedures.

The authors explain that the purpose of the 72-hour methylprednisolone therapy was to prolong the suppression of CRS in combination with TCZ. Recent data on corticosteroid efficacy in COVID-19 is encouraging, however, there was no explanation of the steroid choice or treatment duration. Moreover, even though the authors acknowledged the potential cointervention bias with the addition of methylprednisolone, the title of the study does not acknowledge this, potentially misleading readers. Although described as a limitation by the authors, the lack of a 'standard care' control group further limits interpretation of the relevance of TCZ's perceived efficacy.

Descriptions of TCZ dosage lacked overall clarity. The authors mention the use of an "optional" second dose 12 hours after the first, which did not exceed 800 mg. However, this was seemingly not considered when analysing the results, with no indication of how many patients received a second dose. Additional doses of TCZ may have influenced patient outcomes and is therefore an important confounder not acknowledged. This was similarly seen in a study by Klopfenstein et al, which stated that participants received "one or two doses" of TCZ but did not specify which did better. 3 IL-6 levels were measured with the authors claiming that IL-6 may be a good prognostic indicator for the management of the CRS. However, they also showed a statistically significant increase in IL-6 levels post-TCZ, when comparing day 0 to day 6. They suggested that this could be explained by the "ongoing cytokine storm" but this was not discussed further. Moreover, the stated limitation of lack of long-term follow up does not allow readers to determine the long-term effects of TCZ on IL-6 in COVID-19. Table 2 on the characteristics of patients included in the study is unclear and inconsistent. For example, the authors state that there were 80 SARS-CoV-2-positive patients (n=80) included in the study, although when stating the gender, data show only 79 patients (45 males, 56.96%; 34 females, 43.04%). This inconsistency is replicated when giving data on other patient characteristics. The authors mention that data was taken from electronic health records and perhaps there was incomplete data. This could have been discussed, to avoid confusion. Despite recent literature on TCZ as a treatment option in COVID-19 being encouraging, there is still limited data on efficacy. A recent Lancet study by Kewan et al demonstrated that TCZ resulted in shorter median time (8 vs 13 days) to clinical improvement and shorter duration of invasive MV (7 vs 10 days) in TCZ versus no TCZ cohorts, respectively. 4 Furthermore, RECOVERY, the largest trial to-date evaluating the efficacy of interventions for COVID-19 involves a second randomisation for patients who deteriorate to either TCZ or control. The recent inclusion of TCZ is based on evidence suggesting its potential role in the management of severe COVID-19. 5 Given the theorised role of IL-6 in COVID-19, future studies investigating other IL-6 antagonists such as Sarilumab would be welcome, given its higher affinity for the IL-6 receptor compared with TCZ. 6 Overall, TCZ is a promising therapeutic candidate for severe COVID-19. However, there is currently insufficient evidence supporting its routine use with a desperate need for larger, high-quality studies before firm conclusions are made about clinical safety and efficacy.

Early use of tocilizumab in the prevention of adult respiratory failure in SARS-CoV-2 infections and the utilization of interleukin-6 levels in the management

Elevated interleukin-6 and severe COVID-19: A meta-analysis

Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients

Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study

Profile of sarilumab and its potential in the treatment of rheumatoid arthritis

The authors declare that they have no financial or non-financial conflicts of interest.