key: cord-0798182-fouoqq9q
authors: Klopfenstein, Timothée; Gendrin, Vincent; Kadiane‐Oussou, N'dri Juliette; Conrozier, Thierry; Zayet, Souheil
title: Tocilizumab in COVID‐19 pneumonia: Practical proposals based on a narrative review of randomised trials
date: 2021-04-21
journal: Rev Med Virol
DOI: 10.1002/rmv.2239
sha: 84f635b9e70035dd1683b323b556219747acef51
doc_id: 798182
cord_uid: fouoqq9q

In this article, we express our opinion about tocilizumab as an effective treatment in coronavirus disease 2019, based on a narrative review and a deep analysis of tocilizumab randomised trial results. Eight trials were included. No one was in favour for controlled arm about main endpoint of death or mechanical ventilation incidence at day 28–30. Five trials on heterogenous populations seem to not demonstrate tocilizumab efficacy, but showed encouraging results in subgroup analysis on severe/critical patients (in favour for tocilizumab). Trials on severe/critical COVID‐19 pneumonia as REMAP‐CAP and RECOVERY showed mortality benefit of tocilizumab administration; CORIMUNO, REMAP‐CAP and RECOVERY showed that tocilizumab decreased the incidence of mechanical ventilation. No safety signal about tocilizumab used was noticed in all trials. We concluded that tocilizumab reduces mortality and mechanical ventilation requirement if administered with the right timing in COVID‐19 pneumonia. The challenge now is to define the optimal group and timing for tocilizumab benefit and we suggest that: (i) tocilizumab has a place in treatment of severe/critical COVID‐19 pneumonia, with a high level of O(2) flow or noninvasive ventilation or high flow nasal cannula; (ii) possibly early after intubation in patients on mechanical ventilation. Initiating tocilizumab in critically ill patients early before irreversible respiratory failure, especially in patients at an inflammatory stage could be the key to successful outcome.

Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world making more than one hundred million of infected people and at least 2.7 million deaths. 1 Until now, corticosteroids have been the only treatment proven to reduce mortality with strong evidence. 2 Death due to SARS-CoV-2 mainly results from acute respiratory distress syndrome (ARDS). 3 Markers of inflammation such as C-reactiveprotein (CRP), ferritin, and interleukin-6 are significantly associated with mortality. 4, 5 Coronavirus disease 2019 (COVID-19)-related multiple-organ failure and ARDS are mainly caused by cytokine storm. 6 Post-viral hyper-inflammation, which begins in the second week of the disease explains disease severity. 7 Cytokine storm reactions are mainly related to inflammatory cytokines, especially to interleukin-6 (IL-6), 8 which play a major role (with IL-1β and IL-8) in mediating acute lung injury 9 leading to ARDS. In our center we managed a cohort of 206 COVID-19 patients using tocilizumab (a recombinant humanized anti-interleukin-6 (IL-6) receptor 10 ) which we feel can be an effective treatment to reduce mortality and invasive mechanical ventilation requirement in COVID-19 11 ; a metaanalysis of cohort studies supported this impression suggesting an association between tocilizumab and lower mortality. 12 However, since July, the first results of randomised clinical trials (RCTs) [13] [14] [15] have not shown an impact on short term mortality. In November, Huang et al. 16 published a meta-analysis of five RCTs and concluded that tocilizumab does not provide mortality benefit for severe COVID-19 patients. In January 2021, we discussed the lack of positive results of these five RCTs which contrast with cohort studies; our main conclusion was that heterogenous population may explain this and tocilizumab should be effective in severe patients. 17 Three new RCTs have now been published or are at a pre-published state. [18] [19] [20] Veiga et al. 18 raised the question that tocilizumab may possibly increase the risk of death in opposition to REMAP-CAP and RECOVERY which showed mortality benefit of tocilizumab administration. We think that a deep and updated discussion is necessary.

Here we discuss the contradictory results of these eight RCTs [13] [14] [15] [18] [19] [20] [21] [22] especially about the impact of tocilizumab on mortality rate and mechanical ventilation incidence to try to assess if there is an optimal group and timing for tocilizumab administration.

The meta-analysis of Huang et al. 16 showed no effect on short-term mortality (during the first month) of tocilizumab administration in COVID-19 hospitalised patients; thus, the five other RCTs seem to have shown no effect in favour or disfavour of tocilizumab. [13] [14] [15] 21, 22 Moreover, Veiga et al. trial was stopped early in July 2020 after an increase in deaths 23 A few assumptions can be discussed to explain this contradiction on mortality effect in these in RCTs results.

Firstly, a lack of statistical power seems manifest in some RCTs. Secondly, we only have the results of short-term mortality, after a follow-up of one month after administration. We can expect that tocilizumab may decrease the risk of long-term complications and possibly death by reducing incidence or Intensive Care Unit (ICU) admissions. 12 For example, in COVACTA, 13 The heterogenous population included in RCTs probably explains the heterogeneity of the results on mortality. 17,24 A meta-analysis of retrospective cohort studies suggests a possible association between tocilizumab and lower mortality. 12 Our assumption to explain the disparity between RCTs and retrospective cohort studies is that retrospective cohort populations were more homogenous than RCTs population. In fact, tocilizumab was mainly used as an off label rescue treatment in critical COVID-19 patients in retrospective cohorts. For example in Italy, in Brescia, in a cohort of 100 patients, tocilizumab was often used in ICU beds and sometimes in the general ward as no ICU beds were available 28 ; or in France, in the Nord Franche-Comté Hospital, in our cohort of 206 patients, among the 30 patients in the tocilizumab group the mean oxygen therapy flow at tocilizumab onset was 10.5 L/min and most patients were not admitted in ICU in regard to their comorbidities and tocilizumab was used as a rescue treatment. 11 We do not think that methodological bias only, is enough to explain the gap that tocilizumab efficacy showed in retrospective cohort studies and the conclusions in the first RCTs, 12, 17, 24 the difference in populations may also explain this contrast and sub-group analyses in severe/critical COVID-19 patients are imperatives in RCTs.

A meta-analysis on the five RCTs conducted by Tleyjeh et al. 12 showed that tocilizumab decreased the incidence of mechanical ventilation in COVID-19 hospitalised patients (with a low risk of bias). Among these five RCTs the two RCTs 14,15 which did not show benefit of tocilizumab used on mechanical ventilation incidence in COVID-19 pneumonia had wide confidence intervals (about comparisons on mechanical ventilation incidence) and benefits cannot be ruled out. Furthermore, they focus on a selected population of moderate COVID-19 pneumonia. In Stone et al. 14 RCTs confirm retrospective cohorts and the fact that tocilizumab decreased the incidence of mechanical ventilation in COVID-19 hospitalised patients. 12 In countries facing a huge challenge in terms of ICU beds while dealing with this outbreak, tocilizumab may be helpful to manage the crisis in term of public health. For example, the UK government was the first government to make tocilizumab available to patients with severe COVID-19. 29 

Finding the optimal group of patients likely to have the greatest benefit is probably the main challenge. Primum non nocere! That way, tocilizumab administration to patients with a low level of oxygen requirement seems to be ineffective according to Stone et al. and Salvarini et al. conclusions. 14, 15 However, as we discussed above, the mortality rates in these two studies were <5% and any conclusions should be taken with caution. In Veiga et al. trials 18 

Salvarini et al. 15 Stone et al. 14 Salama et al. 22 Hermine et al. 21 Veiga et al. 18 Rosas et al. 13 Horby et al. 20 Gordon et al. 19 Study 

Salvarini et al. 15 Stone et al. 14 Salama et al. 22 Hermine et al. 21 Veiga et al. 18 Rosas et al. 13 Horby et al. 20 Gordon et al. 19 Essay of classification Note: Bold represents results with significant differences. There were no significant results in favour for control in any of these five categories.

Abbreviations: HFNC, high flow nasal cannula; ICU, Intensive Care Unit; IMV, invasive mechanical ventilation; NA, not applicable; NIV, non-invasive ventilation; RCT, randomised clinical trial; TCZ, tocilizumab. 1 All doses were tocilizumab intravenous infusion of 8 mg/kg (maximum 800 mg), except for the second dose of Hermine et al. which was a fixed dose of 400 mg. 2 The ordinal scale score range from 1 to 7 for each study but was defined differently. Less than nine patients without respiratory O 2 support at baseline. 5 Only one patient was with supplemental O 2 only or none respiratory support at baseline. 6 We noticed a result in favour of TCZ or in favour of control if they were at least one statistically significant result for the category concerned. The 'Hospitalization characteristics' category included clinical evolution on ordinal scale score, duration of hospitalisation and duration of ICU or IMV. 7 We used the RoB 2: the revised Cochrane risk-of-bias tool for randomised trials.

KLOPFENSTEIN ET AL. The optimal group of patients likely to have a benefit after tocilizumab administration seems to be severe and critical COVID-19 patients. 13 In this population finding the optimal timing for tocilizumab administration is crucial. Hermine et al. 21 To conclude, tocilizumab appears to reduce mortality and mechanical ventilation requirement in severe/critical COVID-19 pneumonia. Due to heterogenous populations in RCTs, secondary analyses of subgroups are needed and further subgroup analyses are likely to be helpful as more results are reported to define the optimal group and timing for tocilizumab benefit. Currently, we think that tocilizumab has a place in treatment of severe/critical COVID-19 pneumonia with a high level of O 2 flow (possibly as of >3 L/min or at least at a level of oxygen flow ≥6 L/min) or noninvasive ventilation or high flow nasal cannula and possibly early after intubation in patients on mechanical ventilation, especially in patients at an inflammatory stage.

Initiating tocilizumab in critically ill patients early before irreversible respiratory failure could be the key.

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Tocilizumab in COVID-19 pneumonia: Practical proposals based on a narrative review of randomised trials

The authors thank Mrs Charlotte Bourgoin and Elodie Bouvier for their strong implication in the present work. They also thank the management team of the Hospital Nord Franche-Comté and the

pharmacists team for having made available Tocilizumab outside its approved indication. Special acknowledgements to the whole HNFC tocilizumab multidisciplinary team and to all the physicians, caregivers (nurses and orderlies) and patients. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

All authors declare no competing interests.

Vincent Gendrin, N'dri Juliette Kadiane-Oussou and Thierry Conrozier revised the final manuscript.

Due to the retrospective nature of the study, the Ethics & Scientific Committee of Nord Franche Comté Hospital determined that patients consent was required only for the off-label use Tocilizumab. We make sure to keep patient data confidential and in compliance with the Declaration of Helsinki.

https://orcid.org/0000-0003-4334-9889