Discussion
To the best of our knowledge, this study is the first meta-analysis
built only on the most recent cohort studies to investigate the safety
and efficacy of tocilizumab in severe COVID-19. The study searched for
the best available evidence evaluating the role of tocilizumab in
patients with severe COVID-19 and provided moderate to high quality
retrospective cohort studies including 1473 patients in 6 studies.
Tocilizumab succeeded in reducing the mortality rate significantly at
all-time points; 7, 14, 21, 28 days pooled from all the included
studies. Moreover, heterogeneity among the study findings was not
significant ensuring that the study findings are consistent. The
preventive effect tocilizumab from all-cause mortality was confounded by
unequal distribution of some baseline factors, therefore sensitivity
analysis was performed after removing the most confounded studies.
Repeating the analysis after exclusion of the only two studies with
serious risk of confounding bias ensured that the conclusion is robust
through finding a little or not at all change in the results after
exclusion of the two studies.
Tocilizumab was not superior to the control group regarding improvement
in the respiratory supportive level and clinical improvement. This may
be due to the low number of patients and studies included in the
analysis to estimate pooled RR of either clinical improvement or
improvement in the respiratory support level.
In contrast to our results, a recently published meta-analysis that was
conducted by Lan et al., (Lan et al., 2020) failed to show
significant reduction in all-cause mortality associated with
tocilizumab. These results could be explained by the difference in the
included studies, where they pooled case-control studies and pre-print
studies. Furthermore, the safety of tocilizumab was not investigated.
Regarding the safety of the tocilizumab, the present meta-analysis
reported that the incidence of neutropenia and new infections were the
only statistically significant parameters in the tocilizumab group. The
overall safety outcome favored the control group, although it did not
affect the mortality rate because the majority of the reported cases
were mild.
Many side effects of tocilizumab have been reported since it has been
approved for us in different indications. It includes neutropenia,
thrombocytopenia, increased liver enzymes, hypersensitivity,
hyperlipidemia, infection, and injection site reactions..etc (Bannwarth
& Richez, 2011).
A recent phase 3 clinical trial conducted by Roche was published in
August 2020 and provided disappointing results regarding the efficacy of
the tocilizumab in the treatment of severe COVID-19 patients (Roche,
2020). This comes congruent with the results provided by our systematic
review and metanalysis.
We recommend further randomized clinical trials including larger sample
size to be conducted in different stages of the disease, and further
studies to clearly identify the exact pathogenesis behind the COVID-19
cytokine storm.
The current evidence of using tocilizumab in severe COVID-19 was based
on having a hyper inflammatory conditions (Campochiaro et al., 2020; Ip
et al., 2020; Kewan et al., 2020) rather than using H-score to predict
cytokines storm which is not validated in COVID-19 patients (Leverenz &
Tarrant, 2020). Actually, it was validated to predict hemophagocytic
lymphohistiocytosis (HLH) in rheumatic patients (Fardet et al., 2014).
Patients’ stratification and well-defined criteria for hyper
inflammation-related COVID-19 should be addressed in the future studies
to maximize the tocilizumab benefits.