To the Editor:
We compliment the retrospective study by Narain et al1 in CHEST (March 2021) that analyzed and compared the risk of death with different immunotherapies in patients with coronavirus disease 2019 (COVID-19). The findings of the study had some implications for the use of immunotherapy in this patient population. Specifically, the study found that the use of corticosteroids reduced the risk of death (hazard ratio [HR], 0.66; 95% CI, 0.57-0.76), but no survival advantage was observed with the use of tocilizumab, an IL-6 receptor monoclonal antibody (HR, 0.79; 95% CI, 0.47-1.32), both compared with standard of care in patients with COVID-19. The outcomes of the study replicated the findings in the clinical trials2 , 3 of corticosteroids and tocilizumab respectively which demonstrated opposing results for the two immunotherapies.
Perhaps the most surprising finding from the study was the reduced risk of death with the administration of both corticosteroids and tocilizumab.1 Such findings cannot be treated as if the beneficial effects are arising solely from the corticosteroids because the observed risk reduction was even greater than the risk reduction with corticosteroid alone (HR, 0.44; 95% CI, 0.35-0.55); it implied that there must be some forms of synergism that exist between corticosteroids and tocilizumab in patients with COVID-19. Similarly, this synergism had also been suggested in a randomized controlled trial3 of tocilizumab in patients with COVID-19, in which the primary analysis observed no difference on day 28 mortality rate with tocilizumab compared with usual care (HR, 0.92; 95% CI, 0.33-2.53), but the subgroup analysis revealed a reduced risk of death in patients who receive tocilizumab plus dexamethasone compared with those who receive usual care plus dexamethasone (HR, 0.13; 95% CI, 0.021-0.78).
Narain et al1 failed to highlight this finding that could have very significant clinical implications. The mechanism that underlies the synergism between corticosteroids and tocilizumab is unclear, but we postulate that reduced bioactivity to corticosteroids for some reason and in at least certain patients with COVID-19 could lead to failure of corticosteroids to retard the effects IL-6, because IL-6 has been shown to be inhibited by corticosteroids. This reduced bioactivity may or may not be related to polymorphisms in the IL-6 gene (IL-6 174GG genotype) that has been associated with resistance to corticosteroids.4 In addition, administration of corticosteroids had also been shown to contribute to an enhanced IL-6-induced proinflammatory acute-phase response.5 We believe that the routine combination of corticosteroids with tocilizumab is worthy of more evaluation of its clinical outcomes in patients with COVID-19.
Footnotes
FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.
References
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