Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study

Abstract

Background We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. Methods We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. Results During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8–14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355–0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619–0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352–0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449–0.804), p < 0.001] (interaction p = 0.094). Conclusions These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. Trial registration European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 Electronic supplementary material The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users.

Neutralizing Autoantibodies to Type I IFNs in >10% of Patients with Severe COVID-19 Pneumonia Hospitalized in Madrid, Spain

“…Furthermore, when analyzing the treatments received by the patients, we did not find a significant association between the presence of neutralizing autoantibodies and the administration of corticosteroids (p = 0.14), bolus of corticosteroids (p = 0.61), tocilizumab against the IL-6 receptor (p = 0.32), or even response to IFN-beta-1b therapy (p = 0.34). These factors have been repeatedly related to the severity and high rates of mortality [16][17][18].…”

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically Ill COVID-19 Patients

“…A large analysis coming from 18 study sites from Spain included patients with severe COVID-19 of which 268 were treated with tocilizumab and 238 were comparators. Mortality was 16.8% and 31.5%; this difference remained even with corticosteroid treatment (19). Three randomized clinical trials are available for hospitalized patients with severe illness.…”

“…The copyright holder for this preprint this version posted January 26, 2021. ; https://doi.org/10.1101/2021.01.20.21250182 doi: medRxiv preprint novel SARS-Cov-2 virus through A PErsonalized immunotherapy approach) was an exploratory phase II trial where patients with critical COVID- 19 were allocated to open-label treatment with anakinra or tocilizumab if they were presenting with MAS or CID, respectively. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

A Response to: Letter to the Editor Regarding Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort

“…We appreciate the interest in our manuscript [1], and thank Dr. Janapala et al [2] for the letter, and the Editor for giving us the opportunity to respond.…”