Infect Dis Ther (2021) 10:1811–1813 https://doi.org/10.1007/s40121-021-00444-4 LETTER 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 Belén Ruiz-Antorán . Aránzazu Sancho-López . Ferrán Torres . Ana Fernández-Cruz on behalf of the TOCICOV study group Received: March 25, 2021 / Accepted: March 26, 2021 / Published online: April 29, 2021 Ó The Author(s) 2021 Keywords: Tocilizumab; Steroids; COVID-19; letter, and the Editor for giving us the oppor- SARS-CoV-2; Mortality tunity to respond. In response to Dr. Janapala, we would like to note that we are fully aware of the limitations DIGITAL FEATURES of retrospective observational studies and the risk of bias derived from diverse factors, but To view digital features for this article go to mainly from differences in baseline character- https://doi.org/10.6084/m9.figshare.14308061. istics between groups. Nevertheless, there are different strategies that can be implemented to Dear Editor, minimize these limitations and increase the robustness of the conclusions reached. In our We appreciate the interest in our manuscript study [1], specifically to avoid bias derived [1], and thank Dr. Janapala et al. [2] for the from differences between groups and account for potential confounders, we have used a well- established and scientifically sound method- ology, the inverse probability of the treatment B. Ruiz-Antorán (&)  A. Sancho-López Clinical Pharmacology Department, Instituto de weights (IPTW) technique. The details, and Investigación Sanitaria Puerta de Hierro-Segovia de some key scientific references on which these Arana, Hospital Universitario Puerta de Hierro- methods rely on, are provided in our manu- Majadahonda, Madrid, Spain script. The IPTW technique generates a pseudo- e-mail: bruizantoran@gmail.com population in which the two groups are bal- F. Torres anced across baseline covariates. Any reader Medical Statistics Core Facility, August Pi i Sunyer can therefore check the baseline comparability Biomedical Research Institute, Hospital Clinic, Barcelona, Spain in Table 1 of our manuscript, and confirm that all variables achieved a \ |11%| standardized F. Torres difference (STD), except for the interleukin-6 Biostatistics Unit, Faculty of Medicine, Autonomous (IL-6). The latter remained unbalanced since University of Barcelona, Barcelona, Spain the amount of missingness did not allow us to A. Fernández-Cruz compensate for that observed. The IPTW Infectious Diseases Unit, Internal Medicine analysis for assessment of the study outcomes Department, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Hospital has been based on this well-balanced Universitario Puerta de Hierro-Majadahonda, population. Madrid, Spain 1812 Infect Dis Ther (2021) 10:1811–1813 Dr. Janapala et al. might have misunderstood In conclusion, in spite of the fact that our the methodology, focusing on the raw data study is an observational one and, as such, has instead of the IPTW analysis for assessing base- the inherent limitations thereof, our findings line comparability. Also, by no means have we raised the need to conduct appropriate ran- substantiated the baseline comparability on a domized clinical studies to confirm results. We hypothetical lack of statistical significance but are pleased to see that consistent benefits have on small STD. Please note that, in fact, no been shown in several published randomized p values have been provided for the IPTW controlled studies, e.g., the RECOVERY trial [3], baseline comparability. which has recently demonstrated that tocilizu- With regard to the time from the onset of mab is an effective treatment for hospitalized symptoms of COVID-19 to the inclusion of patients with COVID-19 who have hypoxia and patients in the study (day 0 for the control evidence of inflammation, where the benefits of group), it is noted that, as a matter of fact, the tocilizumab were clearly seen among those also mean (SD) results are also provided in Table 1, receiving treatment with a systemic and for the IPTW analysis were 10.41 (4.71) and corticosteroid. 10.12 (5.42) for the tocilizumab and the control group, respectively. The median [25th–75th percentiles] were not reported in the manu- ACKNOWLEDGEMENTS script but they were also similar: 10 [7–13] and 9 [6–13] for tocilizumab and the control group, We thank the members of the TOCICOV study respectively. Notably, the STD were - 0.2%, group for their contribution to the work. which may be considered very small on the STD scale, thus ruling out any potential impact of Funding. No funding or sponsorship was this variable on the study outcomes. received for this study or publication of this Finally, concerning the use of medicinal article. drugs other than the study treatment of interest (tocilizumab), we would like to point out that Authorship. All named authors meet the all these treatments were used in the context of International Committee of Medical Journal clinical practice, and all of them were used Editors (ICMJE) criteria for authorship for this concomitantly with tocilizumab (and not article, take responsibility for the integrity of instead of). At the time of the analysis of our the work as a whole, and have given their study, continuous evidence became available approval for this version to be published. regarding the lack of efficacy of hydroxy- chloroquine, azithromycin, and lopinavir/ri- Authors’ Contributions. Conceptualization tonavir in the treatment of COVID-19, so it was and study design: A.S.L., B.R.A, A.F.C. Method- not considered appropriate to carry out a sub- ology: B.R.A., A.F.C., A.S.L, F-T. Data collection: group analysis to account for the potential All authors. Data interpretation: A.S.L., B.R.A., influence of these drugs, as they had already A.F.C. F.T. Writing first draft: A.S.L., B.R.A, proved to be ineffective. A.S.L., F-T, A.F.C. Critical revision for important Additionally, the hypothesis of our study intellectual content: All authors. Final approval: was to evaluate the efficacy of tocilizumab as All authors. All authors agree to be account- anti-inflammatory and immunomodulatory able for all aspects of the work by ensuring that therapy in patients with COVID-19 who are questions related to the accuracy or integrity of purportedly in the inflammatory phase of the any part of the work will be appropriately disease, where steroids would have a similar and investigated and resolved. A.F.C. and B.R.A. had potentially synergic role. This, together with full access to all the data in this study and take the positive results that had been reported for complete responsibility for the integrity of the steroids, led us to consider it appropriate to data and the accuracy of the data analysis. analyze the effect of combined use of steroids plus tocilizumab therapy. Infect Dis Ther (2021) 10:1811–1813 1813 Disclosures. Belén Ruiz-Antorán, Aránzazu REFERENCES Sancho López, Ferrán Torres and Ana Fernán- dez-Cruz have nothing to disclose. 1. Ruiz-Antorán B, Sancho-López A, Torres F, Moreno- Torres V, et al. Combination of tocilizumab and Compliance with Ethics Guidelines. This steroids to improve mortality in patients with severe article is based on previously conducted studies COVID-19 infection: a Spanish, multicenter, cohort study. Infect Dis Ther. 2020. https://doi.org/10.1007/ and does not contain any new studies with s40121-020-00373-8. human participants or animals performed by any of the authors. 2. Janapala RN, Patel J, Belfaqeeh O, Alhashmi A, Pourmand A. Tocilizumab and steroids, mortality Open Access. This article is licensed under a benefits in severe COVID-19 patients. Infect Dis Ther. 2021 Creative Commons Attribution-NonCommer- cial 4.0 International License, which permits 3. Horby PW, Pessoa-Amorim G, Peto L, et al. Tocilizu- any non-commercial use, sharing, adaptation, mab in patients admitted to hospital with COVID-19 distribution and reproduction in any medium (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021. or format, as long as you give appropriate credit https://doi.org/10.1101/2021.02.11.21249258. to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by- nc/4.0/.