Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: A retrospective cohort study

Gianluca Russo; Angelo Solimini; Paola Zuccalà; Maria Antonella Zingaropoli; Anna Carraro; Patrizia Pasculli; Valentina Perri; Raffaella Marocco; Blerta Kertusha; Cosmo Del Borgo; Emanuela Del Giudice; Laura Fondaco; Tiziana Tieghi; Claudia D’Agostino; Alessandra Oliva; Vincenzo Vullo; Maria Rosa Ciardi; Claudio Maria Mastroianni; Miriam Lichtner

doi:10.1371/journal.pone.0257376

Peer Review History

Original SubmissionMarch 19, 2021
1 Jul 2021 Decision Letter - Francesco Di Gennaro, Editor PONE-D-21-08792 Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: a retrospective cohort study PLOS ONE Dear Dr. Russo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by 2 May. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Francesco Di Gennaro Academic Editor PLOS ONE Additional Editor Comments : only some minor suggestions to improve your paper Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a technically clean and sound paper with statistical analysis performed rigorously. Moreover, limitations are explained appropriately. The entire paper is presented in an intelligible fashion and clearly written. Reviewer #2: Generally the manuscript was well written and easy to read. The authors have reported a treatment option that could potentially be of significant benefit in a group of Covid patients. I have only 2 comments: 1. The overall idea of demonstrating the benefit of TCZ in addition to other standard therapy, in a group of patients who are extremely diverse in terms of severity and nature of the illness is extremely difficult. Although the authors did acknowledge this with a statement in the Discussion Pg 2- "It is important to highlight that clinical management of COVID-19 hospitalized patients is complex and not standardized also for the respiratory support" - the authors could elaborate more on how the clinical management was standardised with perhaps a hospital policy with the assistance of a standard algorith or flow chart that could pose some level of standardisation in the treatment. 2. In the limitation section the authors should include the small numbers that could limit the validity of the results. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. 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Revision 1
4 Jul 2021 Author Response Response to the reviewers’ comment: First of all, we would like to thank the reviewers for their comment. Below, our reply to the points raised by the reviewers: 3. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: Yes Reviewer #2: No Authors: We added a file with all data underlying our findings as supplementary material and we added the sentence “All relevant data are within the manuscript and its Supporting Information files”. Reviewer#2: 1. The overall idea of demonstrating the benefit of TCZ in addition to other standard therapy, in a group of patients who are extremely diverse in terms of severity and nature of the illness is extremely difficult. Although the authors did acknowledge this with a statement in the Discussion Pg 2- "It is important to highlight that clinical management of COVID-19 hospitalized patients is complex and not standardized also for the respiratory support" - the authors could elaborate more on how the clinical management was standardised with perhaps a hospital policy with the assistance of a standard algorith or flow chart that could pose some level of standardisation in the treatment. Authors: the sentence considered was not referred to our setting, but it was in general. Although that, we agree with the reviewer and we have modified the mentioned sentence and added a new one as follows: “In general, it is important to highlight that the clinical management of COVID-19 hospitalized patients is complex and not standardized also for the respiratory support, with SoC being possibly different among clinical centres and overtime. In order to better standardize the clinical management of our patients, a simplified flow-chart for internal use was established”. 2. In the limitation section the authors should include the small numbers that could limit the validity of the results. Authors: the small number of patients has been added as study limitation as requested Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0257376.r002
16 Jul 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-08792R1 Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: a retrospective cohort study PLOS ONE Dear Dr. Russo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address the issues and revise accordingly. Please submit your revised manuscript by Aug 30 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Robert Jeenchen Chen, MD, MPH Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #3: the paper is interesting in its concept and being based on "real life experience', the data offers a different prospective about use of TCZ either alone or in conjunction with GCs, as the published results about this drug is controversial. however, this manuscript could benefit from some modifications to pinpoint its significant results. Abstract: In conclusion subsection, re-write it to be more concise and to the point, according to your results does use of TCZ alone was beneficial to patients or adding GCS was more beneficial? introduction: It is apparent that this study took place in Italy, please add sentence referring to death rate by age in Italy (if available). in the first paragraph discussing cytokines, reference no. 8 reported low level of IL-6 in association with critical COVID-19, please add more rationale for optioning to use drug act against IL-6 receptors (i;e bolster what is written in references 6,9 and 10). does the presence of more virus variants affects the efforts to establish standardized therapy? please clarify in introduction. sentence linked to reference 11 is ambiguous, please clarify. please add three-sentences paragraph about TCZ, the cornerstone of this study. Method section: Figure 1 needs more bolstering, it would be best if the flowchart contains original enrolled number, number of patients that were excluded and their exclusion criteria, eligible enrolled patients and their inclusion criteria, distribution of patients on groups with subdivision number of deaths in every group, number of patients discharged alive, number of patients who needed ICU. In SOC, does this hospital/region/national guidelines, please clarify as a footnote. the dose of TCZ is somewhat different from the one used in Rashad et al., 2021 and Albertini et al., 2021, does the different dosage affected the measured outcomes/survivability? authors mentioned "the majority of patients received methylprednisolone, please add the exact number, and what about he remaining patients in the group, did they receive dexamethasone? please clarfiy. Results: group classification belongs to method section, please amend. does the co-morbidity at admission affected the survival rate? results in its current format are confusing, please reorder to pinpoint the most significant results of the study. start with epidemiological data (age, co-morbidities, time between appearance of signs and admission, signs at admission). followed by baseline parameters, treatment groups and parameters, adverse effects and survival rate and end with multivariate COX hazard regression model. no need to repeat drugs used in SOC protocol in results section. this paragraph " intubation occurs more frequently in TCZ group, 2/3 with TCZ+ GCs), please clarify this result, which group exactly? and what number "26" stands for? Discussion: although there were conflicting results about usage of TCZ, it was not discussed extensively, please amend. also, based on your results, which was more beneficial, TCZ alone, TCZ with GCs or SOC alone? please discuss does different GCs used affected the results outcomes? does co-morbidities affect outcome regardless of used therapeutic regimens which co-morbidity benefit/ worsen by TCZ either alone or in conjunction with GCS? Conclusion it is preferable if conclusion does not contain references, please re-write this section and use "take home message" of your most significant results and recommendations based on your results ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0257376.r003
Revision 2
19 Aug 2021 Author Response RESPONSE TO REVIEWER (19th August 2021) Reviewer #3: the paper is interesting in its concept and being based on "real life experience', the data offers a different prospective about use of TCZ either alone or in conjunction with GCs, as the published results about this drug is controversial. however, this manuscript could benefit from some modifications to pinpoint its significant results. Abstract: Q1. In conclusion subsection, re-write it to be more concise and to the point, according to your results does use of TCZ alone was beneficial to patients or adding GCS was more beneficial? A1. Modified as requested Introduction: Q2. It is apparent that this study took place in Italy, please add sentence referring to death rate by age in Italy (if available) A2. We thank the reviewer for the suggestion. Data (with the corresponding reference) have been changed Q3. in the first paragraph discussing cytokines, reference no. 8 reported low level of IL-6 in association with critical COVID-19, please add more rationale for optioning to use drug act against IL-6 receptors (i;e bolster what is written in references 6,9 and 10). A3. Reference n.8 is a review comparing IL-6 serum level in severe COVID-19, hyperinflammatory ARDS, sepsis, and CRS in the setting of CAR-T cells Therapy. The paper shows that the peak of serum IL-6 in severe COVID-19 was lower than what observed in the other conditions known to be associated to high serum level of IL-6. Tocilizumab is already authorized for the treatment of the CRS in the setting of CAR-T cells Therapy. We thanks the reviewer for its suggestion and, in order to avoid misinterpretation, the sentence has been modified focusing on the lower peak of IL-6 in severe COVID-19 in comparison to the other clinical conditions that have been specified in the manuscript. Q4. does the presence of more virus variants affects the efforts to establish standardized therapy? please clarify in introduction. A4. We thank the reviewer for the suggestion, but our paper did not take in account viral variants (and their potential impact on pathogenesis and treatment) because that is beyond the objective of our study. Q5. sentence linked to reference 11 is ambiguous, please clarify. A5. The sentence related to ref 11 is about the results of the RECOVERY trial in which the reduced mortality related to the corticosteroid therapy was evident only in patients in need of oxygen support (being possibly harmful in those receiving CCS and not in need of oxygen supply (RR 1.19)) Q6. please add three-sentences paragraph about TCZ, the cornerstone of this study. A6. The sentences have been added as requested Method section: Q7. Figure 1 needs more bolstering, it would be best if the flowchart contains original enrolled number, number of patients that were excluded and their exclusion criteria, eligible enrolled patients and their inclusion criteria, distribution of patients on groups with subdivision number of deaths in every group, number of patients discharged alive, number of patients who needed ICU. A7. We have modified the figure 1 taking in account the reviewer suggestions and we have also better specified inclusion criteria in the main manuscript Q8. In SOC, does this hospital/region/national guidelines, please clarify as a footnote. A8. SoC was based on advices (not properly guidelines) from a panel of experts of the Italian Society of Infectious and Tropical Diseases (SIMIT, Società Italiana di Malattie Infettive e Tropicali) and this has been added in the text Q9. the dose of TCZ is somewhat different from the one used in Rashad et al., 2021 and Albertini et al., 2021, does the different dosage affected the measured outcomes/survivability? A9. We agree with the reviewers about the heterogeneity of the dosage (and ways of administration: sc, iv) of TCZ used in different studies and we cannot answer properly to this question because, as in our study, no Therapeutic Drug Monitoring has been done as in all other published studies on TCZ use in COVID-19. Pharmacokinetic studies on TCZ are available only among few rheumatologic patients (and healthy controls), but not in COVID-19 patients. Furthermore, in order to be more precise on this aspect (and showing the heterogeneity among studies), in Table S2 which resumes observational studies on TCZ in COVID-19, the doses and ways of administration have been already specified as footnote of the table for each study: this aspect has been also already raised in the discussion section. Q10. authors mentioned "the majority of patients received methylprednisolone, please add the exact number, and what about he remaining patients in the group, did they receive dexamethasone? please clarfiy. A10. As suggested by the reviewer, the proportion of patients taking methylprednisone or other CCS (dexamethasone) has been specified in the manuscript. Results: Q11. group classification belongs to method section, please amend. A11. Modified as suggested. Q12. does the co-morbidity at admission affected the survival rate? A12. Yes, the coefficient of the sum of comorbidities was significant in the fully adjusted survival analysis at 14-days (HR 1.23 95%CI: 1.10-1.38, p<0.001) and 28-days (HR 1.20, 95%CI: 1.10-1.32, p<0.001). A specific sentence has been added in the results section. Q13. results in its current format are confusing, please reorder to pinpoint the most significant results of the study. Start with epidemiological data (age, co-morbidities, time between appearance of signs and admission, signs at admission) followed by baseline parameters, treatment groups and parameters, adverse effects and survival rate and end with multivariate COX hazard regression model. A13. We thank the reviewer for the suggestion that we have followed by modifying the organization of the results as requested Q14. no need to repeat drugs used in SOC protocol in results section. A14. Modified as suggested Q15. this paragraph " intubation occurs more frequently in TCZ group, 2/3 with TCZ+ GCs), please clarify this result, which group exactly? and what number "26" stands for? A15. We observed 26 cases oro-tracheal intubation: 17 in TCZ+CCS and 7 in TCZ group. The sentence has been modified as requested. Discussion: Q16. although there were conflicting results about usage of TCZ, it was not discussed extensively, please amend. A16. We did not agree with this observation. Results of many different studies on TCZ use in COVID-19 (all resumed in Table S2 and S3) have been discussed, as well as factors hampering results comparison between and among studies. Q17. also, based on your results, which was more beneficial, TCZ alone, TCZ with GCs or SOC alone? please discuss does different GCs used affected the results outcomes? A17. As already stated in the discussion section of the manuscript, the co-administration of corticosteroid was protective without improving tocilizumab outcomes effect, excepting in cases with more severe respiratory disease. This concept has been added in the discussion as requested. Moreover, as requested, it has been specified that the use of different corticosteroid molecules (methylprednisolone and dexamethasone) did not changed study outcomes Q18. does co-morbidities affect outcome regardless of used therapeutic regimens which co-morbidity benefit/ worsen by TCZ either alone or in conjunction with GCS? A18. Although interesting, we did not test an hypothesis for the interaction between co-morbidities and treatment groups because it was beyond the study objectives. Moreover, we do not think that the number of patients in some of the groups is enough to perform this analysis Conclusion Q19. it is preferable if conclusion does not contain references, please re-write this section and use "take home message" of your most significant results and recommendations based on your results A19. We thank the reviewer for the suggestion, and we have modified the text accordingly Attachments Attachment Submitted filename: Response to reviewer_PONE-D-21-08792R1.docx https://doi.org/10.1371/journal.pone.0257376.r004
1 Sep 2021 Decision Letter - Robert Jeenchen Chen, Editor Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: a retrospective cohort study PONE-D-21-08792R2 Dear Dr. Russo, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Robert Jeenchen Chen, MD, MPH Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Authors have taken care of all comments and my recommendation is to accept this paper for publication Reviewer #3: The authors have answered all the raised questions and addressed all the comments / suggestions precisely. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #3: No https://doi.org/10.1371/journal.pone.0257376.r005
Formally Accepted
2 Sep 2021 Acceptance Letter - Robert Jeenchen Chen, Editor PONE-D-21-08792R2 Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: a retrospective cohort study Dear Dr. Russo: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Robert Jeenchen Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257376.r006

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