Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study

Napassorn Teeratakulpisarn; Supattra Chiewroongroj; Thummaporn Naorungroj; Ranistha Ratanarat

doi:10.1371/journal.pone.0308069

Peer Review History

Original SubmissionMarch 21, 2024
22 Apr 2024 Decision Letter - Jiawen Deng, Editor PONE-D-24-03848Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 PatientsPLOS ONE Dear Dr. Ratanarat, 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 Jun 06 2024 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: https://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, Jiawen Deng Academic Editor PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. 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 2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [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: Partly Reviewer #2: Partly ******** 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: No Reviewer #2: No ****** 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: Thank you for the opportunity to review the manuscript "Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 Patients". The authors seek to address the knowledge gap in optimal dose and duration of steroid dosing in COVID-19 pneumonia patients using a retrospective cohort study, categorizing cumulative dexamethasone dosing over 14 days into quartiles. Major questions to address: - why did the authors choose to study an intervention duration of 14 days? (most of the cited studies included 10 day duration) - why did the authors choose to study cumulative dexamethasone dosing by quartiles? (most cited studies included high intensity vs lower intensity vs placebo, high intensity dosing was usually 20mg daily for 5 days followed by 10mg daily for 5 days, total 150mg; although one study did include 8mg 3x daily for 10 days, 240 mg total) - why was the primary outcome in-hospital mortality? (most of the cited studies used 28 day mortality, 28d VFD, and 60 day mortality) - please check references, #2 and #3 do not have functional links - P13 L237-238: please rewrite, "this causal relationship", impossible to determine a causal relationship with a retrospective study Additional issues to address: - please correct grammar, several instances of awkward wording throughout - P4 L62-66: please update reference for pathogenesis and treatment, link does not work - P9 L152: why was lymphocyte count used, but white blood cell count not included? - why were the inclusion criteria limited to patients requiring oxygen therapy? (several cited studies included patients not requiring oxygen therapy) - please edit "hospital mortality" to "in-hospital mortality" throughout Reviewer #2: Thank you for the opportunity to review this manuscript. Teeratakulpisarn et al. present a retrospective study of patients with COVID-19 to determine associations between corticosteroid dosages and patient outcomes. While this is interesting, I am concerned that this study may no longer be as timely and most institutions have specific, predefined dosages at this point in time. The strains/variants have also changed considerably and it is unclear how pertinent this data would be. Major: 1) The study is single-center, across almost 18 months only. This should be further elaborated upon in the limitations as it has a considerable impact on generalizability. Moreover, the emergence of new variants should be discussed as a limitation of the study. 2) While the primary outcome is hospital mortality and secondary outcomes are mortality at different time points, the actual causes of death are not reported. This would be important to note and if unavailable, this is a major limitation as it is unclear as to the mechanism of death. 3) Hospital-acquired infections should be defined and noted with respect to how they were identified. 4) The result section reports median (IQR) but the abstract is in mean (SD) for often the same variables (e.g. dosage). As per the methods, depending on the distribution, the authors should select one and be consistent. 5) The authors should justify and provide references for why and how these quartiles were decided upon. 6) The confidence intervals, particularly for ECMO and ventilator use in Table S1 are extremely wide and depending on the data type (e.g. large number of 0s relative to 1s), the authors should consider other techniques such as negative binomial regressions (https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/) Minor: 1) Title: Consider rephrasing to "The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort study" or something similar 2) Abstract - Conclusion: The authors should ensure all data is presented in the form of associations rather than causal given the study design. Consider changing "risk factor" to "associated with" 3) Through out the manuscript causal language is used (e.g. "increased"). This should all be reworded to "higher" or "lower," etc. 4) Key message: Please clarify what a "J-curve" really means, especially in the key message section. "Linked" should also be modified to "associated." 5) Introduction: The first paragraph, especially the first sentence should be revised to reflect the current climate of COVID-19. Specifically, I would not call it "emerging" at this point in time. 6) Introduction, Lines 79-80: The authors should consider including trials which have indeed looked at steroid dosages (e.g. https://jamanetwork.com/journals/jama/fullarticle/2785529) 7) All acronyms need to be defined (e.g. ECMO, PF, etc). Some percentages in the results are also inadvertently subscripted. 8) Tables: The number of decimal places for the data should be consistent. They would all benefit from inclusion of abbreviation definitions at the bottom of all main and supplementary tables 9) The study would benefit from an English grammar review ****** 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. 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.0308069.r001
Revision 1
29 May 2024 Author Response Professor Jiawen Deng Editor-in-Chief, PLOS ONE Journal May 25th, 2024 Answer to review of: PONE-D-24-03848 ‘Effects of Corticosteroid Intensity on Clinical Outcomes in Hypoxic COVID-19 Patients Professor Jiawen Deng Thank you for your potential interest in publishing our work. We appreciate the valuable comments from the reviewers and believe that their suggestion improved our work. We have revised and added information to our manuscript in response to the reviewers’ comments, and below we provide responses to each issue raised. All comments are restated below followed by our responses and description of the substance and location of any resulting changes made to the revised manuscript. Yours sincerely Napassorn Teeratakulpisarn Thummaporn Naorungroj Asso. Prof. Ranistha Ratanarat Department of Intensive Care Faculty of Medicine Siriraj Hospital Mahidol University Response to Reviewers 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: https://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. RESPONSE: Thank you for your recommendation. We informed the reviewer that this study is a retrospective study. Thus, we haven’t published a preplanned laboratory research protocol. However, we have provided our data in supporting files. Reviewer #1: - Why did the authors choose to study an intervention duration of 14 days? (most of the cited studies included 10 days duration) RESPONSE: We thank the reviewer for this comment. We informed the reviewer that the patients including in this study were received the treatments during the pandemic era of the delta variant before the publication of RECOVRY or REMAP-CAP study. In our institute, we have followed the local guideline adopted from the WHO guideline for corticosteroid tailoring based on individual patient characteristics, severity, and risk factors (1). Moreover, 71.2% of the patients in this study receiving one of systemic corticosteroids for more than 10 days. Hence, we decided to present corticosteroid dosing in a cumulative dexamethasone dose over 14 days. Reference 1 Ratanarat R, Thitayanapong A. Rational use of corticosteroid treatment in the early phase of severe COVID-19: Corticosteroid in COVID-19. Clin Crit Care [Internet]. 2023 Jun. 26 [cited 2024 May 5];31(1):2023:e0010. - Why did the authors choose to study cumulative dexamethasone dosing by quartiles? (most cited studies included high intensity vs lower intensity vs placebo, high intensity dosing was usually 20mg daily for 5 days followed by 10mg daily for 5 days, total 150mg; although one study did include 8mg 3x daily for 10 days, 240 mg total) RESPONSE: We thank the reviewer for this thoughtful comment. There were some reasons why we have chosen to study cumulative dexamethasone dosing by quartiles. First, the characteristics of our patients were more severe COVID-19 compared to most cited studies (1-4) (Supplementary table S4), with a median PF ratio of 151.4 (IQR: 104.8, 224.0) and 53.5% of patients requiring mechanical ventilator support. In our cohort, the median dose of corticosteroid was 165 mg which was exceeding high-intensity dose using in CoDEX trial (5). Furthermore, we did not enroll the patient who did not receive corticosteroid so we did not have placebo group. Second, this study aimed to observe a correlation between the optimal dose (neither too low nor too high) and favorable clinical outcomes in our center, as well as in a previous study conducted by Maia et al (6). Third, we, indeed, have conducted an analysis comparing high vs low intensity dosing, and the results showed there was no significant difference in mortality. However, we hypothesized that the cumulative dose of corticosteroids may not a linear correlation. Therefore, we have attempted to present the corticosteroid dosing in more granular data as shown in this study. Fourth, in the statistical view, dividing cumulative dexamethasone dosing into quartiles would give equal data for each group and it is concordance with box plot analysis. Reference 1 Durr KM, Hendin A, Perry JJ. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. CJEM. 2022 Apr;24(3):266-267. 2 Maskin LP, Bonelli I, Olarte GL, Palizas F Jr, Velo AE, Lurbet MF, et al. High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial. J Intensive Care Med. 2022 Apr;37(4):491-499. 3 Toroghi N, Abbasian L, Nourian A, Davoudi-Monfared E, Khalili H, Hasannezhad M, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2022 Feb;74(1):229-240. 4 Bouaddma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Megarbane B, Garcon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone And Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Sep 1;182(9):906-916. 5 Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316. 6 Maia R, Melo L, Mendes JJ, Freitas PT. Corticosteroids in COVID-19: A double-edged sword—a retrospective study. Med Intensiva (Engl Ed). 2022 Apr;46(4):229-231. - Why was the primary outcome in-hospital mortality? (most of the cited studies used 28-day mortality, 28d VFD, and 60-day mortality) RESPONSE: We thank the reviewer for your comment. We have to use the in-hospital mortality instead of 28-day mortality for primary outcome because according to retrospective data during the pandemic, there was a significant missing data for the 28-day mortality data. Therefore, we have selected in-hospital mortality, which was the most complete mortality outcome, as the primary outcome. - Please check references, #2 and #3 do not have functional links RESPONSE: We apologized the reviewer for these errors. We have already corrected the functional links for reference 2 and 3 in our revised manuscript. - P13 L237-238: please rewrite, "this causal relationship", impossible to determine a causal relationship with a retrospective study RESPONSE: We thank the reviewer for this comment. We have already changed “this causal relationship” to “this correlation” in our revised manuscript on page 16 - Please correct grammar, several instances of awkward wording throughout RESPONSE: We thank the reviewer for this comment. We have rechecked the grammar and made it more appropriately. - P4 L62-66: please update reference for pathogenesis and treatment, link does not work RESPONSE: We thank the reviewer for this comment and We apologized for the error. We have already updated the reference for pathogenesis and treatment of COVID-19 and also corrected the functional links in our revised manuscript. - P9 L152: why was lymphocyte count used, but white blood cell count not included? RESPONSE: We thank the reviewer for your thoughtful comment. We used the lymphocyte count rather than white blood cell counts because there was a significant association between low lymphocyte count and higher severity. References: 1 Hedayati-Ch M, Ebrahim-Saraie HS, Bakhshi A. Clinical and immunological comparison of COVID-19 disease between critical and non-critical courses: a systematic review and meta-analysis. Front Immunol. 2024;15:1341168. Published 2024 Apr 16. 2 Montiel-Cervantes LA, Medina G, Pilar Cruz-Domínguez M, et al. Poor Survival in COVID-19 Associated with Lymphopenia and Higher Neutrophile-Lymphocyte Ratio. Isr Med Assoc J. 2021;23(3):153-159. - Why were the inclusion criteria limited to patients requiring oxygen therapy? (several cited studies included patients not requiring oxygen therapy) RESPONSE: According to the COVID-19 treatment guidelines, systemic corticosteroids should be administered to patients requiring oxygen therapy. Therefore, we recruited only patients who receiving oxygen therapy for our study. Reference: 1 NIH. COVID-19 Treatment Guidelines. Clinical Management Summary. Last Updated: February 29, 2024. Available at: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/clinical-management-of-adults-summary/. - Please edit "hospital mortality" to "in-hospital mortality" throughout RESPONSE: We thank the reviewer for the comment. We have already changed "hospital mortality" to "in-hospital mortality" in our revised manuscript. Reviewer #2: Major: 1) The study is single-center, across almost 18 months only. This should be further elaborated upon in the limitations as it has a considerable impact on generalizability. Moreover, the emergence of new variants should be discussed as a limitation of the study. RESPONSE: We thank the reviewer for this comment. We have already added this information in limitation in our revised manuscript as following: “The patients in the study were recruited only in our institute in the specific time period which was in the delta variant pandemic of SARS-CoV-2. Thus, these results were limited on generalizability and may be inapplicable to the current variant.” 2) While the primary outcome is hospital mortality and secondary outcomes are mortality at different time points, the actual causes of death are not reported. This would be important to note and if unavailable, this is a major limitation as it is unclear as to the mechanism of death. RESPONSE: We thank the reviewer for these comments and we agreed with the reviewer that this is an important issue. We did not report the actual cause of death for each patient. Thus, we have added this information in limitation of our revised manuscript as following “Our study reported hospital mortality as the primary outcome and mortality at different time points as secondary outcomes. We did not report the actual cause of death for each patient, which could result in an unknown mechanism of death that might not be related to COVID-19.” 3) Hospital-acquired infections should be defined and noted with respect to how they were identified. RESPONSE: We thank the reviewer for this comment. We have added the definition of “Hospital-acquired infection” in method at P7 L 122-124 as the following “hospital-acquired infections were including hospital acquired pneumonia, urinary tract infection, bacteremia, catheter related bloodstream infection, and skin and soft tissue infection”. 4) The result section reports median (IQR) but the abstract is in mean (SD) for often the same variables (e.g. dosage). As per the methods, depending on the distribution, the authors should select one and be consistent. RESPONSE: We thank the reviewer for these comments and we apologized for these errors. We have already corrected the results and have reported the median (interquartile range) according to the distribution for every section in the manuscript. 5) The authors should justify and provide references for why and how these quartiles were decided upon. RESPONSE: RESPONSE: We thank the reviewer for this thoughtful comment. There were some reasons why we have chosen to study cumulative dexamethasone dosing by quartiles. First, the characteristics of our patients were more severe COVID-19 compared to most cited studies (1-4) (Supplementary table S4), with a median PF ratio of 151.4 (IQR: 104.8, 224.0) and 53.5% of patients requiring mechanical ventilator support. In our cohort, the median dose of corticosteroid was 165 mg which was exceeding high-intensity dose using in CoDEX (5). Furthermore, we did not enroll the patient who did not receive corticosteroid so we did not have placebo group. Second, this study aimed to observe a correlation between the optimal dose (neither too low nor too high) and favorable clinical outcomes in our center, as well as in a previous study conducted by Maia et al (6). Third, we, indeed, have conducted an analysis comparing high vs low intensity dosing, and the results showed there was no significant difference in mortality. However, we hypothesized that the cumulative dose of corticosteroids may not a linear correlation. Therefore, we have attempted to present the corticosteroid dosing in more granular data as shown in this study. Fourth, in the statistical view, dividing cumulative dexamethasone dosing into quartiles would give equal data for each group and it is concordance with box plot analysis. Reference 1 Durr KM, Hendin A, Perry JJ. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. CJEM. 2022 Apr;24(3):266-267. 2 Maskin LP, Bonelli I, Olarte GL, Palizas F Jr, Velo AE, Lurbet MF, et al. High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial. J Intensive Care Med. 2022 Apr;37(4):491-499. 3 Toroghi N, Abbasian L, Nourian A, Davoudi-Monfared E, Khalili H, Hasannezhad M, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2022 Feb;74(1):229-240. 4 Bouaddma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, Guitton C, Schwebel C, Cohen Y, Bruel C, Marzouk M, Geri G, Cerf C, Megarbane B, Garcon P, Kipnis E, Visseaux B, Beldjoudi N, Chevret S, Timsit JF; COVIDICUS Study Group. High-Dose Dexamethasone And Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022 Sep 1;182(9):906-916. 5 Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316. 6 Maia R, Melo L, Mendes JJ, Freitas PT. Corticosteroids in COVID-19: A double-edged sword—a retrospective study. Med Intensiva (Engl Ed). 2022 Apr;46(4):229-231. 6) The confidence intervals, particularly for ECMO and ventilator use in Table S1 are extremely wide and depending on the data type (e.g. large number of 0s relative to 1s), the authors should consider other techniques such as negative binomial regressions (https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/) RESPONSE: We thank the reviewer for your thoughtful comment. We have discussed our data with statistician and we have determined that the negative binomial regression is typically used for modeling count variables, usually for over-dispersed count outcome variables. However, since our data uses hospital mortality as an outcome, which is a binary outcome, we have opted to use binomial logistic regression for the analysis. References: 1 Statistical Method and Data Analytics [Internet]. UCLA. LOGISTIC REGRESSION \| STATA DATA ANALYSIS EXAMPLES [cited 2024 May 12]. Available from: https://stats.oarc.ucla.edu/stata/dae/logistic-regression/ 2 Statistical Method and Data Analytics [Internet]. UCLA. NEGATIVE BINOMIAL REGRESSION \| STATA DATA ANALYSIS EXAMPLES [cited 2024 May 12]. Available from: https://stats.oarc.ucla.edu/stata/dae/negative-binomial-regression/ Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0308069.r002
19 Jun 2024 Decision Letter - Jiawen Deng, Editor PONE-D-24-03848R1The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort studyPLOS ONE Dear Dr. Ratanarat, Thank you for submitting your revised manuscript to PLOS ONE. While the reviewers no longer have major comments on the revised article, they raised a few minor points that need to be addressed. Specifically, I agree with the reviewers that your manuscript could benefit from English editing. Please submit your revised manuscript by Aug 03 2024 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: https://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, Jiawen Deng Academic Editor PLOS ONE 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. [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 #2: 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: Partly Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: 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 #2: 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 #2: 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: Thank you for the opportunity to review the revised manuscript "The association between corticosteroid dosage and clinical outcomes in COVID-19 pneumonia: A retrospective cohort study" - if the patient population factored into the decision to study dexamethasone quartiles, the title should reflect that this is a study in severe, hypoxemic COVID-19 pneumonia - having no patients receiving corticosteroid or no placebo group should be mentioned in the limitations section - while greatly improved, there are still many instances where the wording is awkward or confusing, while I do not have a specific institute/agency recommendation in mind, this manuscript would benefit from further English grammar review Reviewer #2: I thank the authors for their careful consideration of my comments and their thoughtful replies. I do not have additional recommendations given this thorough revision. ****** 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 #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. 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.0308069.r003
Revision 2
11 Jul 2024 Author Response Reviewer #1: - If the patient population factored into the decision to study dexamethasone quartiles, the title should reflected thst this is a study in severe, hypoxemic COVID-19 pneumonia RESPONSE: We thank the reviewer for this comment. We have changed the title to “Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study” - having no patients receiving corticosteroid or no placebo group should be mentioned in the limitations section RESPONSE: We thank the reviewer for this thoughtful comment. We added the seventh limitation in P18, L 289-292 that “we recruited only hypoxemic patients requiring corticosteroids, and thus, we could not compare the outcomes of these patients with those of patients not receiving corticosteroids.” - while greatly improved, there are still many instances where the wording is awkward or confusing, while I do not have a specific institute/agency recommendation in mind, this manuscript would benefit from further English grammar review RESPONSE: We thank the reviewer for your comment. We have sent our manuscript to AJE academic English editing services for a grammar review and have corrected our manuscript according to their suggestions. Attachments Attachment Submitted filename: Response to Reviewers July 8th, 2024.docx https://doi.org/10.1371/journal.pone.0308069.r004
17 Jul 2024 Decision Letter - Jiawen Deng, Editor Associations between corticosteroid dosage and clinical outcomes in patients with hypoxemic COVID-19 pneumonia: A retrospective cohort study PONE-D-24-03848R2 Dear Dr. Ratanarat, Your manuscript has improved significantly over the last two rounds of revisions. As such, we can now accept your submission for publication in PLOS ONE. Thank you for your insightful submission. 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Jiawen Deng Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0308069.r005
Formally Accepted
26 Jul 2024 Acceptance Letter - Jiawen Deng, Editor PONE-D-24-03848R2 PLOS ONE Dear Dr. Ratanarat, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Jiawen Deng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0308069.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .