Hospitalized patients dying with SARS-CoV-2 infection—An analysis of patient characteristics and management in ICU and general ward of the LEOSS registry

Claudia Raichle; Stefan Borgmann; Claudia Bausewein; Siegbert Rieg; Carolin E. M. Jakob; Steffen T. Simon; Lukas Tometten; Jörg Janne Vehreschild; Charlotte Leisse; Johanna Erber; Melanie Stecher; Berenike Pauli; Maria Madeleine Rüthrich; Lisa Pilgram; Frank Hanses; Nora Isberner; Martin Hower; Christian Degenhardt; Bernd Hertenstein; Maria J. G. T. Vehreschild; Christoph Römmele; Norma Jung; on behalf of the LEOSS Study Group

doi:10.1371/journal.pone.0271822

Peer Review History

Original SubmissionOctober 8, 2021
31 Jan 2022 Decision Letter - Paavani Atluri, Editor PONE-D-21-32351Hospitalized patients dying with SARS-CoV-2 infection – an analysis of patient characteristics and management in ICU and general ward of the LEOSS registryPLOS ONE Dear Dr. Norma Jung, 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 Mar 17 2022 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. 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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 your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well 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. 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: No ****** 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: Interesting study with really good number of patients. It would be interesting to find out the data in the current vaccination era. Palliative consult is a must in all ICU patients, involving them early is very crucial. My revisions include: In the study design - Quotations before "Lean Europe survey (line 96) Table 1: in the BMI group, please replace decimal points instead of comma Reviewer #2: During this COVID-19 pandemic, In-hospital mortality among patients with COVID-19 was reportedly high. It is imperative to study the characteristics of Hospitalized patients dying with SARS-CoV-2 infection. This multicentre analysis has compared and highlighted some of these factors in ICU and general ward from the LEOSS registry. This retrospective data analysis has presented some important findings. Moreover, some of the queries related to the manuscript has been listed below: 1. In the Method section, the authors have mentioned it was a ‘Prospective’ study. However, it looks like a ‘Retrospective’ study. There is a discrepancy on page 5, line no 97 and line no. 107. The author should explain and correct it. 2. Why authors have selected specific dates for the analysis, i.e. March 18 and November 18, 2020. Also, the authors have stated most of the patients (~80%) were in March and April 2020. Is it in line with the first wave in the country? The authors may explain. 3. Page 5, line no 116 was unclear if ‘Table 1 referred to Rüthrich et al. or present study. Rewrite the sentence. 4. Page 7, line no 147, was about Bonferroni correction. The author should calculate and report the correct significant level as the number of tests ~28, <0.01 was inadequate. 5. Lastly, post hoc analysis would also be useful to report, if possible. ****** 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: Yes:** Prabal Kumar Chourasia [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.0271822.r001
Revision 1
18 Feb 2022 Author Response Dear Dr. Atluri, on behalf of all authors, I would like to thank the Editors and the Reviewers for the critical remarks on our manuscript (PONE-D-21-32351: Hospitalized patients dying with SARS-CoV-2 infection – an analysis of patient characteristics and management in ICU and general ward of the LEOSS registry) we received on the 1st February. We are grateful to get the opportunity to resubmit our revised manuscript. We very much appreciate the comments which we considered in the revised version and which we found helpful to improve the clarity of our manuscript. All answers to the comments are highlighted in yellow. We hope that the paper is now of sufficient quality to be published in Plos One. Yours sincerely, Norma Jung, MD Reviewers' comments: Reviewer #1: Interesting study with really good number of patients. It would be interesting to find out the data in the current vaccination era. Palliative consult is a must in all ICU patients, involving them early is very crucial. My revisions include: In the study design - Quotations before "Lean Europe survey (line 96) Thanks – we skipped the Quotations Table 1: in the BMI group, please replace decimal points instead of comma Thanks – we changed to points. Reviewer #2: During this COVID-19 pandemic, In-hospital mortality among patients with COVID-19 was reportedly high. It is imperative to study the characteristics of Hospitalized patients dying with SARS-CoV-2 infection. This multicentre analysis has compared and highlighted some of these factors in ICU and general ward from the LEOSS registry. This retrospective data analysis has presented some important findings. Moreover, some of the queries related to the manuscript has been listed below: 1. In the Method section, the authors have mentioned it was a ‘Prospective’ study. However, it looks like a ‘Retrospective’ study. There is a discrepancy on page 5, line no 97 and line no. 107. The author should explain and correct it. Thanks for this helpful remark – patients were recruited prospectively and data documented retrospectively. For more clarity, we scipped the word prospective in the method section. Line 97: “Data were retrieved from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) registry, a multi-center non-interventional cohort study.” 2. Why authors have selected specific dates for the analysis, i.e. March 18 and November 18, 2020. Also, the authors have stated most of the patients (~80%) were in March and April 2020. Is it in line with the first wave in the country? The authors may explain. Thanks for your question. Start day of our study (March 18) is the start day of the LEOSS-cohort, end day of our study (November 18) was set to the date of data retrieval from the ongoing cohort study, following this, we started with our analysis. Yes -March and April 2020 were the time of the first wave in the country- we included this information in the discussion section-chapter discussion – limitations Line 266: “Our data derive to a high extent from the beginning of the pandemic – with 88% of the patients recruited in March and April 2020, during the first pandemic wave.” 3. Page 5, line no 116 was unclear if ‘Table 1 referred to Rüthrich et al. or present study. Rewrite the sentence. Thanks for this remark. For more clarity we rewrote the sentence from: “For more details see Rüthrich et al.(1) , Table 1.” into “For more details see Table 1 in the study of Rüthrich et al. (1). (Line 116) 4. Page 7, line no 147, was about Bonferroni correction. The author should calculate and report the correct significant level as the number of tests ~28, <0.01 was inadequate. Thanks for your accurate review. Please excuse the inattentiveness, this sentence suggesting multiple testing was supposed to be deleted in the current version, as the statistical methods used do not require a Bonferroni adjustment. We performed univariate analyses with the different parameters in one dataset(same patient groups, each parameter is tested once, no multiple testing, no post-hoc analysis). We skipped the sentence and inserted instead: “Reported p values are 2-sided and p<0.05 was considered statistically significant.” . We adjusted the highlighting of the statistically significant parameters in the tables. 5. Lastly, post hoc analysis would also be useful to report, if possible. Thanks for your advice. We already answered your question in the previous section (4). https://doi.org/10.1371/journal.pone.0271822.r002
15 Jun 2022 Decision Letter - Paavani Atluri, Editor PONE-D-21-32351R1Hospitalized patients dying with SARS-CoV-2 infection – an analysis of patient characteristics and management in ICU and general ward of the LEOSS registryPLOS ONE Dear Dr. Jung, 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 Jul 30 2022 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, Paavani Atluri 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: Authors have addressed all the comments in the main text. A couple of minor edits are suggested in the abstract to align with the main text listed below: 1. Abstract Page 4 line 60 Remove ‘prospective’ term 2. Abstract Page 4 line 65 second sentence is unclear if 67% of 4310 or 67% of 580. Suggest to add ‘Among 580 patients,’ before the text. I have no further comments in the MS. ****** 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 #2: Yes: Prabal Chourasia ******** [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.0271822.r003
Revision 2
22 Jun 2022 Author Response Reviewers' comments: Reviewer #2: Authors have addressed all the comments in the main text. A couple of minor edits are suggested in the abstract to align with the main text listed below: 1. Abstract Page 4 line 60 Remove ‘prospective’ term Thanks – we removed “prospective”. 2. Abstract Page 4 line 65 second sentence is unclear if 67% of 4310 or 67% of 580. Suggest to add ‘Among 580 patients,’ before the text. Thanks for your helpful remark – we added “among 580 patients”. I have no further comments in the MS. https://doi.org/10.1371/journal.pone.0271822.r004
8 Jul 2022 Decision Letter - Paavani Atluri, Editor Hospitalized patients dying with SARS-CoV-2 infection – an analysis of patient characteristics and management in ICU and general ward of the LEOSS registry PONE-D-21-32351R2 Dear Dr. Jung, 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, Paavani Atluri Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0271822.r005
Formally Accepted
21 Jul 2022 Acceptance Letter - Paavani Atluri, Editor PONE-D-21-32351R2 Hospitalized patients dying with SARS-CoV-2 infection – an analysis of patient characteristics and management in ICU and general ward of the LEOSS registry Dear Dr. Jung: 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. Paavani Atluri Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271822.r006

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