Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study

Sonsoles Salto-Alejandre; Silvia Jiménez-Jorge; Nuria Sabé; Antonio Ramos-Martínez; Laura Linares; Maricela Valerio; Pilar Martín-Dávila; Mario Fernández-Ruiz; María Carmen Fariñas; Marino Blanes-Juliá; Elisa Vidal; Zaira R. Palacios-Baena; Román Hernández-Gallego; Jordi Carratalá; Jorge Calderón-Parra; María Ángeles Marcos; Patricia Muñoz; Jesús Fortún-Abete; José María Aguado; Francisco Arnaiz-Revillas; Rosa Blanes-Hernández; Julián de la Torre-Cisneros; Luis E. López-Cortés; Elena García de Vinuesa-Calvo; Clara M. Rosso; Jerónimo Pachón; Javier Sánchez-Céspedes; Elisa Cordero; on behalf of The COVIDSOT Working Team

doi:10.1371/journal.pone.0250796

Peer Review History

Original SubmissionJanuary 11, 2021
8 Feb 2021 Decision Letter - Stanislaw Stepkowski, Editor PONE-D-21-01017 Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study PLOS ONE Dear Dr. Pachon, 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. ============================== The main criticism is the quality of writing. The authors need to re-edit the entire manuscript for English and grammer. The manuscript needs to be revised as indicated by the reviewers: Reviewer # 1: The manuscript is well written. I have one question: in the analysis, there were 10 patients that were discharged and readmitted during the study period. For those 10 patients, how many days between their discharge and readmission? How many of them yield unfavorable outcomes? Will the results change significantly if including their 2nd hospital admission episode in the logistic regression? Because the p-value for lactate dehydrogenase >= 300 is just slightly smaller than 0.05 and its 95% CI is also very close to 1, it is possible that a slight change in the data would change the conclusion. The same for Lymphocytes < 1, p-value close to 0.05 and 95% CI close to 1. Another question is: some variables were “dichotomized based on normal ranges” in the analysis. I would like to know if these thresholds were determined by authors or based on some well-established or well-accepted criteria. Reviewer # 2 This is an interesting paper. The study is well designed and with proper statistical analysis of the data. However, the manuscript is poorly written and needs extensive editing to correct for typos and grammatical errors. I have few minor comments. Line 159: Replace confusion by confounding Line 311. Clarify hypothetically Line 327: Spell out the “abovementioned unfavorable outcomes” Line 329: What is severity risk factor? Line 349: Replace “cardiopathy” with “cardiomyopathy” Line 351: Add “and” after “included, “ Line 377: Replace “proved” with “showed”. Line 385: Replace “accurate” with “strong ============================== Please submit your revised manuscript by Mar 22 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). 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Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ 5. One of the noted authors is a group; The COVIDSOT Working Team. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. [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: Yes ****** 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: 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: The manuscript is well written. I have one question: in the analysis, there were 10 patients that were discharged and readmitted during the study period. For those 10 patients, how many days between their discharge and readmission? How many of them yield unfavorable outcomes? Will the results change significantly if including their 2nd hospital admission episode in the logistic regression? Because the p-value for lactate dehydrogenase >= 300 is just slightly smaller than 0.05 and its 95% CI is also very close to 1, it is possible that a slight change in the data would change the conclusion. The same for Lymphocytes < 1, p-value close to 0.05 and 95% CI close to 1. Another question is: some variables were “dichotomized based on normal ranges” in the analysis. I would like to know if these thresholds were determined by authors or based on some well-established or well-accepted criteria. Reviewer #2: This is an interesting paper. The study is well designed and with proper statistical analysis of the data. However, the manuscript is poorly written and needs extensive editing to correct for typos and grammatical errors. I have few minor comments. Line 159: Replace confusion by confounding Line 311. Clarify hypothetically Line 327: Spell out the “abovementioned unfavorable outcomes” Line 329: What is severity risk factor? Line 349: Replace “cardiopathy” with “cardiomyopathy” Line 351: Add “and” after “included, “ Line 377: Replace “proved” with “showed”. Line 385: Replace “accurate” with “strong” ****** 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:** sadik A. khuder [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.0250796.r001
Revision 1
10 Mar 2021 Author Response March 10, 2021 Stanislaw Stepkowski Academic Editor PLOS ONE Dear Dr Stepkowski, We are sending the revised version of our manuscript “Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study (PONE-D-21-01017)”. In this revised version we have addressed all the questions and the requests of the Reviewers, which are detailed below. Moreover, to assure the quality of writing we have made a proofreading process to re-edit the entire manuscript for English and grammar. Regarding the Journal additional requirements, we have: 1. assured to meet the PLOS ONE´s requirements; 2. included in the Methods section the information about the participants recruitment and demographics (line 123); 3. uploaded the minimal anonymized data set as Supporting Information files (S7 File); 4. added the ORCID iD of the corresponding author in Editorial Manager; and 5. added the information on the COVIDSOT Working Team in the acknowledgments section. We hope that this revised version of the manuscript will fulfill the requirements to be accepted for publication in PLOS ONE. Kind regards, Jerónimo Pachón, MD, PhD Emeritus Professor of Medicine Institute of Biomedicine of Seville, Virgen del Rocio University Hospital, University of Seville Av. Manuel Siurot s/n, 41013, Seville, Spain Email: pachon@us.es ORCID: 0000-0002-8166-5308 Reviewer # 1: The manuscript is well written. I have one question: in the analysis, there were 10 patients that were discharged and readmitted during the study period. For those 10 patients, how many days between their discharge and readmission? How many of them yield unfavorable outcomes? Will the results change significantly if including their 2nd hospital admission episode in the logistic regression? Because the p-value for lactate dehydrogenase >= 300 is just slightly smaller than 0.05 and its 95% CI is also very close to 1, it is possible that a slight change in the data would change the conclusion. The same for Lymphocytes < 1, p-value close to 0.05 and 95% CI close to 1. Thanks to the Reviewer by his positive appreciation of the manuscript. Please see below the answers to the two questions. Regarding the question on the 10 patients readmitted during the study period: i) the median of days from discharges to readmissions was 7 days (range 1 to 19); therefore, we consider the readmission as part of the same episode of SARS-CoV-2 infection; ii) only one patient needed intensive care after readmission, but he also required it during his first admission; and the 10 patients were discharged alive after the readmissions; iii) in summary, there was no change in the number of unfavorable outcome (a composite of ICU admission and/or death) in the cohort of the 210 solid organ transplantation recipients. Another question is: some variables were “dichotomized based on normal ranges” in the analysis. I would like to know if these thresholds were determined by authors or based on some well-established or well-accepted criteria. To examine factors associated with unfavorable clinical outcome, we dichotomized quantitative variables based on normal ranges, and after addressing their effect as continuous variables. The cut-offs used to dichotomize the variables were chosen based both in the normal values and in the cut-offs associated with unfavorable outcome when we analyzed the general population (Salto-Alejandre S et al. J Infect 2021 Feb;82(2):e11-e15. doi: 10.1016/j.jinf.2020.09.023. Epub 2020 Sep 25). Following the Reviewer question, to clarify it we have changed the sentence of the previous manuscript as follows: “… quantitative variables were dichotomized based on normal ranges and in the cut-offs associated with unfavorable outcome in the general population [28], after addressing their effect as continuous.” (lines 155-157 of the revised manuscript). We have added this new reference [28] in the manuscript. Reviewer # 2 This is an interesting paper. The study is well designed and with proper statistical analysis of the data. However, the manuscript is poorly written and needs extensive editing to correct for typos and grammatical errors. I have few minor comments. Thanks to the Reviewer by his positive appreciation of the design and the data analysis. Line 159: Replace confusion by confounding We have replaced confusion by confounding (line 159 of the revised manuscript), as requested by the Reviewer. Line 311. Clarify hypothetically Besides the main objective of the study, we wanted to supply descriptive data on patients with possible poorer outcome, because of graft dysfunction (12 patients) or developing COVID-19 in the period of maximal immunosuppressive therapy as it is the first month after receiving the transplant (6 patients). In this regard “hypothetically” was used as synonymous of “possible”. To clarify it, we have substituted the sentence “Two subgroups of the study population were considered, hypothetically, of higher risk” for “Two subgroups of the study population were considered of possible higher risk” (line 309 of the revised manuscript). Line 327: Spell out the “abovementioned unfavorable outcomes” Following the Reviewer request we have changed it to “ICU admission and/or death” (lines 318-319 of the revised manuscript). Line 329: What is severity risk factor? Severity was used as synonymous of unfavorable outcome. To clarify it, we have changed this sentence as follows: “… as a risk factor for unfavorable outcome.” (lines 319-320 of the revised manuscript). Line 349: Replace “cardiopathy” with “cardiomyopathy” Following this request, we have replaced “cardiopathy” with “cardiomyopathy” (line 340 of the revised manuscript). Line 351: Add “and” after “included, “ As requested, we have added “and” (line 342 of the revised manuscript). Line 377: Replace “proved” with “showed”. As requested, we have replaced “proved” with “showed” (line 368 of the revised manuscript). Line 385: Replace “accurate” with “strong”. As requested, we have replaced “accurate” with “strong” (line 376 of the revised manuscript). Attachments Attachment Submitted filename: Response to Reviewers_10-3-21.docx https://doi.org/10.1371/journal.pone.0250796.r002
14 Apr 2021 Decision Letter - Stanislaw Stepkowski, Editor Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study PONE-D-21-01017R1 Dear Dr. Pachon, 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, Stanislaw Stepkowski Academic Editor PLOS ONE Additional Editor Comments (optional): None 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: The authors have addressed all of my comments appropriately. I recommend acceptance of this manuscript. ****** 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:** Sadik Khuder https://doi.org/10.1371/journal.pone.0250796.r003
Formally Accepted
19 Apr 2021 Acceptance Letter - Stanislaw Stepkowski, Editor PONE-D-21-01017R1 Risk factors for unfavorable outcome and impact of early post-transplant infection in solid organ recipients with COVID-19: A prospective multicenter cohort study Dear Dr. Pachón: 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. Stanislaw Stepkowski Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0250796.r004

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