COVID-19 in lung transplant recipients—Risk prediction and outcomes

Jan C. Kamp; Jan B. Hinrichs; Jan Fuge; Raphael Ewen; Jens Gottlieb

doi:10.1371/journal.pone.0257807

Peer Review History

Original SubmissionJuly 23, 2021
9 Aug 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-23993 COVID-19 in lung transplant recipients - risk prediction and outcomes PLOS ONE Dear Dr. Kamp, 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 revise accordingly. Please submit your revised manuscript by Sep 23 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. 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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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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: The subject included in the manuscript is of the utmost importance for broad medical community. Firstly, COVID-19 is the novel disease of unknown long-term consequences. Secondly, undoubtedly it will be present in population for many years, if not decades. Therefore every report sheds a new light on the condition we will be facing in the years to come. It is reviewer satisfaction to be able to congratulate the Authors. The forwarded paper is meticulous, comprehensive, and precise. It is astounding that out of more than 1000 LTx individuals, solely more then 30 have gotten ill. Definitely this indicates accurate measures introduced to prevent them from being infected, some of them you have mentioned in the manuscript. I am quite aware of the leading role of the Hannover Medical School in Europe in lung transplantation. Therefore I got impression the COVID-19 is not affecting seriously this population. It is reassuring message, which perhaps might be more openly emphasized. In the discussion section you have made an extensive comparison with other LTx centers. Generally speaking reading this manuscript has been a teachable moment. Reviewer #2: Thank you for submititng this retrospective analysis of one of the largest cohort in europe in COVID period. The paper is well written. Statistics were performed rigorously Can you support few precision 1 can you explain why recent lung transplant seems to be less affected and the high proportion of preexisting CLAD. Is a particularity of your global cohort ? 2 in discussion line 290 : "hospital stays were significately shorter". This result may be explain due to the therapeutics engaged in lung transplant patient (dialysis - ECMO) and not in the general population. 3 line 346 you assay that the lack of control group. Can you develop this point. You can realize propensive score with your cohort, especially on CLAD ****** 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:** geoffrey Brioude [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.0257807.r001
Revision 1
16 Aug 2021 Author Response Rebuttal letter – Response to Reviewers Reviewer #1: The subject included in the manuscript is of the utmost importance for broad medical community. Firstly, COVID-19 is the novel disease of unknown long-term consequences. Secondly, undoubtedly it will be present in population for many years, if not decades. Therefore every report sheds a new light on the condition we will be facing in the years to come. It is reviewer satisfaction to be able to congratulate the Authors. The forwarded paper is meticulous, comprehensive, and precise. It is astounding that out of more than 1000 LTx individuals, solely more then 30 have gotten ill. Definitely this indicates accurate measures introduced to prevent them from being infected, some of them you have mentioned in the manuscript. I am quite aware of the leading role of the Hannover Medical School in Europe in lung transplantation. Therefore I got impression the COVID-19 is not affecting seriously this population. It is reassuring message, which perhaps might be more openly emphasized. In the discussion section you have made an extensive comparison with other LTx centers. Generally speaking reading this manuscript has been a teachable moment. Comment #1: Thank you very much for your appreciative comments. We are very pleased about this kind feedback. You suggested giving a little more emphasis on the small amount of lung transplant recipients from our institution affected by COVID-19. In fact, approximately 4 percent of our recipients have been infected by SARS-CoV-2 during the observation period what is comparable to the numbers in the German general population. However, the estimated number of unreported / undetected cases might be considerably higher in the general population so we added the following sentence to our discussion: Lines 283-284: The incidence of SARS-CoV-2 infections in our patient-cohort during the observation period was similar to nationwide German incidence (figure 3). However, it might be possible that the number of unreported / undetected cases were considerably higher. Reviewer #2: Thank you for submititng this retrospective analysis of one of the largest cohort in europe in COVID period. The paper is well written. Statistics were performed rigorously. Can you support few precision: Comment #2: We thank you for the valuable comments which helped to improve the manuscript. We have addressed all your comments below and provided explanations where information was requested. 1) can you explain why recent lung transplant seems to be less affected and the high proportion of preexisting CLAD. Is a particularity of your global cohort ? Thank you for these questions. Chronic lung allograft dysfunction (CLAD) is the most important limiting single factor of long-term survival after lung transplantation, accounting for >40% of deaths beyond the first year.1,2 The amount of lung transplant recipients with pre-existing CLAD in our work seems not to be unexpectedly high as CLAD is a major issue in these patients. Almost one third of our reciepints alive are affected with CLAD. As presented in figure 3, the incidence trend of SARS-CoV-2 infections in our cohort was very similar to that from the German general population. We added a sentence to the manuscript to highlight the relevance of CLAD in lung transplant recipients: Lines 302-303: The most important limiting single factor of long-term survival in LTx recipients is CLAD, responsible for >40% of deaths beyond the first year (17). 1) Verleden GM, Glanville AR, Lease ED, Fisher AJ, Calabrese F, Corris PA, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019 May;38(5):493-503. doi: 10.1016/j.healun.2019.03.009. Epub 2019 Apr 3. PMID: 30962148. 2) Van Herck A, Frick AE, Schaevers V, Vranckx A, Verbeken EK, Vanaudenaerde BM, et al. Azithromycin and early allograft function after lung transplantation: A randomized, controlled trial. J Heart Lung Transplant. 2019 Mar;38(3):252-259. doi: 10.1016/j.healun.2018.12.006. Epub 2018 Dec 14. PMID: 30686699. 2) in discussion line 290 : "hospital stays were significately shorter". This result may be explain due to the therapeutics engaged in lung transplant patient (dialysis - ECMO) and not in the general population. Thank you for this comment. We added this potential explanation to the discussion section: Lines 271-274: In this work, in-hospital mortality was 22% (compared to 46% in our study) and hospital stays were significantly shorter (14 vs. 19 days) what might potentially be explained due to the therapeutics engaged in LTx recipients (e.g. exctracorporeal therapies) rather than in the general population. 3) line 346 you assay that the lack of control group. Can you develop this point. You can realize propensive score with your cohort, especially on CLAD Thanks again for this important consideration and the excellent statistical discussion point. The patient cohort affected by COVID-19 is rather small. We agree that this is a limitation for all forms of multivariate analyses used in small sample sizes. We have recognized propensity score matching as an in-vogue method but we must at the same time acknowledge inherent limitations of this method. Indeed, we discussed to use this method beforehand instead of traditional covariate adjustment. After statistical advice and following recent guidance for statistical reporting we decided against using propensity score matching.3 No change in the revised manuscript regarding this point. 3) Harhay MO, Donaldson GC. Guidance on Statistical Reporting to Help Improve Your Chances of a Favorable Statistical Review. Am J Respir Crit Care Med. 2020;201(9):1035-1038. doi: 10.1164/rccm.202003-0477ED. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0257807.r002
13 Sep 2021 Decision Letter - Robert Jeenchen Chen, Editor COVID-19 in lung transplant recipients - risk prediction and outcomes PONE-D-21-23993R1 Dear Dr. Kamp, 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 #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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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: (No Response) Reviewer #2: Tak you for this answer. All the comments were discussed and appropriate modifications done. No further modifications ****** 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: Yes:** Brioude Geoffrey https://doi.org/10.1371/journal.pone.0257807.r003
Formally Accepted
15 Sep 2021 Acceptance Letter - Robert Jeenchen Chen, Editor PONE-D-21-23993R1 COVID-19 in lung transplant recipients - risk prediction and outcomes Dear Dr. Kamp: 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.0257807.r004

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