A comparison study of temporal trends of SARS-CoV2 RNAemia and biomarkers to predict success and failure of high flow oxygen therapy among patients with moderate to severe COVID-19

Hiroshi Koyama; Kazuya Sakai; Kiyomitsu Fukaguchi; Hiroki Hadano; Yoshihisa Aida; Tadashi Kamio; Takeru Abe; Mototsugu Nishii; Ichiro Takeuchi

doi:10.1371/journal.pone.0305077

Peer Review History

Original SubmissionJanuary 28, 2024
15 Mar 2024 Decision Letter - Ennio Polilli, Editor PONE-D-24-01802A comparison study of temporal trends of SARS-CoV2 RNAemia and biomarkers to predict success and failure of high flow oxygen therapy among patients with moderate to severe COVID-19PLOS ONE Dear Dr. Koyama, 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 Apr 29 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, Ennio Polilli Academic Editor PLOS ONE Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In this instance it seems there may be acceptable restrictions in place that prevent the public sharing of your minimal data. However, in line with our goal of ensuring long-term data availability to all interested researchers, PLOS’ Data Policy states that authors cannot be the sole named individuals responsible for ensuring data access (http://journals.plos.org/plosone/s/data-availability#loc-acceptable-data-sharing-methods). Data requests to a non-author institutional point of contact, such as a data access or ethics committee, helps guarantee long term stability and availability of data. Providing interested researchers with a durable point of contact ensures data will be accessible even if an author changes email addresses, institutions, or becomes unavailable to answer requests. Before we proceed with your manuscript, please also provide non-author contact information (phone/email/hyperlink) for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If no institutional body is available to respond to requests for your minimal data, please consider if there any institutional representatives who did not collaborate in the study, and are not listed as authors on the manuscript, who would be able to hold the data and respond to external requests for data access? If so, please provide their contact information (i.e., email address). Please also provide details on how you will ensure persistent or long-term data storage and availability. 3. 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: 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: 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: 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 article entitled “A comparison study of temporal trends of SARS-CoV2 RNAemia and biomarkers to predict success and failure of high flow oxygen therapy among patients with moderate to severe COVID-19” by Koyama et al. reports use of chronological trend of laboratory parameters including LDH, IL-6 and SARS-CoV2 RNAemia to predict HFNC failure and success. The manuscript is well-written and I feel that the manuscript is suitable for publication in PLOS ONE after the following issues are addressed: 1. For readers who are not familiar with SARS-CoV2 RNAemia, perhaps brief introduction on SARS-CoV2 RNAemia is needed. 2. IL-6, LDH and SARS-CoV2 RNAemia seem to differ between the failure and success group on or starting from Day 4 – authors need to state clearly that chronological trend of LDH, IL-6 and SARS-CoV2 RNAemia can be predictive markers of late HFNC failure but not early HFNC failure. 3. Table 1: Are the values median or average? The values in parenthesis – are these range or interquartile? 4. In Introduction, the authors stated that ROX index in the early hours of HFNC can be used to predict HFNC failure but the current paper lacks trends in the ROX index following the HFNC treatment. The authors have already addressed this as one of the limitations of study but without comparing the performance of the proposed markers (LDH, IL-6 etc.) to that of ROX index, it may be hard to convince the readers why other markers would be needed. Particularly considering that the ROX index, SpO2%, and SpO2/FiO2 ratio at the time of admission already exhibited significant differences between the failure and success groups (Table 1). Perhaps in addition to Kaplan-Meier Curve, ROC curve can be made and area under ROC curve can be calculated to show specificity and sensitivity of these markers. Reviewer #2: This research study aims to investigate relationship between the failure of high-flow nasal cannula therapy in COVID-19 patients and blood parameters and level of SARs-CoV-2 RNA by performing the longitudinal study. The manuscript well organized and written clearly. The concern I have is on the results and data analyses detail. Although the research appears sound, I have a few concerns that prevent me from accepting the manuscript at the present stage. 1. Please provide detail whether there is any guideline to separate early HFNC failure as <3 day and failure group (on or after day4)? 2. In page 19, please provide data explanation (Figure 2 and Table 2) on day 7 in the text. 3. Since it seems that the laboratory parameter and SARS-CoV2 RNAemia were different among early and late failure, please provide more detail characteristics of the patients between these 2 groups in Table 1 to understand whether there is any baseline difference that might affect patient outcome. 4. In S1 figure, there was a problem with the figure. Only part of figure was shown. ****** 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.0305077.r001
Revision 1
9 May 2024 Author Response We wish to express our appreciation to the reviewers for his or her insightful comments, which have helped us significantly improve the paper. Reviewer #1: The article entitled “A comparison study of temporal trends of SARS-CoV2 RNAemia and biomarkers to predict success and failure of high flow oxygen therapy among patients with moderate to severe COVID-19” by Koyama et al. reports use of chronological trend of laboratory parameters including LDH, IL-6 and SARS-CoV2 RNAemia to predict HFNC failure and success. The manuscript is well-written and I feel that the manuscript is suitable for publication in PLOS ONE after the following issues are addressed: 1. For readers who are not familiar with SARS-CoV2 RNAemia, perhaps brief introduction on SARS-CoV2 RNAemia is needed. Reply: We supplemented the sentence with the clarification: “SARS-CoV2 RNAemia, which indicates the presence of SARS-CoV-2 viral RNA in the bloodstream.” 2. IL-6, LDH and SARS-CoV2 RNAemia seem to differ between the failure and success group on or starting from Day 4 – authors need to state clearly that chronological trend of LDH, IL-6 and SARS-CoV2 RNAemia can be predictive markers of late HFNC failure but not early HFNC failure. Reply: In Table 2 and the result section of the univariate logistic regression, we emphasized “late” failure in the sentences. 3. Table 1: Are the values median or average? The values in parenthesis – are these range or interquartile? Reply: We added a footnote below Table 1 to provide clarification on the presented values as follows: “Notes: Continuous variables are presented as medians with interquartile ranges in square brackets and were analyzed using the Mann–Whitney U test. Categorical variables are presented as numbers and percentages in parentheses and were analyzed using Fisher’s exact test”. 4. In Introduction, the authors stated that ROX index in the early hours of HFNC can be used to predict HFNC failure but the current paper lacks trends in the ROX index following the HFNC treatment. The authors have already addressed this as one of the limitations of study but without comparing the performance of the proposed markers (LDH, IL-6 etc.) to that of ROX index, it may be hard to convince the readers why other markers would be needed. Particularly considering that the ROX index, SpO2%, and SpO2/FiO2 ratio at the time of admission already exhibited significant differences between the failure and success groups (Table 1). Perhaps in addition to Kaplan-Meier Curve, ROC curve can be made and area under ROC curve can be calculated to show specificity and sensitivity of these markers. Reply: We acknowledge the reviewer's observation regarding the absence of a direct comparison between the trends of respiratory parameters and each laboratory marker, which could be considered a limitation of our study, as we also addressed in the discussion section. However, it's crucial to note that in real clinical settings, clinicians often base their judgments not solely on respiratory status but also on laboratory trends following pharmacological intervention. Hence, we believe that our findings offer valuable insights for clinicians. In response to the reviewer's suggestion, we conducted additional analyses to calculate the AUROC of each laboratory marker for predicting HFNC failure, as depicted in S1 Figure in the revised manuscript. The results revealed high AUROC values for LDH and IL-6 on Day 4 in predicting late failure, which aligns with the findings of the univariate logistic regression. These findings collectively suggest that monitoring the trends of LDH and IL-6 post-treatment initiation assists clinicians in estimating disease trajectory. Reviewer #2: This research study aims to investigate relationship between the failure of high-flow nasal cannula therapy in COVID-19 patients and blood parameters and level of SARs-CoV-2 RNA by performing the longitudinal study. The manuscript well organized and written clearly. The concern I have is on the results and data analyses detail. Although the research appears sound, I have a few concerns that prevent me from accepting the manuscript at the present stage. 1. Please provide detail whether there is any guideline to separate early HFNC failure as <3 day and failure group (on or after day4)? Reply: There is no universal definition regarding the timing of HFNC failure to date. In the current study, we categorized the early failure group that failed before the 2-point blood tests on Day 1 and Day 4, and the late failure group that failed after the 2-point blood tests. 2. In page 19, please provide data explanation (Figure 2 and Table 2) on day 7 in the text. Reply: We added the data explanation on Day 7 in the result section as follows: “On Day7, following the exclusion of 5 patients who experienced HFNC failure between Day 4 and Day 7, a significant difference was observed in broader laboratory markers: NL ratio (6.70 vs 25.14, respectively, p<0.001), IL-6 (10.65 vs 30.3, respectively, p=0.003), LDH (410.0 vs 636.0, respectively, p<0.001), and D-dimer (1.60 vs 7.00, respectively, p=0.041) between the success and late failure group”. 3. Since it seems that the laboratory parameter and SARS-CoV2 RNAemia were different among early and late failure, please provide more detail characteristics of the patients between these 2 groups in Table 1 to understand whether there is any baseline difference that might affect patient outcome. Reply: We further conducted a comparison among three groups: success, early failure group, and late failure group. In order to facilitate readers' understanding of the disparities in baseline characteristics, we separately documented these analyses in S1 table, in addition to Table 1. 4. In S1 figure, there was a problem with the figure. Only part of figure was shown. Reply: We revised the legend of S2 figure (S1 figure on the initial manuscript) to provide clarification as follows: “The scatter plot and regression line with a 95% confidence interval (shown in gray) shows a correlation between log-transformed SARS-CoV2 RNA level (vertical axis) and laboratory parameters on Days 1, 4, and 7 (horizontal axis), with the Pearson correlation coefficient (r) indicating the strength and direction of the correlation”. Attachments Attachment Submitted filename: Responce_to_reviewers_HFNC.docx https://doi.org/10.1371/journal.pone.0305077.r002
23 May 2024 Decision Letter - Ennio Polilli, Editor A comparison study of temporal trends of SARS-CoV2 RNAemia and biomarkers to predict success and failure of high flow oxygen therapy among patients with moderate to severe COVID-19 PONE-D-24-01802R1 Dear Dr. Koyama, 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 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, Ennio Polilli Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0305077.r003
Formally Accepted
29 May 2024 Acceptance Letter - Ennio Polilli, Editor PONE-D-24-01802R1 PLOS ONE Dear Dr. Koyama, 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. Ennio Polilli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0305077.r004

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 .