Specific patterns of vital sign fluctuations predict infection and enable sepsis diagnosis in pediatric burn patients

Farzin Sadeq; Jonah Poster; Chris Chu; Joan Weber; Martha Lydon; Maggie Dylewski Begis; Robert Leo Sheridan; Korkut Uygun

doi:10.1371/journal.pone.0263421

Peer Review History

Original SubmissionSeptember 27, 2021
18 Oct 2021 Decision Letter - David G. Greenhalgh, Editor PONE-D-21-31157Specific patterns of vital sign fluctuations predict bloodstream infection in pediatric burn patientsPLOS ONE Dear Dr. Uygun, 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 Dec 02 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). 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, David G. Greenhalgh, MD 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. 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 Additional Editor Comments: Academic Editor: Please address the concerns of the reviewers and we will re-evaluate the paper. [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: 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: This is an interesting article that highlights the importance and difficulty of diagnosing sepsis in the setting of severe burn injury. I have some concerns for the authors: 1. It seems from the data that MAP dips are the most relevant correlation with sepsis. I suggest that a multivariate regression analysis would provide a better insight into the weight or importance of MAP dips relative to other variables. 2. What is the time frame between MAP dips and other variables (fever, HR spikes)? In other words, do these events occur within a similar time frame or do they only occur within the same 24 hour period but do not occur within an hour of each event. 3. Does the time frame between each variable event correlate to sepsis prediction or accuracy? For example, do events that occur relatively close together (fever, HR spikes, and MAP dips) lead to a more accurate sepsis prediction? Reviewer #2: The authors presented a manuscript examining the fluctuation in patterns of simple vital signs data to predict “diagnose” blood stream infection in paediatric burn patients. They included retrospective data from 200 children with >20% TBSA. This work builds on their previously published research of the role of temperature patterns to predict blood stream infection. I thoroughly enjoyed reading the manuscript, it is well written, referenced, and a good study design despite the package of limitations that comes with retrospective studies. The strength of the study is taking positive blood culture as the “golden standard/reference standard” for defining sepsis rather than other scoring systems that are either not validated or have low reliability. Others have used clinical diagnosis of burn specialist surgeons and critical care physicians as the reference standards for validation to avoid this problem. Furthermore, all these current sepsis scores are difficult to apply to paediatric burns patients. Early diagnosis of sepsis and immediately initiating management was shown to save many lives of our patients. In future, advancement of bedside microbiological sequencing may give all clues that clinicians need for our sick burn patient. However, until then, a simple clinical algorithm would be extremely useful to diagnose sepsis, confidently and reliably. This manuscript is an important step in this path and may lead to a simple global sepsis scoring criteria for early paediatric burn sepsis diagnosis. I’d congratulate the author on perusing a simple solution for a very difficult problem and I am looking forward seeing the data from their prospective ongoing project. My comments are: 1. Title: I fully understand the authors are factual and careful with the title wording. As I personally believe this study would be a step forward in sepsis diagnosis in paediatric burn patients, I would suggest using the keywords (sepsis, diagnosis), to be straight to the point. 2. The whole dilemma of burn sepsis scorings is ‘sepsis definition’ and setting ‘Reference Standard/Golden Standard’ to check the reliability of a new scoring system. The authors used Positive Blood Culture (PBC), which is superior to other unvalidated or unreliable scores as definition, however, there are problems regarding interpretations of PBC in clinical practice. Would the author please elaborate why PBC was used and its limitations? Would the authors discuss their views using the “clinical diagnosis of sepsis by burn specialist surgeon and critical care physician” for sepsis definition as reported by Yan et al, 2018, as a reference standard for future trials? 3. The authors have explained the use of empiric antibiotics after taking blood cultures and the effect on vital signs. Would they please elaborate on how many started the therapy and when, in each group? 4. It would be interesting to the reader if the authors elaborate on why this simple scoring system has lower specificity than sensitivity? Would that be related to the use of PBC as the ‘Reference Standard’? ****** 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:** Naiem S Moiemen [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.0263421.r001
Revision 1
13 Dec 2021 Author Response Reviewer #1: This is an interesting article that highlights the importance and difficulty of diagnosing sepsis in the setting of severe burn injury. I have some concerns for the authors: Thank you for your insightful comments to add clarity on the study methods and analyses for our article. Please see our comments below. 1. It seems from the data that MAP dips are the most relevant correlation with sepsis. I suggest that a multivariate regression analysis would provide a better insight into the weight or importance of MAP dips relative to other variables. Author Response: We have performed two multivariate regression analyses to determine the weight of each independent variable (fever spikes, HR spikes and MAP dips) relative to the other variables. Our regression analyses found that HR spikes were significant and held more statistical weight in the prediction metric than MAP dips or fever spikes. Location of Revision: 124-125, 207-211 2. What is the time frame between MAP dips and other variables (fever, HR spikes)? In other words, do these events occur within a similar time frame or do they only occur within the same 24 hour period but do not occur within an hour of each event. Author Response: The variables (fever spikes, HR spikes and MAP dips) all occurred within the same 24 hour study timeframes, however the variables did not occur within an hour of each other. Location of Revision: 353-355 3. Does the time frame between each variable event correlate to sepsis prediction or accuracy? For example, do events that occur relatively close together (fever, HR spikes, and MAP dips) lead to a more accurate sepsis prediction? Author Response: While we did not detect any immediate trends between the timing of measurements and sepsis accuracy, future studies would benefit from a larger sample size. The exact timing of the measurements depends on a large number of factors and notions in the clinic setting, and therefore it would take a significantly larger patient study sample to be able to analyze such trends. We are currently working on acquiring multi-hospital data sets to achieve such analyses. Location of Revision: 355-360 Reviewer #2: The authors presented a manuscript examining the fluctuation in patterns of simple vital signs data to predict “diagnose” blood stream infection in paediatric burn patients. They included retrospective data from 200 children with >20% TBSA. This work builds on their previously published research of the role of temperature patterns to predict blood stream infection. I thoroughly enjoyed reading the manuscript, it is well written, referenced, and a good study design despite the package of limitations that comes with retrospective studies. The strength of the study is taking positive blood culture as the “golden standard/reference standard” for defining sepsis rather than other scoring systems that are either not validated or have low reliability. Others have used clinical diagnosis of burn specialist surgeons and critical care physicians as the reference standards for validation to avoid this problem. Furthermore, all these current sepsis scores are difficult to apply to paediatric burns patients. Early diagnosis of sepsis and immediately initiating management was shown to save many lives of our patients. In future, advancement of bedside microbiological sequencing may give all clues that clinicians need for our sick burn patient. However, until then, a simple clinical algorithm would be extremely useful to diagnose sepsis, confidently and reliably. This manuscript is an important step in this path and may lead to a simple global sepsis scoring criteria for early paediatric burn sepsis diagnosis. I’d congratulate the author on perusing a simple solution for a very difficult problem and I am looking forward seeing the data from their prospective ongoing project. My comments are: Thank you for your insightful comments to add clarity on the study methods and discussion for our article. Please see our comments below. 1. Title: I fully understand the authors are factual and careful with the title wording. As I personally believe this study would be a step forward in sepsis diagnosis in paediatric burn patients, I would suggest using the keywords (sepsis, diagnosis), to be straight to the point. Author Response: Thank you for bringing this to our attention. We have amended the title of the article to “Specific patterns of vital sign fluctuations predict infection and enable sepsis diagnosis in pediatric burn patients” to further clarify the main objectives of the study. Location of Revision: 4-5 2. The whole dilemma of burn sepsis scorings is ‘sepsis definition’ and setting ‘Reference Standard/Golden Standard’ to check the reliability of a new scoring system. The authors used Positive Blood Culture (PBC), which is superior to other unvalidated or unreliable scores as definition, however, there are problems regarding interpretations of PBC in clinical practice. Would the author please elaborate why PBC was used and its limitations? Would the authors discuss their views using the “clinical diagnosis of sepsis by burn specialist surgeon and critical care physician” for sepsis definition as reported by Yan et al, 2018, as a reference standard for future trials? Author Response: Positive blood cultures are used at our pediatric burn institution as the current reference standard because they are superior in sepsis accuracy, compared to other unvalidated scoring systems. However, it is also possible to miss infections using blood cultures alone, and the clinical team will often order pan (sputum and urine) cultures for further accuracy. Before obtaining the positive blood cultures, the clinical team correctly administered empiric antibiotics for 38 patients in the infection group. We were unable to confirm antibiotic use in 11 patients due to limited access to medical records prior to 2011. The clinical team incorrectly administered empiric antibiotics for 35 patients in the control group, which were later confirmed by the routine negative blood cultures. The clinical team correctly diagnosed 11 patients that did not require empiric antibiotics during their inpatient stay. The Yan et al. study suggests that using clinical diagnoses made by the clinical team as the reference standard is a strong approach for timely identification of sepsis in burn patients. We agree with a similar approach reported by Yan et al., as clinician diagnoses are based on clinical signs of sepsis, such as vital sign fluctuations. The main motivation behind this current study was to develop a rigorous predictive metric that statistically interpreted these clinical signs of sepsis already used by the clinical team to enable sepsis diagnoses. 3. The authors have explained the use of empiric antibiotics after taking blood cultures and the effect on vital signs. Would they please elaborate on how many started the therapy and when, in each group? Author Response: In the infection group, 38 patients were confirmed to be on antibiotics during the study timeframe. We were unable to confirm the use of antibiotics in 11 patients in the infection group due to limited access to medical records prior to 2011. In the control group, 35 patients were confirmed to be on antibiotics during the study timeframe, and 11 patients were confirmed to not require antibiotics during their inpatient stay. Location of Revision: 301-305 4. It would be interesting to the reader if the authors elaborate on why this simple scoring system has lower specificity than sensitivity? Would that be related to the use of PBC as the ‘Reference Standard’? Author Response: We believe that the simple scoring system has a lower specificity than sensitivity because a few of the patients tend to narrowly miss the cutoff for spikes. It is possible that a longer observation period may increase the accuracy of the cutoff for spikes, which has been the case for predicting infections in our prior work. Location of Revision: 272-275 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0263421.r002
19 Jan 2022 Decision Letter - David G. Greenhalgh, Editor Specific patterns of vital sign fluctuations predict infection and enable sepsis diagnosis in pediatric burn patients PONE-D-21-31157R1 Dear Dr. Uygun, 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, David G. Greenhalgh, MD 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: Thank you for addressing all of my concerns. The paper is well written and worthy of publication. This adds to the current literature on identifying sepsis in burn patients. Reviewer #2: Thanks for addressing all the comments. Surely this has strengthened the manuscript. I believe this work would be a good addition to the literature that is definitely in need of similar contributions. I hope your finding would be validated in a multi-centre trial in the near future. Congratulations for the good work ****** 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:** Dr. Naiem Moiemen https://doi.org/10.1371/journal.pone.0263421.r003
Formally Accepted
28 Jan 2022 Acceptance Letter - David G. Greenhalgh, Editor PONE-D-21-31157R1 Specific patterns of vital sign fluctuations predict infection and enable sepsis diagnosis in pediatric burn patients Dear Dr. Uygun: 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. David G. Greenhalgh Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0263421.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 .