PONE-D-23-32136Application of the Sepsis-3 criteria to describe sepsis epidemiology in the Amsterdam UMCdb intensive care datasetPLOS ONE

Dear Dr. Edinburgh,

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 Feb 18 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,

Dong Wook Jekarl

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. Note from Emily Chenette, Editor in Chief of PLOS ONE, and Iain Hrynaszkiewicz, Director of Open Research Solutions at PLOS: 

Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data).

3. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

"TE is funded by Engineering and Physical Sciences Research Council (EPSRC) National Productivity

Investment Fund (NPIF) EP/S515334/1, reference 2089662. A CC BY or equivalent licence is applied

to the AAM arising from this submission. We would like to thank Professor Stephen J Eglen for his

supervision and mentorship of TE’s PhD."

Please be informed that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

"TE is funded by Engineering and Physical Sciences Research Council (EPSRC) National Productivity Investment Fund (NPIF) EP/S515334/1, reference 2089662."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. Thank you for stating the following financial disclosure: 

"TE is funded by Engineering and Physical Sciences Research Council (EPSRC) National Productivity Investment Fund (NPIF) EP/S515334/1, reference 2089662."

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

5. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). 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 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 recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

7. 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

Reviewer #3: Yes

Reviewer #4: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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: PONE-D-23-32136

Williams et al present an analysis of the epidemiology and sepsis in patients in a mixed ICU in the Netherlands using the open access Amsterdam UMCdb. Overall they have several interesting findings, including that a significant proportion of patients progressed from sepsis to septic shock and a relatively lower mortality associated with sepsis than non-infectious conditions. The results are presented clearly, the figures are clear and support the manuscript, and the discussion in appropriate. My main concern (as highlighted below) is on the comparison between patients who received less vs greater than 4 days of antibiotics (this led to me marking “No” under “Has the statistical analysis been performed appropriately and rigorously?”).

COMMENTS

1. Methods, Identification of sepsis and septic shock – how did you define “a new course of antibiotics”? Could this have been just for one or two days? The concern would be including sick patients who get empiric antibiotics but then the providers quickly realize that they have a non-infectious illness.

2. Methods – were you able to gather data for patients after they left the ICU, or just while in the ICU? After reading the discussion I realize the answer but this should be clear in the methods and is important when considering duration of antibiotic therapy (among other variables).

3. Results, identification of sepsis and septic shock – how did the authors define when an episode “ended” (and therefore when the patient would be eligible for a new episode)?

4. Results, identification of sepsis and septic shock – For the sensitivity analysis requiring 6+ hours of NA infusion, what was the difference that was statistically significant? This is confusing as written and I am unsure what the comparison is here.

5. Results, identification of sepsis and septic shock – the last sentence of this section reports shorter LOS among patients who received < 4 days antibiotics than patients who received > 4 days antibiotics. However, if you don’t capture antibiotics that were prescribed after patients left this ICU, then patients probably got shorter antibiotic durations because they were discharged (instead of being discharged once they stopped antibiotics and where therefore “better”). Please clarify.

6. Results, ICU mortality – the discussion here about <4 vs >4 days antibiotics is confusing for similar reasons as above.

7. Table 1. I am a little surprised that only 57.9% and 42.0% of patients with sepsis and septic shock, respectively, received 4 days of antibiotics. This gets back to comment #1 – did these patients receive short antibiotic courses? I would assume that patients who actually had sepsis or septic shock would receive > 5-7 days of antibiotics (unless they died or were discharged)

8. Figure 6 – recommend re-labeling the titles for panels c-f to be “Survival curves among patients with…” to make these panels clearer and harmonize with panels a and b.

9. Figure S1 – at what timepoint did you define the outcome? Ie, how long did you follow patients to determine whether they were still in the ICU?

10. Table S2 – as above, unless I am confused about which patients were eligible to receive < 4 vs >4 days of antibiotics, then I am not sure this is an appropriate comparison.

Reviewer #2: Generally is a very interesting manuscript. However:

English language editing is needed.

Legends with explanations under ever figure are needed

it would be very interesting if authors added the causes of death in both subgroups (> 4 days and < 4 days.)

Reviewer #3: Despite the fact that this is a retrospective cohort study, with limited information prior to and after ICU admission, it is a remarkable study, giving unique information on sepsis epidemiology according to Sepsis-3 definition. Well-wrighten, well-designed study and great depiction of the results. Well-structured discussion with appropriate focus on study insights and previous investigation. The inclusion of Ethics Approval number for secondary research and statement of harmonization with the Helsinki Declaration would be appreciated as informed consent is waived.

Reviewer #4: The manuscript is well-written and thorough. The authors have provided comprehensive and detailed data and offered information on various epidemiological aspects of septic patients in the ICU using Sepsis-3 criteria. The research article features an advanced-level statistical analysis that ensures high quality. The conclusions are supported by the data and cover essential aspects for clinicians. I appreciate that you mentioned the disparity in the frequency of particular antibiotics among various ICUs due to the varying resistance profiles.

The infection was defined as a new course of antibiotics or an escalation in antibiotic therapy. In the primary analysis, the performance of microbial cultures was not considered in the diagnosis of infection. How did the clinicians decide to initiate the antibiotic treatment if not based on cultures? It will be interesting to know if they used some biomarkers (CRP, procalcitonin).

In the methods section, it may be helpful to mention the measurement of survival probability using Kaplan-Meier curves, as this is already described in the figures section.

I would like to ask for clarification on the exclusion criteria. Between paragraphs one and four of the methods, there is a difference in the day of admission when the SOFA score was measured. Is day 0 set as the first day of admission?

If the Amsterdam ICU’s protocols are published somewhere it would be interesting to be cited.

I would like to share a few minor comments. I would suggest that the percentages have the same form: numbers or letters. For example, paragraph three of the Results section: “Seventy-three percent (2,423/3,304) of ICU admissions for sepsis without shock were associated with IV antibiotics for at least 4 days or until end of ICU stay, compared to 84.0% (1,389/1,654) admissions with septic shock.”, or paragraph 3 of the abstract: “Forty-eight percent of emergency medical admissions and 37.0% of emergency surgical admissions were for sepsis.”

Some additional corrections: We sought to apply the Sepsis-3 criteria "to" characterise the septic cohort in the Amsterdam University Medical Centres database (Amsterdam UMCdb).

Because pre-ICU data "are" limited in the Amsterdam UMC database.

**********

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: Yes: Max Adelman

Reviewer #2: Yes: Maria Lagadinou

Reviewer #3: Yes: Michailides Christos

Reviewer #4: Yes: Charikleia Chourpiliadi

**********

[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.

Application of the Sepsis-3 criteria to describe sepsis epidemiology in the Amsterdam UMCdb intensive care dataset

PONE-D-23-32136R1

Dear Dr. Edinburgh,

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,

Dong Wook Jekarl

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: