PONE-D-25-06586Does postoperative IL-6 improve early prediction of infection after pulmonary cancer surgery? A two-centre prospective studyPLOS ONE

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“P.G. Noordzij is a member of the advisory board of Roche Diagnostics on the perioperative use of biomarkers. P.G. Noordzij, T.C.D. Rettig and T. Reniers conduct a separate research study on perioperative biomarkers funded by Roche Diagnostics. All other authors have no conflicts of interest.”

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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

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

Reviewer #4: Yes

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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

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: Dear Authors

You have done a fascinating research, but there are some issues that should be solved:

1. Key words must be reconsidered.

2. title is not attracting enough. for this high level kind of work, there must be a better title.

3. the language and the grammar is not acceptable for publication.

4. your references are not up to dated. please provide the latest related references.

5. introduction part has not introduced the Problem.

6. most importantly, the discussion part. you should compare your work to the latest related research's and write what makes your research Distinctive.

7.. you said " The study was preregistered on the 13th

of July 2018, prior to conducting the research with The Netherlands Trial Register (NTR), currently

available via the International Clinical Trial Registry Platform (ICTRP), with registration number NLOMON25075.

Ethical approval of the study protocol was obtained on the 23th of July 2018 by the

‘Toetsingscommissie Wetenschappelijk Onderzoek Rotterdam e.o.’ (TWOR, number NL.64754.101.18)". what took you research so long to be completed? just a question out of curiosity.

Kind regards

Reviewer #2: The study could not elucidate a conclusive findings. The !L-6 biomarker has been hypothized to be associated with post-operative infection which has not been established in this study.

It is concluded in the manuscript that "There are, however, also several limitations. We evaluated the added value of the inflammatory biomarkers relative to a core model based

on clinical reasoning. Ideally we would have investigated incremental value on a validated postoperative

infection risk model in pulmonary surgery. Secondly, the limited sample size resulted in broad confidence

intervals of the c-statistic and other performance measures. As a consequence, a moderate incremental

value may have been missed. Additionally, the sample size was too small to analyse independent

predictive performance relative to open vs. minimal invasive surgery, which is known to affect

postoperative inflammatory biomarker concentrations.(9) Taken together, we cannot conclude yet on the

clinical relevance of IL-6 and CRP demonstrated by these predictive performance measures."

Reviewer #3: Thank you for conducting this interesting study. Here are my comments that help improve the paper.

Short title: I suggest the short title to be “IL-6 to predict infection in pulmonary surgery”

Introduction: It would be better if more detailed information is added on sepsis and inflammation.

Results: The first paragraph under study population section in your result shows the process to reach your sample size and should be in methods and materials section under inclusion & exclusion criteria. Under postoperative infection section, what is the difference between the 28 postoperative infections and the 45 postoperative infection events? Either it should be rewritten or amended based on the actual findings. Please clarify it. In biomarker kinetics section, the concentrations of biomarkers (IL-6, CRP) before and after surgery/operation needs to be clarified. For example, the concentration of IL-6 is 6.1pg/ml (preoperative) and 3.4pg/ml (postoperative); can it be? Clarify.

Introduction: In the result you stated that IL-6 was associated with postoperative infection. However, your discussion/conclusion didn’t support this finding. What is your basis for this conclusion? Justify it.

Reviewer #4: Dear authors,

very good research and the findings add to already existing knowledge we have on the risk of postoperative infections.

Here are a few comments/questions for your attention.

Review: Does postoperative IL-6 improve early prediction of infection after pulmonary cancer

surgery? A two-centre prospective study

General Comments

- Overall some of the findings of this paper are very important. Understanding the added value of IL-6 and CRP levels as an early predictor of infection after pulmonary cancer surgery is essential.

- The knowledge is useful for patient care and aid clinicians to minimize the risk of postoperative infection. Very good attempt by the authors.

Section specific comments

Title

- It could be worded to Does postoperative serum or plasma IL-6 improve early prediction of infection after pulmonary cancer surgery? A two-centre prospective study

- In the manuscript reference is made to blood sample but it’s not clear if plasma or serum was used. Using IL-6 could be misleading, a more specific matrix linked to the IL-6 levels would be appropriate, e.g. serum IL-6 or Plasma IL-6

Summary/Abstract

- Please clarify in the conclusion whether IL-6 is plasma or serum

Introduction

- It is good that the authors mentioned the well-established fact that IL-6 concentrations are elevated after surgery, trauma, and clinical illness.

Methods

- Study procedures and biomarker sampling – the authors mention “Blood samples were drawn from an arterial line directly after induction of general anaesthesia (further referred to as ‘preoperative sample’), and after 6, 9, 12, 24, 48, and 72 hours. Blood samples were

centrifuged and stored in a freezer at -80 °C and shipped to the clinical chemistry lab of the Sint Antonius hospital Nieuwegein for batch analysis.”

a. Can the authors specify what type of blood collection tubes, how many tubes and the volume of blood drawn?

b. Is it correct to assume that EDTA-blood was used for WBC measurements? Authors should provide clarity in the text.

c. What types of matrix was derived from the blood samples that were centrifuged and stored in a freezer at -80 °C? plasma or serum?

d. The goal was to determine if IL-6 and CRP levels observed within the first 24 hours after surgery are associated with postoperative infection risk. What is the justification of not including timepoints 0 and 3 hours?

Results

- In Table 1, there is significant difference for the surgery duration (in minutes) and blood loss between patients with and without postoperative infection. Considering that patients with infection had higher IL-6 levels, did the authors find any correction between the surgery time/intraoperative blood loss with the IL-6 levels?

- Since preoperative (Timepoint 0) and 3 hour postoperative levels of IL-6 were not presented in this study, how do the authors justify that Postoperative peak IL-6 concentrations occurred after 6 hours in the majority of patients?

- Base on the results, can the authors base their findings to IL-6 levels possibly reflect the severity of postoperative infection?

Discussion

- The general presentation in the discussion section looks ok.

- Considering the weight of gender(male) and age to their predictive performance model, the arguments could have benefitted from it although those facts are well established.

- Authors could consider the delta change in these biomarkers respective to the timepoints as a marker of postoperative infection risk, severity and/or recovery outcomes.

Figure 1

Preoperative (Time=0 hours) levels of the biomarkers are shown. Throughout the manuscript, there is no mention of this timepoint sampling. Where did this timepoint come from and were the levels indeed zero?

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Reviewer #1: Yes:  Mohammad Amin Bakhshan

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes:  Daniel Antwi-Berko

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Attachments

Attachment

Submitted filename: Review notes Plos ONE_IL-6.docx

Does postoperative plasma IL-6 improve early prediction of infection after pulmonary cancer surgery? A two-centre prospective study

PONE-D-25-06586R1

Dear Dr. Reniers,

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.

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Kind regards,

Ennio Polilli

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

Reviewer #4: All comments have been addressed

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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

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #4: Yes

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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

Reviewer #4: Yes

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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

Reviewer #4: Yes

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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: Manuscript has been improved

Still the title can be improved further to become more meaningful

The conclusion should be more clear and precise. Concrete findings would be more helpful for further studies...

Reviewer #4: (No Response)

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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: Yes:  Mohammad Amin Bakhshan

Reviewer #2: No

Reviewer #4: Yes:  Daniel Antwi-Berko

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