PONE-D-23-19398CAN SERUM INTERLEUKIN 34 LEVELS BE USED AS AN INDICATOR FOR THE PREDICTION AND PROGNOSIS OF COVID-19?PLOS ONE

Dear Dr. karahan,

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 Mar 15 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,

Nilanka Perera, MD, PhD

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. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.  

Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services.  If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.

Upon resubmission, please provide the following: 

● The name of the colleague or the details of the professional service that edited your manuscript

● A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file)

● A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

3. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.mdpi.com/2075-4426/11/9/891/htm

https://academic.oup.com/jleukbio/article-abstract/104/5/931/6935404?redirectedFrom=fulltext&login=false

https://pubmed.ncbi.nlm.nih.gov/29313563/

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

4. In the online submission form, you indicated that "The data is available from the author and will be provided if needed.". 

All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.

This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. 

5. 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. 

Additional Editor Comments:

1. The sample size of 40 (20 in critically ill and non-severe categories) is not clear. Please justify how you arrived at the sample size to address the research questions.
2. Statistical analysis mention that data in a skewed distribution is given as median (max-min). Tables have median (IQR). Please correct the text.
3. Figure legends are not adequate. It should stand out. Please describe the figures appropriately. 
4. Make sure that sentences do not start with a number. Please edit
5. References: Some have the doi while others do not. Add the doi for all references
6. Conclusion: One sentence on mortality due to thromboembolic phenomenon is not appropriate to the results of the study. Should conclude based on the current study results.
7. Describe the ICU group (ventilator req, NIV support...etc). 

[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: No

**********

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: While the authors' attempt to find answers to dilemmas of clinical significance is greatly appreciable, there are a few things that warrant further clarification.

1. Firstly, have all the COVID-19-positive patients (excluding dexamethasone administration and age <18) mentioned in the said period between 01.09.2022 and 24.10.2022 included in the study?

2. Were patients whose IL-34 levels drawn before dexamethasone administration included in the study? How come the ICU patients included in the study not receive dexamethasone?

3. How was the control group selected? While the COVID-19-negative patients were included in the study, on what basis were the specific 40 patients selected?

4. Why were patients with CO-RADS 3 eliminated from the study?

5. Were the autoimmune or cancer history evaluated for the included patients to see if either is contributing to the elevated IL-34?

6. Was upper respiratory viral panel tested on all the patients? Was the possibility of concurrent viral infections causing elevated IL-34 evaluated?

7. Line 189-190 appears to be an incomplete sentence.

8. What is the relevance of Paragraph 4 i.e. Line 193-208 for this study?

As mentioned earlier, this is a great topic of relevance that the authors have targeted. However, the authors should provide concrete evidence to strongly support the study's conclusion eliminating all confounding factors.

Reviewer #2: In this study, IL-34 levels were studied in 40 COVID-19- positive patients and 40 COVID-19- negative patients to provide information about the disease's diagnosis, severity, and prognosis. They found that IL-34 was successful in predicting the diagnosis of COVID-19.

This is a very original work, but I have some objections and questions:

1- The number of patients studied is small.

2- The characteristics of ICU patients need to be clarified (such as their underlying diseases, disease severity, respiratory support treatments they receive, severity of lung involvement, given treatments other than steroids, etc.)

3- Why were patients tested for hs-CRP instead of CRP? In addition, why were lipid profile and troponin I examined in the patients? IL-34 has been associated with cardiovascular complications in some COVID studies (see references provided). Did the authors have such a purpose in this study?

Clinical Implications of IL-32, IL-34 and IL-37 in Atherosclerosis: Speculative Role in Cardiovascular Manifestations of COVID-19.

Law CC, Puranik R, Fan J, Fei J, Hambly BD, Bao S.Front Cardiovasc Med. 2021 Aug 6;8:630767. doi: 10.3389/fcvm.2021.630767.

Association of Interleukin-32 and Interleukin-34 with Cardiovascular Disease and Short-Term Mortality in COVID-19.

Kaufmann CC, Ahmed A, Muthspiel M, Rostocki I, Pogran E, Zweiker D, Burger AL, Jäger B, Aicher G, Spiel AO, Vafai-Tabrizi F, Gschwantler M, Fasching P, Wojta J, Huber K.J Clin Med. 2023 Jan 27;12(3):975. doi: 10.3390/jcm12030975.

4- The introduction and discussion part of the article are very long. Especially in the discussion section, between lines 193 and line 257 contain unnecessary details. If the information here is desired to be associated with the study results or the purpose of the study, more effort should be made to clarify.

5- Many parts of the article mentioned that IL-34 is an essential determinant in diagnosing COVID-19, and even the authors gave a cut-off value, saying that "IL-34 levels higher than 31.75 pg/mL can predict COVID-19". I have an objection to this finding and its interpretation.

COVID-19 is diagnosed by performing a PCR test on the taken samples to show the SARS-CoV-2 virus. IL-34 and other cytokines are shaped according to the immune response of the person (host) and determine the severity of the disease, organ involvement, and prognosis.

**********

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: Gulbin Aygencel

**********

[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.

PONE-D-23-19398R1Can serum interleukin 34 levels be used as an indicator for the prediction and prognosis of COVID-19?PLOS ONE

Dear Dr. karahan,

Thank you for revising  your manuscript and addressing majority of reviewer comments. As there is a minor suggestion to improve the paper, we suggest you to edit and submit the revision to consider for publication.  

==============================

Please submit your revised manuscript by May 03 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,

Nilanka Perera, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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. 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: I appreciate the authors clarifying the questions posed. Couple of unanswered questions.

1. How come the ICU patients included in the study did not receive

dexamethasone?

2. Were the autoimmune or cancer history evaluated for the included patients to see if either is contributing to the elevated IL-34? While this question was partly clarified, did any of the patients get serologic testing for antibodies? Or were assumed to be negative based on clinical history. Especially with COVID having a lot of respiratory and renal failure similar to a lot of pulmonary/renal syndromes associated with vasculitis, were they definitely ruled out?

3. I would recommend some of the explanations here be incorporated into the article for better clarity.

Reviewer #2: (No Response)

**********

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: 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.

Can serum interleukin 34 levels be used as an indicator for the prediction and prognosis of COVID-19?

PONE-D-23-19398R2

Dear Dr. karahan,

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,

Nilanka Perera, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: