PNTD-D-24-01931

Unveiling Fatal Complications: Predicting Hemophagocytic Lymphohistiocytosis in SFTS Patients

PLOS Neglected Tropical Diseases

Dear Dr. Zhang,

Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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 within 60 days Jun 01 2025 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 plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Richard A. Bowen, DVM PhD

Academic Editor

PLOS Neglected Tropical Diseases

Andrea Marzi

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Additional Editor Comments:

Thank you for your submission. Your manuscript has been reviewed by three experts and they offer suggestions for improvement. Please evaluate their comments, edit your manuscript and respond to those comments. We look forward to seeing a revised version.

Journal Requirements:

1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: Bo Zhang, Jia-le Gong, Hao-long Zeng, and Qin Liao. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

The list of CRediT author contributions may be found here: https://journals.plos.org/plosntds/s/authorship#loc-author-contributions

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https://journals.plos.org/plosntds/s/submission-guidelines#loc-parts-of-a-submission

3) We have noticed that you have uploaded Supporting Information files, but you have not included a list of legends. Please add a full list of legends for your Supporting Information files after the references list.

4) In the online submission form, you indicated that "The data for this study can be made available upon reasonable request to the corresponding author, Due to privacy and confidentiality concerns, the relevant datasets are not publicly available.". All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either

- In a public repository

- Within the manuscript itself

- Uploaded as supplementary information.

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Reviewers' Comments:

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods:

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The objectives for this paper – identifying predictive biomarkers for HLH and markers for. HLH mortality – are clearly stated. There are no citations provided for the methods section, however, and therefore it is difficult to ascertain whether the methods used were appropriate or if they were novel to the manuscript. Additionally, in 102, the author refers to a “big data platform”, please provide the specific data platform. The n-size for the total population and the population that were HLH positive appear appropriate to address the objective of this manuscript.

Results:

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The analysis presented matches the analysis plan. The results are clear and completely presented. The figures do appear slightly blurry, and this should be fixed before publication, but the content of the figures is clear.

Conclusions:

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The conclusions drawn are clearly supported by the data presented. The authors additionally contextualize their findings within the larger body of research or attempt to explain how their work disagrees with prior studies (i.e., the diarrhea results). The authors do discuss some limitations to their work, and while some are very clear, such as markers that could have been studied, some are far too vague. Specifically, the authors should expand on the phrase “influencing factors may not have been included”. Overall, this manuscript has significant public health relevance, as it provides critical diagnostic criteria and relationships between them to predict HLH.

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: ※Minor comments:

1.What is the full name of APTT in line 113?

2.It is necessary to correct the usage of spacing in the manuscript, as there were many errors (line 114, 121, 123, 125, 127, 151~155, Table 1~3, 166, 169, 171, 190~195, and etc…). For example: in table 1 '(n=272)', the letter 'n' should be italicized, and there should be a single space between each character like ‘(n = 272)’.

Reviewer #2: (No Response)

Reviewer #3: In general, the paper should be reviewed for grammatical errors, such as in Line 90, which should say “We gathered hospitalized SFTS patients…”

Summary and General Comments:

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: ※Major comments:

1.The authors of this study provide insufficient explanation regarding the changes in the blood coagulation mechanism associated with increased procalcitonin (PCT) levels. The hypothesis that PCT elevation worsens the prognosis of SFTS patients by enhancing systemic inflammation lacks sufficient supporting evidence. Providing a discussion on the correlation between PCT and disseminated intravascular coagulation (DIC) would strengthen the argument. Additional explanation in the Discussion section is essential.

2."In Table 1&2, which compares non-HLH and HLH patients, the HLH-classified group shows increased APTT and TT, decreased fibrinogen, and increased D-dimer, all indicating reduced blood coagulation activity. This could suggest that SFTS patients diagnosed with HLH may have impaired coagulation function, potentially leading to a lower incidence of DIC. However, as the authors mentioned in lines 268–269, critical SFTS patients are at high risk due to progression to DIC and MODS, which seems contradictory. Furthermore, as seen in the outcome data, patients classified as HLH show a significantly higher mortality rate. The authors appear to have skipped an in-depth discussion of this discrepancy and moved directly to analyzing risk factors in HLH-classified SFTS patients. A more thorough discussion of Table 1&2 is essential to provide a clearer interpretation of these findings.

3.Based on the title of the paper, one might anticipate that the research focuses on distinguishing HLH among SFTS patients. However, the precise final conclusion of this study is the identification of important factors for assessing the risk of SFTS patients classified as HLH. Therefore, I believe it is necessary to revise the title.

Reviewer #2: (No Response)

Reviewer #3: Zhang and their collaborators set out to identify biomarkers to predict HLH in SFTS patients and, further, predict mortality amongst HLH patients. This work involved comprehensive blood panels and statistical analysis on 272 SFTS patients from Tongji Hospital. Their analysis identified that platelet counts, ALT/AST ratios, LDH, and DD were all predictive risk factors for HLH. They also determined that Age, fibrinogen (FIB), and procalcitonin (PCT) were all strong predictors of mortality due to HLH. These results allowed the authors to establish diagnostic thresholds that can be used by other doctors when treating SFTS and SFTS-HLH patients. On its face, this paper is a significant step forward towards understanding and combating SFTS. However, this paper is not without issues, some of which are major and some minor, that must be addressed before it is accepted. The primary issue that requires significant revisions is that the authors failed to provide any citations within the methods section. I am unable to determine whether the methods used are novel or adapted from existing work due to the absence of citations, which makes it impossible to evaluate the study's originality and reproducibility. The secondary issue is that the limitation section, particularly when discussing confounding factors, is too vague to be interpreted appropriately. Once these two issues are addressed, I see no reason why this manuscript should not be accepted.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: PNTD-D-24-01931_reviewer_submitted.pdf

PNTD-D-24-01931R1Unveiling Fatal Risk Factors: Predicting Hemophagocytic Lymphohistiocytosis in SFTS PatientsPLOS Neglected Tropical Diseases Dear Dr. Zhang, Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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 within 30 days Jul 03 2025 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 plosntds@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pntd/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers '. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Richard A. Bowen, DVM PhD

Academic Editor

PLOS Neglected Tropical Diseases

Andrea MarziSection EditorPLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

Additional Editor Comments : Thank you for modifying your manuscript to address reviewer comments - I think we both agree that it is significantly improved. I would ask that you make two further minor revisions if possible:

1) Figures 1 and 2 remain low quality and will not be good for publication - are you able to re-create them in a higher quality form? The new Figure 3 looks much improved.

2). The precision of numbers in tables is excessive and unnnecessary. For example: Table 1, first 2 lines have Females as 148 (54.412) and Males as 45.558. Please change these to 54.4 and 45.6% respectively. Please do the same for all of the numbers presented in your tables, restricting all figures to 1 number after the decimal point. Thank you - that will improve readability. Journal Requirements:

1) Thank you for stating "All authors declare that there is no conflict interest." If you have no competing interests to declare, please state "The authors have declared that no competing interests exist"

[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.]

Figure resubmission: 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. If there are other versions of figure files still present in your submission file inventory at resubmission, please replace them with the PACE-processed versions. Reproducibility: To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Mr Zhang,

We are pleased to inform you that your manuscript 'Unveiling Fatal Risk Factors: Predicting Hemophagocytic Lymphohistiocytosis in SFTS Patients' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Richard A. Bowen, DVM PhD

Academic Editor

PLOS Neglected Tropical Diseases

Andrea Marzi

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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Thank you for modifying your manuscript in response to reviewer and editor suggestions. It will be a valuable contribution to the field.