PNTD-D-24-01734

Association between serum ferritin and mortality in patients with severe fever with thrombocytopenia syndrome�a retrospective cohort study

PLOS Neglected Tropical Diseases

Dear Dr. Yang,

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Kind regards,

Gregory Gromowski

Academic Editor

PLOS Neglected Tropical Diseases

Abdallah Samy

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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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?

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Reviewer #1: T

Reviewer #2: Wenyan Xiao et al retrospective analysis using data from patients diagnosed with SFTS at the Second Affiliated Hospital of Anhui Medical University,and found the association between serum ferritin levels and in-hospital mortality in patients with SFTS, a study with a relatively large sample, also had some important findings.

Reviewer #3: (No Response)

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: 1) Single-center, retrospective study.

2) The changes of serum ferritin levels were not dynamically displayed and analyzed.

Reviewer #3: After PSM, SMD should be reported.

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: 3) The stage changes of acute viral infection and the course of the disease significantly affect the results of laboratory tests, that is, in the critical stage of SFTS infection, especially when accompanied by multiple organ damage such as pancreatitis, encephalitis, etc., the inflammatory markers and serum ferritin levels of patients will be significantly increased.

4) Therefore, the level of serum ferritin is uncertain in the course of disease, but it will obviously increase in the case of multiple organ inflammation. At this time, the predictive role of serum ferritin is not very important.

Reviewer #3: Further explanation is needed regarding why serum ferritin is associated with increased mortality. Is it due to sepsis (DOI: 10.3389/fnut.2021.747547) or cytokine storm (DOI: 10.1038/s41467-022-34560-7; 10.1038/s41584-022-00899-w)?

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: The paper reported an association between serum ferritin and mortality in patients with severe fever with thrombocytopenia syndrome (SFTS). It was found that serum ferritin levels are linearly associated with the mortality risk in SFTS patients. Specifically, when serum ferritin levels exceed 10,000 ng/ml, the mortality rate significantly increases. Thus, serum ferritin levels may serve as a valuable prognostic biomarker for assessing the mortality risk in SFTS patients. The study is well - designed, and its results are highly useful for predicting the prognosis of SFTS.

1. Results: Regarding the results section, particularly the "receiver operating characteristic (ROC) curve of serum ferritin for predicting in - hospital mortality in patients with SFTS", the authors are recommended to offer more detailed information. This could include aspects such as the area under the curve (AUC) value, the optimal cut - off point determined from the ROC analysis, and the sensitivity and specificity values at different thresholds. Such additional details would enhance the comprehensiveness and interpretability of the results.

2. Serum ferritin is generally regarded as having both pro - inflammatory and anti - inflammatory properties. Its function is intricate and context - dependent. As a result, it cannot be simply classified as a strictly pro - inflammatory or anti - inflammatory marker. In different physiological and pathological conditions, serum ferritin can exhibit diverse effects on the inflammatory response. For example, in certain acute - phase responses, it may act as a pro - inflammatory factor by being upregulated in response to inflammatory cytokines. However, in maintaining iron homeostasis, it can play an anti - inflammatory role by regulating the availability of iron, which is crucial for immune cell function and the prevention of oxidative stress - related inflammation.

3. Throughout the text, some minor adjustments have been made to enhance the fluency and clarity of the English.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

Summary and General Comments :

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Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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Reviewer #1: Yes:  Quan Liu

Reviewer #2: No

Reviewer #3: No

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Dear Dr. Yang,

We are pleased to inform you that your manuscript 'Association between serum ferritin and mortality in patients with severe fever with thrombocytopenia syndrome�a retrospective cohort study' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

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

Best regards,

Gregory Gromowski

Academic Editor

PLOS Neglected Tropical Diseases

Abdallah Samy

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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