Dear Associate Research Fellow Huang,

Thank you very much for submitting your manuscript "Major acute cardiovascular events after dengue infection– A population-based observational study" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

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[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

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[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

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Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Husain Poonawala

Associate Editor

PLOS Neglected Tropical Diseases

Paul Newton

Deputy Editor

PLOS Neglected Tropical Diseases

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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: all are yes.

Reviewer #2: Yes.

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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: all are yes.

Reviewer #2: The analysis presented match she analysis plan and the results are clearly and completely presented. However, a table describing the demographic characteristics of all the groups included in the study, including the individuals who had influenza and onychomycosis, should be added.

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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: all are yes.

Reviewer #2: Yes,

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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: age group (0-40 years, “40-60 years” [41-60 years?], and >60 years).

Reviewer #2: (No Response)

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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: The current study was aimed to evaluate the association between Dengue virus (DENV) infection and major adverse cardiovascular events (MACEs, including acute myocardial infarction [AMI], heart failure and stroke). This is a population-based observation study. All laboratory confirmed dengue cases in Taiwan during 2009 and 2015 were included by Center for Disease Control (CDC) notifiable database. The primary outcome of the incidence of MACEs within one year of dengue was observed in 1,247 patients. They found that AMI, stroke and heart failure are significantly higher in the immediate time period (within one week) after dengue infection, especially in patients with >60 years of age, female gender and severe admission dengue cases. The authors concluded that cardiovascular events triggered by dengue virus are potentially preventable. Patients with dengue fever should be carefully monitored during the acute phase of disease to ensure early recognition of symptoms of AMI, stroke or heart failure. Whether dengue virus vaccination reduces the risk of MACEs in patients with a high risk of cardiovascular disease is an intriguing question.

This is an interesting study with some novel findings and clinical implications. The study was well-conducted. The conclusions were supported by the results. The manuscript was well-written.

Some points concerned:

1. On page 3, line 6: …. the “dengue associated of MACE” (“dengue-associated MACE” ?) should be taken into……

2. On page 3, line 10: …. becomes a vivid “thread” (“threat”?) to non-tropical countries…..

3. On page 4, line 7: …stroke, heart failure, arrhythmia and “cardiomyositis” (“myocarditis”?)…

4. On page 9, line 6-7, (also in Tables 1, 3): ... we performed analyses in subgroups defined according to age group (0-40 years, “40-60 years” [41-60 years?], and >60 years), sex,…..

5. On page 14, line 10-11: …The risks of “ischemic stroke hemorrhagic stroke and heart failure” (“hemorrhagic stroke, ischemic stroke and heart failure”?) remained increased (IRR 4.33, 3.17, and 2.45, respectively),…..

6. On page 19, line 4-5: …contractility and eventually leading (“to”?) decompensation……

7. On page 19, line 10-11: …were frequent if “routine” electrocardiogram was “routinely” (redundant? Deleted?) performed for DENV-infected…..

8. On page 19, line 1 from the bottom: …if they attack in some specific patient groups, such as the “elder” (“elderly”?).

9. On page 20, line 2-3: …At higher “altitudes” (latitude”?), cases of DENV infection are usually clustered during summer,……

Reviewer #2: The manuscript entitled “Major acute cardiovascular events after dengue infection– A population-based observational study” by Wei et al. is well written and reports interesting results. This study aimed to perform a large-scale evaluation of the association between Dengue virus infection and major adverse cardiovascular events. They observed significantly increased incidence rate ratio for major cardiovascular events (hemorrhagic stroke, ischemic stroke, acute myocardial infarction, and heart failure) mainly within the first week after the onset of Dengue virus infection. The study design is adequate and the results support its conclusions. However, some adjustments should be performed in the manuscript:

1- The text excerpt “DENV is taken up into macrophages…DENV-infected myotubes” (lines 252-259) was literally copied from the study cited by the reference 17, which is considered as plagiarism. Therefore, the aforementioned excerpt should be completely rewritten and all the manuscript should undergo a careful plagiarism check.

2- The reference 16 does not support the information from lines 220-222. Another study that supports the data from that excerpt should be chosen to replace the reference 16.

3- I suggest the inclusion of a table describing the demographic characteristics of all the groups included in the study, including the individuals who had influenza and onychomycosis.

Below are some language errors that should be eliminated:

1- Line 73: The word “Aedes” should be written in italics.

2- Line 75: The word “attitudes” should be replaced with “altitudes”.

3- Line 110: The word “and” should be added before the word “NS1”.

4- Line 200: A comma should be added between the words “ischemic stroke” and “hemorrhagic stroke”.

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Reviewer #1: No

Reviewer #2: No

Figure Files:

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References

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.

Dear Associate Research Fellow Huang,

We are pleased to inform you that your manuscript 'Major acute cardiovascular events after dengue infection– A population-based observational study' 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,

Husain Poonawala

Associate Editor

PLOS Neglected Tropical Diseases

Paul Newton

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

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: All are yes.

Reviewer #2: (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: All are yes.

Reviewer #2: (No Response)

**********

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: All are yes.

Reviewer #2: (No Response)

**********

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: None.

Reviewer #2: (No Response)

**********

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: The manuscript has been revised satisfactorily according to the reviewer's comments and suggestions.

Reviewer #2: The authors have edited the manuscript according the suggestions from peer review.

**********

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