PNTD-D-24-00849Characterization of Dengue Patients in Vietnam: Clinical, Virological, and IL-10 Profiles during 2021- 2022 outbreaksPLOS Neglected Tropical DiseasesDear Dr. Velavan, 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 Mar 18 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.

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Adly M.M. Abd-Alla, Prof asso.

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?

-Were correct statistical analysis used to support conclusions?

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

Reviewer #1: The objective of the study is clearly stated, and the population well described. There is no ethical concern and the statical analysis was well presented. The authors did not show how they arrived at the sample size. I assumed convenient sampling method was employed. The author should state clearly the sampling technique that was used.

Reviewer #2: This paper describes an important topic that is growing in impact as numbers of dengue cases are rising in many disparate geographic areas of the globe. Its strengths include the numbers of cases studied, the inclusion of clinically severe cases and the detailed analysis of Il-10 promotor polymorphism associations with disease severity allowing for dengue serotypes. An additional strength is the exclusion of infection by closely related flaviviruses.

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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: The analysis plan is good and well presented. The figures and tables are sufficient. The author might consider removing figure 1b because same data is well presented in Table 1.

Reviewer #2: The analysis of associations for polymorphisms using logistic regression models and different assignments of gene transmission (*dominant, recessive and so on) is appropriate, and the findings are of interest.

The results are clearly presented.

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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: The conclusion was clear, and the study was well discussed but the public health implication is not clearly stated

Reviewer #2: As mentioned there may be other chemo-cytokines that are relevant to this topic and further comments on this topic may be helpful for context, including in the discussion. Are there any in vitro data looking at Il10 promotor polymorphisms in ex vivo experiments that might shed light on the functional relevance of these polymorphisms? For example, on the timing of release of Il-10 (PMCID: PMC11508614 DOI: 10.3390/ijms252011238) and with relevance to another earlier model of infection, which the authors might consider worth mentioning in discussion (reference abstract appended).

Lancet

. 1997 Jan 18;349(9046):170-3. doi: 10.1016/s0140-6736(96)06413-6.

Genetic influence on cytokine production and fatal meningococcal disease

R G Westendorp 1 , J A Langermans, T W Huizinga, A H Elouali, C L Verweij, D I Boomsma, J P Vandenbroucke

Affiliations expand

PMID: 9111542 DOI: 10.1016/s0140-6736(96)06413-6

Erratum in

Lancet 1997 Mar 1;349(9052):656. Vandenbrouke JP [corrected to Vandenbroucke JP]

Abstract

Background: To assess the genetic influence on cytokine production and its contribution to fatal outcome, we determined the capacity to produce tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) in families of patients who had had meningococcal disease.

Methods: We studied 190 first-degree relatives of 61 patients with meningococcal disease; we also studied 26 monozygotic twins. Production of cytokines was determined during endotoxin stimulation of whole-blood samples ex-vivo. Heritability was estimated in a pedigree-based maximum-likelihood model. DNA was typed for the G to A transition polymorphisms at position -308 and -238 in the TNF gene promoter.

Findings: Heritability in monozygotic twins was 0.60 for the production of TNF and 0.75 for the production of IL-10. Families with low TNF production had a tenfold increased risk for fatal outcome (OR 8.9, 95% CI 1.8-45), whereas high IL-10 production increased the risk 20-fold (19.5, 2.3-165). Families with both characteristics had the greatest risk. The transition polymorphisms in the TNF gene promoter were not associated with outcome.

Interpretation: Genetic factors substantially influence production of cytokines. An innate anti-inflammatory cytokine profile may contribute to fatal meningococcal disease.

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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: (No Response)

Reviewer #2: Minor Revision

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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: Overall the study is well executed and the paper well written

The inheritance model analysis section should be part of the statistical analysis.

Reviewer #2: The paper is well written.

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Dear Prof. Dr Velavan,

We are pleased to inform you that your manuscript 'Characterization of Dengue Patients in Vietnam: Clinical, Virological, and IL-10 Profiles during 2021- 2022 outbreaks' 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,

Adly M.M. Abd-Alla, Prof asso.

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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