Dear Dr. Khan,

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

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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.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

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: it is dscussing an interesting novel topic (DENV Serotype-Genotype Profiling and Its Association with Primary Stress Hormone in Dengue-Positive Patients). the manuscript is well designed and well written. the introduction, methods, results and discussion are well written and well presentes with good flaw of ideas.

Reviewer #2: The manuscript titled DENV Serotype-Genotype Profiling and Its Association with Primary Stress Hormone in Dengue-Positive Patients" reports on results from an observational study that aiming to explore whether there is a relationship between DENV serotypes/genotypes and stress hormone levels (specifically cortisol and adrenaline) in dengue-positive patients in Karachi, Pakistan. I have some concerns with the manuscript in its current version, please refer the followings:

1. The title suggests a mechanistic or causal relationship ("association") but the study design does not support causality—this is a cross-sectional observational study. Please adjust the title to reflect the descriptive nature of the analysis, e.g., “Profiles of Stress Hormones in Relation to DENV Serotypes among Dengue-Positive Patients.”

2. The abstract promises a novel exploration of hormonal response to DENV genotypes, but the results do not show statistically meaningful differences. Furthermore, it claims “modest positive correlation” but does not substantiate it with statistical significance or effect sizes. Please revise the abstract to reflect the exploratory and non-significant nature of the findings, and include correlation coefficients with p-values or confidence intervals where possible.

3. Large portions of the epidemiological background in the Introduction are devoted to general dengue epidemiology, which adds little to the justification of the study. Please streamline the background and focus instead on highlighting gaps in the literature related to host hormonal responses by serotype or genotype.

4. The rationale behind linking stress hormones (cortisol, adrenaline) with specific DENV genotypes is not grounded in any referenced theoretical or biological framework. There is no citation suggesting that serotype-specific viral behavior would mechanistically affect the HPA axis. Thus, authors must provide a mechanistic hypothesis or at least cite prior work showing links between DENV variants and neuroendocrine responses to strengthen their premise.

5. Previous studies on hormonal response in infectious diseases exist, but this work neither builds on nor properly distinguishes itself from them. So what differentiates this study must be clearly articulated—whether it’s geographic specificity, inclusion of whole-genome phylogenetics, or a novel analytic approach.

6. This is a descriptive, cross-sectional design, which is not sufficient to make any inference on interaction or impact between hormones and genotypes. Thus, conclusions implying serotype-hormone effects should be reworded to emphasize association without assuming directionality or causality.

7. There's no sample size justification or power calculation, making it unclear whether the study is adequately powered to detect the hypothesized associations. Please include a power analysis to justify whether the study was sufficiently powered to detect differences in hormone levels between serotypes.

8. The study was done in a limited geographic region and over a short time period. External validity is not addressed. This could limit generalizability to other settings or populations. Please clarify this limitation in the discussion section.

9. There is an ambiguity in patient selection and controls. The description lacks clarity on how negative controls were defined and matched. Thus, authors must clarify inclusion/exclusion criteria for controls, matching strategy (if any), and whether potential confounders were balanced between groups.

10. The use of correlational analysis with vague effect sizes and no correction for multiple testing is scientifically weak. For example, reporting weak positive correlations without FDR or Bonferroni correction inflates type I error. Authors may fix this by applying correction methods and reporting adjusted p-values.

11. The discussion implies biological importance of observed hormone differences without theoretical or empirical support. This could mislead readers into overinterpreting minor variations. Please tone down speculative interpretations unless supported by literature or strong statistical evidence.

12. Please improve the comparison with prior literature. Particularly, the manuscript does not engage with earlier studies on hormonal changes in dengue, missing an opportunity to contextualize findings in light of immune-endocrine interactions in viral infections.

13. I think part of the discussion is speculative in interpretation. The phylogenetic inference about multiple introductions of DENV into Pakistan does not align with the main hypothesis and seems tangential. To address this, authors may either connect the phylogenetic insights to disease severity or patient outcomes or move this section to supplementary results if not central to the main research question.

14. Authors claim about potential application in outbreak management. Is this accurate? Given the study design is observational in nature, and most of the findings are hard to implicate to somewhat actionable, this claim should be reworded to suggest that findings are hypothesis-generating rather than directly informing public health strategies.

15. Why do you think, or not, the study can warrant changes in diagnostic, clinical, or public health approaches? The current data are not robust or generalizable enough to warrant such changes. However, it may contribute to the body of exploratory biomarker research pending validation in larger, multi-site cohorts.

16. I worry about the use of only non-parametric tests limits analytical depth, and there's no multivariate control for confounders. Authors should consider multivariable regression models adjusting for age, sex, infection status, and time since symptom onset to better elucidate relationships.

17. More details should be added to patient demographics potentially influencing cortisol/adrenaline levels (e.g., time of sample collection, medications, comorbidities). These factors could significantly confound hormone measurements and must be accounted for or discussed as limitations.

18. Consider to add more relevant studies in the discussion, such as by stating: "Although our cohort is based in Karachi rather than Mexico, global shifts in serotype prevalence—as documented by Mendoza‑Cano et al. (2025)—underscore the relevance of investigating whether new serotypes (e.g., DENV‑3) elicit different host physiological responses.” Ref: PLOS One. 2025 May 22;20(5)\:e0324754

19. Introduction can benefit from the addition of: “As example in Indonesia, dengue control efforts are increasingly compromised by widespread resistance of Aedes aegypti to standard insecticides, notably pyrethroids and organophosphates—especially across Java and neglected rural areas—highlighting the need for sustainable alternatives such as plant-based biolarvicides (Kasman et al., 2025) \[e‑1819]”

20. To lay the biological foundation for exploring hormonal vs. immune biomarker patterns, authors may incorporate the following: “Elevated pro-inflammatory cytokines such as TNF‑α, IL‑6, and IL‑17, along with differential IL‑10 responses in dengue hemorrhagic versus classical dengue, highlight the immune axis in severity progression—supporting theoretical rationale for exploring stress hormone–cytokine interplay (Masyeni et al., Narra J 2024;4(1)\:e309)”

21. Authors have not made the underlying data publicly available as recommended by PLOS ONE. This contradicts the journal’s data availability policy, which emphasizes transparency and reproducibility. Authors must deposit the complete dataset in a public repository or provide access upon request, along with metadata and a clear data availability statement in the manuscript.

Reviewer #3: - Address Unequal Group Sizes:

The unbalanced distribution of serotypes (DENV-1: 80%; DENV-2: 16%; DENV-3: 0.7%; co-infections: 3.3%) may limit statistical power for comparisons involving DENV-3 and co-infections. Implement post-hoc tests (e.g., Dunn’s test) following the Kruskal-Wallis test to identify specific differences between serotypes, accounting for unequal group sizes.

- Adjust for Multiple Comparisons:

The study conducts multiple comparisons (e.g., hematological parameters across serotypes). To reduce the risk of Type I errors, apply corrections such as the Bonferroni or False Discovery Rate (FDR) method for multiple tests, ensuring more reliable p-values.

- Increase Control Group Size:

The control group (n=15) is small compared to the patient group (n=150), potentially limiting the power of comparisons (e.g., Mann-Whitney U tests). Increasing the control group size would improve the robustness of differences observed in stress hormone levels

- Incorporate Phase-Specific Analysis:

The absence of fever phase data is a noted limitation. Stratify analyses by disease phase (febrile, critical, or recovery) to explore variations in stress hormone levels, which could strengthen the interpretation of cortisol and epinephrine findings.

- Report Phylogenetic Confidence Measures:

The phylogenetic analysis lacks details on node confidence (e.g., bootstrap values). Include bootstrap or posterior probability values for the maximum likelihood tree generated by W-IQ-TREE to validate conclusions about multiple DENV-1 introductions.

- Discuss Clinical Relevance of Weak Correlations:

The Spearman correlations showed weak coefficients (e.g., r=0.184 for cortisol, r=-0.228 for hemoglobin). Provide a deeper discussion on the clinical significance of these weak associations and assess whether the sample size was sufficient to detect stronger relationships.

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes:Samir Mansour Moraes CassebSamir Mansour Moraes CassebSamir Mansour Moraes CassebSamir Mansour Moraes Casseb

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Dear Dr. Khan,

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 Feb 12 2026 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.. 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.. 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.. 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.

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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 . 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 . 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 . 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,

Harapan Harapan, MD, PhD

Academic Editor

PLOS One

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #4: No

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: Yes

Reviewer #4: 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.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 #2: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #4: Yes

**********

Reviewer #2:Authors have addressed my previous comments, especially by avoiding the inferrence-like statement and explain the statistic power. This manuscript is acceptable for publication.Authors have addressed my previous comments, especially by avoiding the inferrence-like statement and explain the statistic power. This manuscript is acceptable for publication.Authors have addressed my previous comments, especially by avoiding the inferrence-like statement and explain the statistic power. This manuscript is acceptable for publication.Authors have addressed my previous comments, especially by avoiding the inferrence-like statement and explain the statistic power. This manuscript is acceptable for publication.

Reviewer #4:General concern:General concern:General concern:General concern:

The biggest limitation of this study is the lack of data on fever days. Dengue is a very dynamic disease, changing day by day and even hour by hour. Therefore, laboratory data is also very dynamic. For example, during the first 3 days of fever (the febrile phase), we do not expect thrombocytopenia, and leukopenia usually occurs. Hemoglobin levels are also indirectly related; what is more accurately observed is the dynamics of hematocrit. There is also no data related to disease severity (with warning signs or severe dengue, although my assumption is that if hospitalized, they are not patients without warning signs). Stress hormones are certainly highly related to the dynamics of dengue disease progression and its severity. This is also what might cause the results to not show significance. Although each serotype may have varying severity, it also depends on the course of the illness (course of day-fever).

Questions:

In what way exactly is there a direct logical connection from discussing the newly emerging serotypes (such as DENV-3), as cited in Mendoza-Cano et al. in 2025, to the following assertion about self-managed and unreported cases of dengue infection occurring in Pakistan? And precisely how does this issue of underreporting thwart research efforts into identifying host physiological and hormonal responses to newly emerging serotypes in Pakistan?

2. After being presented as a hypothesis, were there any particular clinical findings, characteristics of the virus in your population, or other pilot data to which you wished to draw attention as to why molecular mimicry would be considered as an alternative explanation for the lower cortisol levels?

3. In regards to it being observed that your sources encompass research involving HSV and E71 but not necessarily related to DENV, what exactly would be the biologic rationale or evidential source from literature supporting such a postulate particular to the function of adrenaline in DENV replication? In addenda to this question, what would be the strength of your assertion about "adrenaline not contributing" to DENV replication based exclusively on "very weak correlation" to viral load?

4. Do patients co-infected with both DENV-1 and DENV-2 who had greater numbers of platelets have data related to other clinical features (such as severity grade, rate of hospitalizations due to severe dengue infection, ICU admissions rate, time to recovery) collected to provide direct supportive data to your hypothesis about "super-infection exclusion" contributing to reduced disease severity?

5. Although it would be difficult to generalize to other regions internationally, what specific data suggests "the results do not appear to be confined to any particular sector or subgroup" in Karachi despite being carried out in a single tertiary-level hospital environment in the midst of a major outbreak?

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.

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Reviewer #2: No

Reviewer #4: No

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Profiles of Stress Hormones in Relation to DENV Serotypes among Dengue-Positive Patients

PONE-D-25-27769R2

Dear Dr. Khan,

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.

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Harapan Harapan, MD, PhD

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Yes

Reviewer #4: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: Yes

Reviewer #4: (No Response)

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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.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 #2: Yes

Reviewer #4: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

Reviewer #4: (No Response)

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Reviewer #2: The authors have thoroughly addressed my previous comments. They have appropriately revised the manuscript to avoid inferential overstatement and have clearly discussed its limitations, including the statistical power. The manuscript is now acceptable for publication.

Reviewer #4: (No Response)

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what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.). 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 For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #2: No

Reviewer #4: No

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