-->PONE-D-25-67780-->-->Pertussis outbreak in Serbia – is it finally time to change the national vaccination policy?-->-->PLOS One

Dear Dr. Sovtic

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 all the points raised during the review process.

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Academic Editor

PLOS One

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Reviewers' comments:

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-->Comments to the Author

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

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Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: 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.-->

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: No

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Thanks for inviting me to review this retrospective single-center study of pertussis infections in children treated at a national referral center in Serbia between 2015 and 2025. While the manuscript overall is mostly well written and the data support the conclusions there are some specific areas of ambiguity/weakness that need to be addressed by the authors:

1) The title is a little misleading and should be revised- this is not a report of an outbreak of pertussis or a vaccine policy review. The title should be revised, a more appropriate title could be 'Predictors of mortality and disease severity amongst children with pertussis in Serbia'

2) In the Introduction (line 87-89) the authors state 'the pertussis booster vaccination for pregnant women is recommended... although it is not included in the mandatory schedule'. This is confusing. Do the authors mean that pertussis vaccination for pregnant women is recommended but that uptake is low? Please clarify, and if data are available about vaccine uptake for pregnant women (and the general population) in Serbia, it would be important to include.

3) The introduction should be strengthened to include references and additional context regarding recent concerning increases in pertussis cases and outbreaks in the US/Europe and as note by the WHO and also concerning declines in vaccination rates in some countries (see this article for a relevant summary- Vargas-Zambrano JC, Abrudan S, Macina D. Understanding the Epidemiology and Contributing Factors of Post-COVID-19 Pertussis Outbreaks: A Narrative Review. Infect Dis Ther. 2026 Jan;15(1):19-41. doi: 10.1007/s40121-025-01277-1. Epub 2025 Dec 1. PMID: 41324875; PMCID: PMC12783469.)

4) Methods- line 113-115- please clarify whether the patients included were consecutive patients with pertussis, all patients between the dates mentioned, or were selected in another way (e.g. at random)? How were eligible patients with pertussis identified (e.g. via PCR/serology results, or via a case registry, or via discharge diagnosis data?)?

5) Methods- please describe how positive serology was defined (especially for those who had received vaccination previously) and what serologic test was used.

6) Methods- please given a definition for fully/partially vaccinated in the methods, prior to discussing the results for this metric in line 210. Please also give a clear definition for prematurity.

7) Results- the first paragraph is

8) Results- Table 1 includes vaccination status or the infant/child. Was data regarding maternal vaccination status (i.e. pertussis booster during pregnancy) available? If yes, please include this. If no, then please add this to the discussion as a major limitation of the study

9) Results- line 214- it is not clear what is statistically different here and what the authors mean by 'favoring term births'. Do the authors mean that severe pertussis cases or deaths were significantly frequent among pre-term infants? Please clarify.

10) Results- line 217-218- 'The proportion of unvaccinated patients was significantly higher'- I am not sure what the comparator here is. Please clarify. Do you mean that among severe case of pertussis the proportion unvaccinated was significantly higher?

11) Results- line 228- I am not clear what the p-value of 0.016 refers to. Please clarify. Was apnea significantly more likely than the vomiting or cyanosis, or was it that a significant majority of cases had at least one additional symptom?

12) Discussion- if data about maternal pertussis vaccine booster during pregnancy was not available, please add this to the section discussing Study Limitations.

13) Conclusion- the authors state that 'pertussis outbreaks can still occur', but actually data from WHO and others (see the paper referenced above by Vargas-Zambrano et al) note worrying trends of increased outbreaks/cases in recent years. I recommend re-framing the beginning of the conclusion to remind the reader of the increased public health concern regarding rising pertussis outbreaks/cases in recent years across multiple countries.

More minor suggestions for improvement include the following:

1) Suggest using MV as abbreviation for mechanical ventilation instead of IMV to improve readability.

2) The methods section devotes a lot of space to describing the protocol for routine clinic care for pertussis at the center conducting the study (lines 118-183). This could be abbreviated/summarized.

3) Consider removing the p-values from Table 1- I am not sure they are very meaningful, except for the duration of cough differences which are already explored in the main results section text.

4) Table 2- please state whether the numbers in brackets are the range or interquartile range for each parameter.

5) Results- Line 213- there is a typo and 'first two 10 weeks' should read 'first 10 weeks' I think.

6) Please capitalize the 'f' in figure throughout where you are referring to a specific figure in the manuscript e.g. in line 320.

Reviewer #2: The topic is timely, the setting is clinically meaningful, and the manuscript has the potential to make a useful contribution. The manuscript contains some important descriptive findings, especially the observation that all fatal cases occurred in unvaccinated infants younger than 2 months, and that severe outcomes clustered heavily in very young infants and preterm children. These are meaningful observations and clinically worth reporting.

That said, the manuscript in its current form needs careful revision. My main concerns relate to internal consistency of the reported data, interpretation of the regression analyses, overstatement of model performance, and a title/conclusion that currently go further than the data can comfortably support.

1- At present, there are some obvious inconsistencies that need correction before the findings can be interpreted with confidence. The most striking example is in Table 1, where the vomiting row is not plausible as presented: the overall number is given as 18/107, but the subgroup values are listed as 66/80, 15/16, and 8/11. This cannot be correct and suggests either row displacement or transcription error. Similarly, Table 2 contains values that appear internally impossible, for example a leukocyte median of 27.34 with a range of 8.22–19.55. The same concern applies to other laboratory values in that table. These are not minor formatting issues, because they directly affect trust in the dataset and in the subsequent analyses. Please re-check all tables, denominators, ranges, and corresponding narrative statements very carefully.

2- I understand the intention to identify early predictors of deterioration, and this is clinically worthwhile. However, the number of severe outcomes is very small: 13 PICU admissions, 12 cases requiring invasive mechanical ventilation, and 5 deaths. With events this limited, the models become very unstable, especially when multiple candidate predictors are entered. This instability is visible in Table 3, where some odds ratios are extremely large and have very wide confidence intervals. For mortality in particular, the estimates for N/L ratio and coinfection are extraordinarily imprecise, which suggests sparse-data bias and overfitting rather than robust effect estimation. The use of Firth’s method is sensible, but it does not fully solve the underlying limitation of very few outcome events. I would strongly encourage the authors to simplify the models, reduce the number of predictors, and frame these analyses much more cautiously as exploratory rather than definitive.

3- Some interpretations of the regression findings do not match the reported effect estimates. This needs close checking throughout. For example, in the pneumonia model, the manuscript states that a higher N/L ratio predicted higher odds of pneumonia, but the reported odds ratio is 0.66. An odds ratio below 1 indicates lower odds, not higher odds. This is important because readers will follow the narrative interpretation, and at the moment there is a mismatch between the statistical output and the wording used to explain it. I would recommend a line-by-line check of every regression statement in the Results and Discussion sections against the actual coefficients and direction of association in the table.

4- The claims regarding model performance are too strong for a small retrospective single-centre cohort. The manuscript presents the PICU and IMV models as having excellent or outstanding discrimination, based on AUC values of 0.951 and 0.987, and goes on to describe this as confirmation of model robustness. I think that language is too strong. These performance estimates appear to come from the same dataset used to build the models, and there is no internal validation reported. In a small dataset with very few events, apparent AUC values are often optimistic. Without bootstrapping, cross-validation, or external validation, these models should not be described as robust predictive tools. The results are interesting and hypothesis-generating, but they need a much more restrained interpretation.

5- The title and policy framing should be moderated. The manuscript is based on a retrospective cohort of hospitalised children from a single tertiary centre. That design can certainly provide useful clinical and epidemiological insight, but it does not directly evaluate national vaccination policy, programme effectiveness, maternal vaccine uptake, or population-level prevention strategies. The current title asks whether it is time to change national vaccination policy, and the conclusion states that redefining national immunisation strategies may be the most effective means of protecting vulnerable age groups. I understand why the authors are making this connection, especially given that all fatal cases occurred in infants too young to be vaccinated. However, the study itself provides supportive observational evidence rather than direct policy evaluation. I think the paper would be stronger if the policy implications were framed more cautiously, as one reasonable interpretation of the observed vulnerability in early infancy rather than as a conclusion that follows directly from the data.

6- The study population needs clearer description, particularly in relation to age and vaccination status. The manuscript repeatedly frames the cohort as “infants and young children”, and the median age overall is 2 months. However, Table 1 shows that the fully vaccinated group had a median age of 6 years. This means that the vaccination groups are clearly not age-comparable, which is expected in pertussis, but it makes group comparisons difficult to interpret. For example, differences in cough duration and symptom profile across vaccination groups may simply reflect age structure rather than vaccine effect. This needs to be acknowledged more explicitly, and the manuscript should avoid overinterpreting group differences where age is such a strong confounder.

7. The ethics and consent description needs clarification. The manuscript states that this was a retrospective review of records from 2015 to 2025, approved in November 2025, and that written informed consent for the use of medical data was obtained from parents or legal guardians in accordance with institutional policy. This may be entirely appropriate locally, but as written it raises questions for the reader because retrospective chart reviews often rely on waiver or institutional approval for secondary use rather than fresh written consent. Please clarify how consent operated in practice here. Was consent already part of institutional admission procedures, or was there a specific ethics process for retrospective use of the data? This should be made fully transparent.

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Reviewer #1: No

Reviewer #2: Yes: Dr Mamdooh Alzyood

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-->PONE-D-25-67780R1-->-->Clinical features, disease severity, and outcomes of pertussis in hospitalized children: a retrospective study from Serbia-->-->PLOS One

Dear Dr. Sovtic,

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 (reviewer#2).

Please submit your revised manuscript by Jun 10 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.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• 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, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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 https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Daniela Flavia Hozbor

Academic Editor

PLOS One

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1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. 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.

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

-->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.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The authors have addressed all of my previous concerns/questions. The results section in particular is much more clearly written in this revised manuscript and definitions for seropositivity and vaccination status of mothers has been added which also improves clarity.

Reviewer #2: The authors have responded constructively to the previous round of review and the manuscript is substantially improved. The core findings are clinically meaningful and the analytical concerns raised by Reviewer 2 have been addressed in good faith. The following comments should be addressed before acceptance.

1- The Discussion still contains clinical utility language suggesting the models "may assist clinicians in identifying patients" and "guiding early management decisions." Given that no internal or external validation has been performed, this should be softened. Add a clear statement that prospective validation is required before any clinical application can be considered.

2- The odds ratio for viral coinfection and mortality (47.1, 95% CI 2.5–888.1) is reported in Table 3 with a dash in place of a p-value, and no explanation for its absence. Either provide the p-value or add a brief note clarifying why it is not reported (for example, that Firth's penalized regression was used and conventional p-values are not applicable in this context).

3- The CI width for the coinfection-mortality association (2.5 to 888.1) means the data provide almost no information about the true effect size. Describing this finding as "exploratory" is not sufficient. The authors should state plainly that this estimate is statistically uninformative and should not be interpreted as evidence of a strong effect.

4- Table 1: confirm that the corrected vomiting row values (18/107 overall, 14/80, 1/16, 3/11) are accurate and consistent with the dataset. The subgroup values now sum correctly, but this should be verified against the source data given prior transcription errors in this table.

5- Table 2: the corrected leukocyte IQR within 72 hours (19.51–40.56) is now plausible against the reported median of 27.34. However, it would be worth adding a footnote clarifying that follow-up measurements were not available for all patients, if that is the case, to avoid readers assuming complete data.

6- The sentence in the Results reporting the PICU model fit (Nagelkerke R² = 0.472) and the MV model (Nagelkerke R² = 0.518) should be accompanied by a brief acknowledgement that pseudo-R² values in logistic regression are not directly comparable to R² in linear models and should be interpreted with caution, particularly in small samples.

7- The authors note that vaccination status was excluded from multivariable models due to collinearity with age, which is the correct decision. However, the Results section still includes a comparison of paroxysmal cough prevalence across vaccination groups (85% unvaccinated vs 54.5% fully vaccinated, p=0.039) and interprets this as a vaccine effect. Given the median age of 6 years in the fully vaccinated group versus 1.75 months in the unvaccinated group, this difference almost certainly reflects age rather than vaccination. The interpretation should be revised accordingly.

8- The Acknowledgements disclose the use of QuillBot Premium for language editing. Authors should confirm that this use is consistent with PLOS ONE's policy on AI-assisted writing tools, and if required, provide clarification on the extent of its use.

9- Minor: "Figure" should be capitalised consistently throughout the manuscript when referring to a specific figure. A few instances remain where it appears in lowercase.

Thank you.

**********

-->7. 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: Yes: Dr Mamdooh Alzyood

**********

[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.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

-->PONE-D-25-67780R2-->-->Clinical features, disease severity, and outcomes of pertussis in hospitalized children: a retrospective study from Serbia-->-->PLOS One

Dear Dr. Aleksandar Sovtic,

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 by reviewer#2  during the review process.

Please submit your revised manuscript by Jul 08 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.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• 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, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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 https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Daniela Flavia Hozbor

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #2: All comments have been addressed

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #2: Partly

**********

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

Reviewer #2: I Don't Know

**********

-->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.-->

Reviewer #2: Yes

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

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Reviewer #2: Yes

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-->6. Review Comments to the Author

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Reviewer #2: The authors have responded constructively to the previous review, and the manuscript has improved. The clinical dataset is valuable, particularly as a single-centre retrospective account of severe pertussis in hospitalised children in Serbia. However, several issues still require revision before the manuscript is ready for publication.

1- On mortality analysis. The mortality analysis remains the main concern. There were only five deaths, all occurring in unvaccinated infants younger than two months, and all with documented viral coinfection. The reported odds ratio for viral coinfection and mortality, 47.1 with a 95% CI of 2.5 to 888.1, is too imprecise to be clinically or statistically informative. I recommend removing this estimate from Table 3 and presenting the mortality findings descriptively in the Results. The descriptive pattern is itself important and does not require regression modelling.

2- On AUC and ROC analysis. The reported AUC values for PICU admission and mechanical ventilation are apparent AUCs calculated from the same dataset used to develop the models. No internal or external validation has been performed. These values may therefore overestimate model performance. I recommend either performing internal validation, for example using bootstrap optimism correction, or removing the AUC values and ROC figure. Given the sample size and event numbers, removing them and reframing the models as exploratory association analyses would be the more appropriate option.

3- On prediction-model framing. The manuscript still gives the impression that the models have predictive or clinical risk-stratification value. This should be softened throughout. The models should be described as exploratory and hypothesis-generating only. Any wording implying clinical use, early identification for practice, or management guidance should be removed unless the models are properly validated.

4- On number of outcome events. The models for PICU admission and mechanical ventilation are based on small numbers of events: 13 PICU admissions and 12 cases requiring mechanical ventilation. This creates a risk of overfitting and unstable estimates. This limitation should be stated more clearly in the Results and Discussion.

5- On prematurity estimates. The associations between prematurity and severe outcomes are clinically plausible, but the confidence intervals are very wide. For example, the estimates for PICU admission and mechanical ventilation span more than an order of magnitude. The authors should avoid presenting the point estimates as precise. Phrases such as “more than a 20-fold increase in risk” should be qualified or revised.

6- Table 3 should be revised. I recommend removing the mortality column or limiting it to descriptive information. If the authors retain the table, it should not present unstable mortality estimates in a way that suggests reliable inference.

7- On validation. The heading “Additional validation of multivariable logistic regression models” is misleading, as no validation appears to have been performed. If the section is retained, the heading should be changed to something more accurate, such as “Apparent model discrimination”. However, this section may be unnecessary if the ROC and AUC analyses are removed.

8- The Acknowledgements disclose the use of QuillBot Premium for language enhancement. This is acceptable in principle, but the statement remains broad. Please clarify the nature and extent of use, including which sections were edited, whether the tool was used only for grammar and style, and whether any generative AI tool was used at any stage of drafting, analysis, interpretation, or response preparation.

9- The Conclusions should be tightened. The strongest conclusions relate to the concentration of severe and fatal disease among very young unvaccinated infants, the absence of maternal pertussis vaccination in the cohort, and the importance of preventive strategies targeting early infancy. Predictive-model claims should not feature in the Conclusions unless the models are validated.

10- Please check the manuscript for any remaining wording that implies clinical applicability of the models, and ensure that all figure references, table footnotes, and section headings are accurate.

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Reviewer #2: Yes: Dr Mamdooh Alzyood

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Clinical features, disease severity, and outcomes of pertussis in hospitalized children: a retrospective study from Serbia

PONE-D-25-67780R3

Dear Dr. Aleksandar Sovtic,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #2: All comments have been addressed

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

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Reviewer #2: Yes

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

Reviewer #2: I Don't Know

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Reviewer #2: Yes

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

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Reviewer #2: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #2: The authors have responded constructively to the previous comments and the manuscript has improved substantially. The main methodological concerns have now been addressed, particularly the removal of unstable mortality regression estimates, the removal of ROC/AUC analyses, the clearer framing of the regression models as exploratory and hypothesis-generating, and the clarification of limitations related to the small number of severe outcomes. The revised manuscript now presents the key findings more appropriately, with the strongest conclusions focused on the concentration of severe and fatal pertussis among very young unvaccinated infants and the importance of preventive strategies, including maternal vaccination.

I have no further major concerns. I recommend acceptance. Before final publication, the authors may wish to ensure that any remaining wording implying clinical prediction or direct risk-stratification utility is softened, particularly in the Abstract and Conclusion, but this is an editorial issue rather than a barrier to publication.

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-->7. 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.

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Reviewer #2: Yes: Dr Mamdooh Alzyood

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