PNTD-D-25-01839

Efficacy and safety outcomes reported in human leptospirosis studies to inform the development of a core outcome and core outcome measures set: a systematic review by the COS-LEP study group

PLOS Neglected Tropical Diseases

Dear Dr. Edwards,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Vasantha Kumari Neela

Academic Editor

PLOS Neglected Tropical Diseases

Stuart Blacksell

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: yes

the methodology is acceptable but it would be interesting to note what number of papers were from non English literature.

study design is appropriate

the hypothesis is clear and appropriate

sample size: Not applicable here

analysis is adeqaute

Reviewer #2: The study applies standardised systematic review methods. The study investigates hospitalised patients and attempts to develop a controlled ontology for description of clinical outcomes.

Reviewer #3: The objectives of the study are clearly articulated with a clear testable hypothesis stated

The study design is appropriate to address the stated objectives

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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: analysis can be improved

i would request the authors to please divide the literature available into 3 groups, before the year 2000, year 2000 till 2019, year 2020 till date and provide the difference in methods used for diagnosis and its implication on the final diagnosis. how many cases may be missed by serology or microscopic detection.

the outcome measure and the antibiotic selection is also likely to be different in these 3 time periods. it is possible that before the year 2000, mortality might have been the indicators, where as subsequently organ system dysfunction, time to discharge, duration of ICU stay may be outcome measures.

it would be interesting to build up this story of changing paradigms of outcome here over the decades.

it would be interesting if the entire SE Asian region is combines and compared with other regions during these periods

Reviewer #2: Yes to all

Reviewer #3: The results are clearly and completely presented

The figures (Tables, Images) are of sufficient quality for clarity

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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: conclusions are clear as far as the data interpretation is concerned.

i donot think that this study touches on public health aspects.

Reviewer #2: Yes to all

Reviewer #3: The conclusions are supported by the data presented

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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: i would request the authors to please divide the literature available into 3 groups, before the year 2000, year 2000 till 2019, year 2020 till date and provide the difference in methods used for diagnosis and its implication on the final diagnosis. how many cases may be missed by serology or microscopic detection.

the outcome measure and the antibiotic selection is also likely to be different in these 3 time periods. it is possible that before the year 2000, mortality might have been the indicators, where as subsequently organ system dysfunction, time to discharge, duration of ICU stay may be outcome measures.

it would be interesting to build up this story of changing paradigms of outcome here over the decades.

it would be interesting if the entire SE Asian region is combines and compared with other regions during these periods.

it would be interesting to know the outcomes changing according to antibiotics choices.

Reviewer #2: Not applicable

Reviewer #3: No

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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: In my view, these changes would give us more realistic picture of the leptospirosis story .

Reviewer #2: The manuscript provides a list of categorised outcomes and antibiotics used in a curated list of leptospirosis studies. The main finding presented is that non standardised ontologies are used and that this needs to be improved. The authors mention the WHO guidelines for leptospirosis - what are the recommended antibiotics for treatment? How does that differ from usage in the studies? Is AMR a problem? - unlikely due to the diverse zoonotic sources. The study catalogues the antibiotics used at a study level, would it be more appropriate to look at the number of patients? Is severe leptospirosis resulting in hospitalisation associated with delay in initial diagnosis/delay in seeking medical attention (possible socio-economic factor in LMICs) worth looking into? Is antibiotic therapy ineffective once organ/system shutdown has commenced? How effective is antibiotic therapy for leptospirosis otherwise? (with WHO recommended antibiotics). No mention of disease severity associated with species of Leptospira or serovar - Should this be included as part of the information collected?

Reviewer #3: This manuscript presents a large systematic review of efficacy and safety outcomes reported in human leptospirosis studies, with the objective of informing the development of a core outcome set. The authors synthesise data from 298 studies across 63 countries and apply recognised methodological standards (PRISMA, COMET, PROSPERO). The review clearly demonstrates extensive heterogeneity in outcome reporting, outcome measures, and treatment strategies, and highlights major gaps in patient-centred and harms outcomes. Overall, this is a timely and valuable contribution that addresses an important barrier to evidence-based leptospirosis research.

Major Strengths

• Exceptional breadth and global coverage, including a wide range of study designs.

• Clear demonstration of outcome heterogeneity across all COMET core areas.

• Novel synthesis of outcome measures and treatment practices not previously collated.

Major Comments

1. Influence of descriptive studies

Over half of included studies are descriptive (case reports/series), which likely overemphasises clinician-prioritised and severe outcomes. While acknowledged, the manuscript would benefit from a clearer justification in the Methods and a more explicit discussion of how this may shape the observed outcome landscape and COS development.

2. Outcome grouping and domain assignment

Outcomes and domains were derived inductively. Please clarify whether outcome grouping and mapping to COMET domains were independently reviewed or discussed among authors, and how disagreements were resolved.

3. Patient-reported outcomes

The near-complete absence of patient-reported outcomes is a key finding. The Discussion should more explicitly state that qualitative research and patient engagement will be essential in subsequent COS development phases, and clarify whether this is planned within COS-LEP.

4. Outcome reporting bias assessment

ORBIT assessments were conducted by a single reviewer. Please clarify whether any calibration or secondary checking was undertaken, and briefly discuss how outcome reporting bias may affect COS formulation.

5. Interpretation of treatment heterogeneity

The extensive variability in antimicrobial and adjunctive therapies is well described. To avoid overinterpretation, the discussion should clearly state that these findings contextualise outcome variability rather than evaluate treatment effectiveness.

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Reviewer #1: Yes: Ashish Bhalla

Reviewer #2: No

Reviewer #3: No

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Dear Ms. Edwards,

We are pleased to inform you that your manuscript 'Efficacy and safety outcomes reported in human leptospirosis studies to inform the development of a core outcome and core outcome measurement set: a systematic review' 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,

Vasantha Kumari Neela

Academic Editor

PLOS Neglected Tropical Diseases

Stuart Blacksell

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

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

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 #3: Strengths:

The methodology is rigorous and transparent, following PRISMA and COMET guidelines.

The inclusion of multiple languages and global databases ensures broad representation.

The use of QualSyst and ORBIT tools for quality and bias assessment is appropriate.

Suggestions:

Justify the inclusion of descriptive studies (case reports/series) more explicitly. While acknowledged in the discussion, a brief rationale in the methods would strengthen the approach.

Clarify how outcome grouping and COMET domain mapping were validated (e.g., consensus among authors, steering committee review).

Consider adding a flowchart or table summarizing the data extraction process (e.g., variables extracted, tools used).

**********

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 #3: Strengths:

The results are comprehensive and well-organized, with clear thematic grouping of outcomes and measures.

The use of sunburst charts and treemaps effectively visualizes the heterogeneity in outcomes and treatments.

The global distribution of studies (63 countries) and temporal trends (e.g., shift in antibiotic use) are insightful.

Suggestions:

Highlight key gaps in the results section (e.g., underreporting of patient-centered outcomes, lack of standardized measures).

Discuss the implications of regional variations (e.g., why cephalosporins are more common in recent studies from South Asia).

**********

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 #3: Strengths:

The conclusion is concise and actionable, reinforcing the need for a COS and patient-centered outcomes.

The call for qualitative research and standardized measures is well justified.

Suggestions:

End with a strong, forward-looking statement (e.g., "This review lays the foundation for a COS that could transform leptospirosis research and patient care globally").

**********

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 #3: None

**********

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 #3: Title and Abstract

Strengths:

The title is clear, concise, and accurately reflects the scope of the review.

The abstract effectively summarizes the background, methods, results, and conclusions, adhering to the journal’s requirements.

Suggestions:

Consider emphasizing the global health burden of leptospirosis in the abstract to underscore its relevance.

Clarify the novelty of the review (e.g., "first comprehensive synthesis of outcomes and measures in leptospirosis research").

Introduction

Strengths:

The introduction provides a compelling rationale for the study, highlighting the gap in standardized outcome reporting and its impact on clinical trials.

The global burden of leptospirosis is well contextualized with recent data (e.g., 1.03 million cases/year, USD 29.3 billion productivity loss).

The link between heterogeneous outcome reporting and weak evidence for treatments is clearly articulated.

Suggestions:

Briefly mention why a core outcome set (COS) is urgently needed for leptospirosis, beyond just improving trial quality (e.g., guiding policy, resource allocation).

Add a sentence on the potential impact of a COS on patient care and public health.

Methods

Strengths:

The methodology is rigorous and transparent, following PRISMA and COMET guidelines.

The inclusion of multiple languages and global databases ensures broad representation.

The use of QualSyst and ORBIT tools for quality and bias assessment is appropriate.

Suggestions:

Justify the inclusion of descriptive studies (case reports/series) more explicitly. While acknowledged in the discussion, a brief rationale in the methods would strengthen the approach.

Clarify how outcome grouping and COMET domain mapping were validated (e.g., consensus among authors, steering committee review).

Consider adding a flowchart or table summarizing the data extraction process (e.g., variables extracted, tools used).

Results

Strengths:

The results are comprehensive and well-organized, with clear thematic grouping of outcomes and measures.

The use of sunburst charts and treemaps effectively visualizes the heterogeneity in outcomes and treatments.

The global distribution of studies (63 countries) and temporal trends (e.g., shift in antibiotic use) are insightful.

Suggestions:

Highlight key gaps in the results section (e.g., underreporting of patient-centered outcomes, lack of standardized measures).

Discuss the implications of regional variations (e.g., why cephalosporins are more common in recent studies from South Asia).

Discussion

Strengths:

The discussion critically addresses the heterogeneity in outcome reporting and its implications for evidence synthesis.

The limitations are honestly acknowledged, including the influence of descriptive studies and potential reviewer bias.

The need for patient-reported outcomes and qualitative research is strongly emphasized.

Suggestions:

Strengthen the policy implications: How could a COS influence WHO guidelines, antimicrobial stewardship, or resource allocation?

Address the feasibility of implementing a COS in low-resource settings (e.g., cost, training needs).

Compare your findings with other neglected tropical diseases (e.g., dengue, melioidosis) to highlight unique challenges in leptospirosis.

Conclusion

Strengths:

The conclusion is concise and actionable, reinforcing the need for a COS and patient-centered outcomes.

The call for qualitative research and standardized measures is well justified.

Suggestions:

End with a strong, forward-looking statement (e.g., "This review lays the foundation for a COS that could transform leptospirosis research and patient care globally").

Minor Edits and Clarifications

Abstract: Replace "weak due to poor trial design" with "limited by heterogeneous outcome reporting and trial design."

Introduction: Clarify the timeline of the COS-LEP project (e.g., "This review is Phase 1 of the COS-LEP project").

Methods: Specify if machine translation was used for non-English studies and its potential limitations.

Results: Define abbreviations (e.g., MAT, ELISA) at first use.

Discussion: Avoid overstating the lack of AMR evidence—acknowledge the methodological challenges in testing susceptibility.

Overall Assessment:

This is a high-quality, timely systematic review that fills a critical gap in leptospirosis research. With minor revisions to sharpen the narrative and visuals, it will be a valuable resource for researchers, clinicians, and policymakers. The manuscript is well positioned for acceptance in PLOS Neglected Tropical Diseases.

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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 #3: No