Dear Ms Bourner,

Thank you very much for submitting your manuscript "Challenges in Clinical Diagnosis of Clade I Mpox: Highlighting the Need for Enhanced Diagnostic Approaches" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

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

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

Sincerely,

Wen-Ping Guo

Academic Editor

PLOS Neglected Tropical Diseases

Michael Holbrook

Section Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

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

Reviewer #1: The objectives and hypothesis are clear. The study is reasonable given the working conditions of the target of the survey. The persons to whom the survey were sent is not defined, only as mpox experts or experienced clinicians. It is important to identify more clearly to whom the survey was sent, and it would improve clarity to explain it was sent electronically to persons working remotely in central Africa (to the extent that is correct). The desired sample size was not defined. However, this is a descriptive study and the confidence limits on the resultant measures are provided. The analysis is reasonable, comparing the evaluation of pictures of skin lesions with the underlying diagnoses of mpox or varicella, and measuring agreement among observers.

Reviewer #2: (No Response)

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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 presented corresponds to the plan and are clearly presented. I believe some of the figures are not necessary and do not add to the presentation of the results.

Reviewer #2: (No Response)

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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: In practice, clinicians would have more data than simply the visual inspection of skin lesions to determine if a patient has mpox (disease from MPXV infection) or varicella, and to determine the stage of mpox. Clinicians would know the age of the patient, would know the status of others in the family and perhaps in the community, would know the duration of the illness, and may know something of the vaccination status of the patient. So this study does not replicate the situation of making a diagnosis in the field. At the same time, it provides information on the uncertainty of basing the diagnosis of a potentially life threatening illness and outbreak on only the visual inspection of the skin lesions. The author's reference the WHO case surveillance definition for suspected MPXV infection which includes the presence of typical skin lesions and the low likelihood of an alternative diagnosis (varicella zoster, herpes zoster, measles, herpes simplex, bacterial skin infections, disseminated gonococcus infection, primary or secondary syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, molluscum contagiosum, allergic reaction (e.g., to plants); and any other locally relevant common causes of papular or vesicular rash). The authors state that given the severity of Clade I MPVX with high rates of transmission and mortality, it is important not to rely on visual assessment of the skin lesions and it is very important to increase access to specific diagnostics (currently nucleic acid testing) in central Africa where Clade I is transmitted

This study regarding Clade I MPVX infection compliments the author's prior studies regarding the more common Clade II MPVX infection.

Reviewer #2: (No Response)

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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: Several of the figures seem of limited value to me, without adding to the information in the narrative and tables, if the number of figures is an issue for the publisher. There needs to be more detail about the makeup of the persons who were sent the survey, not just a table of where respondents were based and self report on expertise and number of patients treated. There should be an acknowledgement that clinicians have more data than just the appearance of the lesions when making a diagnosis. The WHO definition is not only based on the appearance of the lesions, as the authors suggest, but also on information that help judge the likelihood of alternate diagnoses.

With these clarifications, the paper could be accepted.

Reviewer #2: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: It is a cleverly managed study regarding an illness of rapidly increasing importance. Although there is widespread agreement that access to pathogen specific diagnostics for Clade I MPVX in remote parts of central Africa (DRC, CAR, Cameroon, Sudan, and South Sudan), this study adds to the growing knowledge of this very important illness and pathogen.

Reviewer #2: I commend the authors for this study, which highlights the critical issue of diagnostic capacity in developing countries, often resulting in incorrect therapeutic interventions. However, it's important to acknowledge that diagnosis is multifaceted, relying not only on images but also on factors like risk assessment, patient history, and physical examination. While the study emphasizes the role of images, it should discuss the broader diagnostic process in its introduction and discussion. Additionally, exploring prior research on the role of images in diagnosing diseases like mumps, smallpox, and varicella, which primarily present with characteristic rashes, would enhance the study's context and significance.

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Reviewer #1: Yes: Jonathan Allen Cohn, MD MS FACP FIDSA

Reviewer #2: Yes: Dawd Siraj

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References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Ms Bourner,

We are pleased to inform you that your manuscript 'Challenges in Clinical Diagnosis of Clade I Mpox: Highlighting the Need for Enhanced Diagnostic Approaches' 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,

Wen-Ping Guo

Academic Editor

PLOS Neglected Tropical Diseases

Michael Holbrook

Section Editor

PLOS Neglected Tropical Diseases

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