Dear Mr xia,

Thank you very much for submitting your manuscript "Chromoblastomycosis: A case series from eastern China" 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. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

This relatively small case series has merit as this disease has rarely been diagnosed from this part of China before, cases came forward as part of a campaign, the initial diagnosis was made with KOH, not biopsy, and most of the isolates were identified as F monophora.

The article would be stronger if these points were emphasised (along with the long period of missed diagnosis in many of them). It would also be stronger if a proper description of the campaign to find cases was described, and the results of this campaign in terms other NTDs described. how many cases of leprosy, sporotrichosis, mycetoma, cutaneous mycobacterial infections etc were found alongside chromoblastomycosis.

The article requires extensive revision and better quality pictures (and preferably before and after treatment pictures) to be acceptable for publication. Please attend to the referees comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. 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,

David W. Denning

Guest Editor

PLOS Neglected Tropical Diseases

Ahmed Fahal

Deputy Editor

PLOS Neglected Tropical Diseases

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

This relatively small case series has merit as this disease has rarely been diagnosed from this part of China before, cases came forward as part of a campaign, the initial diagnosis was made with KOH, not biopsy, and most of the isolates were identified as F monophora.

The article would be stronger if these points were emphasised (along with the long period of missed diagnosis in many of them). It would also be stronger if a proper description of the campaign to find cases was described, and the results of this campaign in terms other NTDs described. how many cases of leprosy, sporotrichosis, mycetoma, cutaneous mycobacterial infections etc were found alongside chromoblastomycosis.

The article requires extensive revision and better quality pictures (and preferably before and after treatment pictures) to be acceptable for publication. Please attend to the referees 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: Please explain in more detail what is meant by a consultation campaign.were there regional

organised clinics specifically seeking cases of chromoblastomycosis or skin disease in general. We

need to know a bit more about this recruitment method.

Was the mycological work, including direct microscopy carried out in a single laboratory ?

Reviewer #2: Suggestions and or comments were attached

Reviewer #3: The authors retrospectively reviewed 11 cases of CBM in one center of Eastern China in three years.

Reviewer #4: The objective can be more clearly stated. It is a prospective study but in the introduction, it stated that "In order to evaluate the clinical characteristics of CBM in Zhejiang,eastern China,we reviewed 11 cases..," which may imply that it was a retrospective study instead.

In page 2, paragraph 1, the author stated: "Patients were recruited between January 2018 and December 2021 and during consultation campaigns conducted in Zhejiang Province.." What was meant by consultation campaigns? Were these "information campaigns" conducted in other clinics so that these kinds of cases were referred to the Hangzhou Third people's Hospital? It may good to describe further the "consultation campaign" and referral system followed since this would give readers an idea on the actual catchment area of the facility. Is Hangzhou Third people's Hospital a specialty hospital?

Since it is a case series, conducted prospectively, it would have been better if pictures of individual cases were taken, and sizes of lesions were recorded. It would be interesting to note if cases with smaller lesion sizes responded to therapy faster and more completely, compared to those with larger and more disseminated lesions.

Was surgery an option in any of the cases? If not, why not?

--------------------

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: Please explain the following phrase - consolidate treatment due to the interference of comorbidity.

Kidney trouble – better chronic renal disease.

Reviewer #2: The use of lesions severity graduation would be this article more interesting for clinicians

Reviewer #3: The study indicated that the most common pathogenic fungus was F.monophora.

Reviewer #4: Figure 1 clinical photos are not clear. It would be good to indicate which particular cases these were.

Since it is a case series, it would be good to include before and after treatment pictures as well.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The authors argue for improving diagnostic ability in rural areas to reduce the risk of misdiagnosis. It

would, be useful here to discuss possible methods of doing this.

Please mention other forms of treatment such as oral terbinafine or heat therapy.

It would be useful in the discussion to on the distribution and case load of chromoblastomycosis in

China. How common is it ? Are there any explanations for the differ ent distribution of organisms ?

Why is F monophora a dominant cause in China ? Is this a true geographic variation or is this because

without molecular tools most such strains have been misidentified as F pedrosoi in the past ?

Reviewer #2: Suggestions and or comments were attached

Reviewer #3: The authors should indicate the limitations of this case series, such as the limited number of the patients, single center study, etc.

Reviewer #4: The conclusions can be improved to refer more to the cases seen in the facility.

--------------------

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: There are some changes needed to the English. Please mention that chromoblastomycosis is

formally designated by WHO as an NTD

Reviewer #2: (No Response)

Reviewer #3: None

Reviewer #4: Page 4, paragraph 1: associated condition, not predisposing

Page 3, paragraph 1: 8 cases were misdiagnosed; Page 4, paragraph 2: 7 cases were diagnosed. Please clarify.

--------------------

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: (No Response)

Reviewer #2: Suggestions and or comments were attached

Reviewer #3: The novelty of this study is relatively low.

Reviewer #4: 1. There may be a need to edit the article for it to be publishable.

2. These are the points that I think are good take-aways from this article

a. All cases were initially evaluated in other clinics before the information campaign and 8 were misdiagnosed. This highlights the importance of educating primary physicians or those who usually initially manage these cases, on recognizing chromoblastomycosis and other skin neglected tropical diseases.

b. All 11 cases were diagnosed with chromoblastomycosis after doing a simple, easy, non-invasive, inexpensive, out-patient procedure, the KOH smear. This illustrates that KOH smear may even be more sensitive in catching these cases compared to punch biopsy.

--------------------

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Reviewer #1: No

Reviewer #2: Yes: Flávio Queiroz-Telles

Reviewer #3: No

Reviewer #4: Yes: Maria Christina Filomena Batac

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Attachments

Attachment

Submitted filename: Chromoblastomycosis in Eastern China.docx

Attachment

Submitted filename: PNTD-D-22-00708_reviewer.pdf

Dear Mr xia,

Thank you very much for submitting your manuscript "Chromoblastomycosis: A case series from eastern China" 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 remove the term dematiaceous and replace with brown pigmented - throughout the manuscript, including the abstract.

There are still some errors of english, which should be improved before final publication. For example 'histopathology, not histopathology of biopsies'

In the abstract just state how many males, not a ratio.

The authors have added helpful information on the other similar presentations. Do they have any sense of trends over time? Is CBM diminishing in frequency, or static? And how does it compare to sporotrichosis, for example.

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.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

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,

Ahmed Fahal, FRCS, FRCSI, FRCSG, MS, MD, FRCP(London)

Section Editor

PLOS Neglected Tropical Diseases

Ahmed Fahal

Section Editor

PLOS Neglected Tropical Diseases

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

Please remove the term dematiaceous and replace with brown pigmented - throughout the manuscript, including the abstract.

There are still some errors of english, which should be improved before final publication. For example 'histopathology, not histopathology of biopsies'

In the abstract just state how many males, not a ratio.

The authors have added helpful information on the other similar presentations. Do they have any sense of trends over time? Is CBM diminishing in frequency, or static? And how does it compare to sporotrichosis, for example.

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 authors have answered my queries

Reviewer #2: The author added the reviwers suggestions or comments to the current manuscript version

Reviewer #4: The paper described that aside from chromoblastomycoses, other subcutaneous mycoses were diagnosed during the same 3-year period of the study. It is good to disclose if these have been described or will be described in another paper, (and include proper citations).

--------------------

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 authors have answered my queries

Reviewer #2: The author added the reviwers suggestions or comments to the current manuscript version

Reviewer #4: Pictures had no accompanying descriptive texts.

It will be good to compare the frequency of cases of subcutaneous mycoses diagnosed over the years in their facility. Has there been an increase in diagnosis due to greater awareness of the disease entities? Or after they have adapted this "routine flowchart" in diagnosing subcutaneous diseases?

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The authors have answered my queries

Reviewer #2: This paper is relevant for the Public Health because chromoblastomycosis is one of the few fungal infections, officially recognized as NTD by the WHO

Reviewer #4: (No Response)

--------------------

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: Nil needed

Reviewer #2: Please note that "dematiaceous fungi "is an obsolete term. "Melanized fungi" is week stablished denomanation for all chromoblastomicosis and phaeohyphomiycosis etiological agents

Reviewer #4: Abstract: Since the sample being described is small, only 11, then it is better to just say outright how many are males and how many are females, instead of giving the ratio of 4.5:1

Terms: histopathology, not histopathology of biopsies

--------------------

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: The authors have answered my queries

Reviewer #2: I suggested a mino revision

Reviewer #4: The flow of the narrative can be improved. Although much improved from the first draft, it needs more editing to be publishable.

--------------------

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: Flavio Queiroz-Telles

Reviewer #4: Yes: Maria Christina Filomena Batac

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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 Mr xia,

We are pleased to inform you that your manuscript 'Chromoblastomycosis: A case series from eastern China' 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,

David W. Denning

Guest Editor

PLOS Neglected Tropical Diseases

Ahmed Fahal

Section Editor

PLOS Neglected Tropical Diseases

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None