Dear Dr Lockwood,

Thank you very much for submitting your manuscript "Diagnosing and treating leprosy in a non-endemic setting in a national centre, London, United Kingdom 1995-2018" 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.

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.

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[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).

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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,

Mauro Sanchez, ScD

Associate Editor

PLOS Neglected Tropical Diseases

Elizabeth Batty

Deputy 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: Sound methodology.

The Abstract says new cases were analyzed, but this is not actually stated in the Methods section of the full paper. It would be interesting to know how many other cases were seen over this time period (previously treated, true relapses, people attending to continue treatment started elsewhere, etc.), although the subject of the paper is clearly limited to new cases.

Reviewer #2: In this retrospective analysis, data was collected from 1995 to 2018 of patients diagnosed with leprosy at the HTD. Data on demographics, migration, travel, symptoms, diagnostics, treatment were collected and reported. The data is clearly presented in Tables (1: Sex and age at diagnosis, 2: Presumed country of acquisition, 3: WHO region of birth, 4: Clinic features of RJ Classification, 5: First referral specialty, 6: Time between arrival in UK and symptom onset). The methods are clearly defined and appropriate

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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 paper is about diagnosis, which is covered well.

One area I think could be xpanded is the information about skin biopsies, which were done on 119 cases, but only 88 (74%) were diagnostic for leprosy. What were the results for the 31 cases that did not indicate leprosy? Were there other diagnoses, or were they mainly 'non-specific' changes? Another question of interest is whether the positivity rate changed over time - perhaps improving in later years, with better techniques, or perhaps declining due to loos of expertise? Were any biopsy results revised on further examination?

As the diagnosis in children is becoming a key indicator of transmission, I think it would be helpful to give more detail about the two child cases - where were they thought to contract leprosy? It would also be helpful to know the age of the persons diagnosed after living in Kosovo and Jamaica, which are probably now non-endemic - one would expect them to be quite elderly.

Reviewer #2: The results of the retrospective analysis are clearly presented in tables. The information is depicted in a clear and concise manner and each table is relevant to the study.

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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: The Conclusions are sound.

Reviewer #2: This is an excellent and important retrospective analysis of patients with leprosy that presented and were treated at HTD from 1995- 2018. The authors discuss that the majority of the patients acquired leprosy in their country of birth "whether prior to arrival in the UK or on return visits". Given the timing of acquisition of leprosy, it was felt that leprosy is not a disease of travellers. Overall, the conclusions appear to be well-supported by the data. I appreciate the data on time between arrival in the UK and symptom onset. Interestingly, 26% had been present in the UK for greater than 10 years. I wonder if the patients with delayed symptoms visited endemic countries for prolonged periods of time allowing for acquisition. I appreciate the author's discussion regarding the potentially long incubation period, which may also explain this interval.

The data on nerve function and number of patient's in reaction at time of diagnosis is valuable as well when patients present with leprosy as a diagnosis.

Overall, this is an excellent and well-written manuscript that has organised and presented a large of amount data regarding patients with leprosy who presented to HTD. It is an important disease to recognize in patients from endemic regions.

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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: (No Response)

Reviewer #2: This is an excellent manuscript with a substantial amount of data that is very relevant to the field of infectious disease among other fields. I recommend minor revision. With these revisions, I recommend accepting this manuscript for publication.

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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: The paper is well presented.

Reviewer #2: This is an excellent, well-written and eloquent retrospective analysis on a large and import color of patients see at HTD from 1995-2018. I want to commend the authors for the amount of data obtained and analyzed. This study highlights several important factors including potentially long incubation time to develop leprosy, diagnostics, treatment with need for multidisciplinary care. The stigma of leprosy is also addressed, which is important. This is an important study and will be a valuable contribution to the literature. I have a few small recommendations.

line 42: please correct comma location: 53, 33.1%

line 272: MDT side effects mentioned.Are there any side effects of ROM that were experienced by patients?

Line 371: thalidomide is mentioned as a treatment. It would be interesting for the authors to list treatments that were used for type 1 reactions and ENL in addition to thalidomide. I do not think patient specific data is needed, just a general list of medications would be interesting.

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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 #1: Yes: Paul Saunderson

Reviewer #2: No

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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 Dr Lockwood,

We are pleased to inform you that your manuscript 'Diagnosing and treating leprosy in a non-endemic setting in a national centre, London, United Kingdom 1995-2018' 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,

Mauro Sanchez, ScD

Academic Editor

PLOS Neglected Tropical Diseases

Elizabeth Batty

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: (No Response)

Reviewer #2: Excellent, well-described.

**********

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: (No Response)

Reviewer #2: (No Response)

**********

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: (No Response)

Reviewer #2: (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: (No Response)

Reviewer #2: (No Response)

**********

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: (No Response)

**********

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: Yes: Paul Saunderson

Reviewer #2: No