PONE-D-21-16802

Risk factors for emerging intraocular inflammation after intravitreal bevacizumab injection for age-related macular degeneration

PLOS ONE

Dear Dr. Mukai,

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.

Both reviewers found the topic of great interest but they note many limitations that have to be addressed before a final decision can be made

Please submit your revised manuscript by Aug 27 2021 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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: Partly

Reviewer #2: No

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

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

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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: No

Reviewer #2: No

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4. 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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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: The authors present an interesting study on a topic of very high interest: intraocular inflammation after brolucizumab. They are invited to consider the following recommendations to further strengthen their work:

The very title of the article is not in agreement with the article. Do the authors investigate bevacizumab (Avastin) or Brolucizumab (Beovu) ?

Define ’others’ in abstract results

Please correct syntax in the last phrase of your abstract: ‘elders’ is not a ‘risk factor’.

Please be more specific in your introduction tha, ‘relatively frequently’.

Describe the percentages for IOI for bevacizumab, ranibizumab and aflibercept and directly compare with the percentages in the brolucizumab studies.

Seems like not all the eyes included in this study were treatment naive. if not, how many weeks/months since the last antiVEGF injection? define your inclusion and exclusion criteria in more detail.

Was FA, IA and SS-OCTA performed to all eyes at every single visit ? This would be interesting in terms of how many imaging tests were the patients undergoing in their regular visits, since this was a retrospective review, not a prospective study.

Methods should be overall more detailed.

What exactly was the technique/protocol followed when injecting?

Were all the injections preformed by the same person ?

If not, what was the technique/protocol of all different treating physicians exactly the same ?

You should define intraocular inflammation in a very strict and precise manner

It would be interesting to investigate whether the injection technique/protocol had any effect on the occurrence of IOI.

Statistical analysis: did the authors check whether their data are normally distributed ?

The authors need to go more in depth and try to explain why the factors they found that were associated with higher IOI rates are risk factors. Please elaborate more in your discussion.

Reviewer #2: The authors present a study regarding "Risk factors for emerging intraocular inflammation after intravitreal bevacizumab injection for age-related macular degeneration". This is a very interesting topic as we are trying to understand the safety profile of this new agent Brolicizumab even though they have the wrong name of medicine in the title which makes it very confusing...

However, the study the authors have presented has very limited analysis and does not add anything to the literature and is missing significant information eg time when IOI was diagnosed, severity of IOI, number of previous anti VEGF injection, what type of of anti VEGF injection, also majority of oateintas had PCV in the IOI group- was it the same as in the IOI group? What about degreee of existing DR in addition to DM. Authors should do a much more through review of all characteristics of patients to provide an analysis of the risk factors in involved in IOI group.

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Reviewer #1: No

Reviewer #2: No

[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.]

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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-21-16802R1Risk factors for emerging intraocular inflammation after intravitreal bevacizumab injection for age-related macular degenerationPLOS ONE

Dear Dr. Mukai,

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.

 The manuscript has improved. There remain some areas for clarification and expansion and we look forward to hte revised version. 

Please submit your revised manuscript by Dec 04 2021 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 rebuttal 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.

We look forward to receiving your revised manuscript.

Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

Journal Requirements:

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.

Additional Editor Comments (if provided):

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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: (No Response)

Reviewer #2: (No Response)

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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: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: I Don't Know

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: No

Reviewer #2: No

**********

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

**********

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 substantially improved their work. They are invited to consider the following additional recommendations:

1. Your abstract’s conclusion seems more like a purpose. Please provide a conclusion that sums up the findings of your study and why they might be clinically relevant. (same way as in the conclusion ion the manuscript)

2. Injection technique varies between different treating physicians. This is well documented for antiVEGF injections. How can the authors be sure that injection technique did not affect the rates of IOI since per line 72, 7 different physicians performed the brolucizumab injections.

3. Please clarify the device used for SS-OCT (line 80)

4. Table 2 is confusing. What do all the ‘1’s represent ? If its individual parents please number the patients.

5. Did the number of previous injections in the non-treatment naive eyes affect the rate of IOI ?

Reviewer #2: Even though the manuscript has improved from pervious version, it still lacks in depth analysis in particular regarding the vision outcomes of IOI and the vision threatening forms of IOI of vasculitis and how they responded and if risk factors described for all IOI also apply for the vision threatening one that is the most concerning

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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.

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: No

[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.]

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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Risk factors for emerging intraocular inflammation after intravitreal brolucizumb injection for age-related macular degeneration

PONE-D-21-16802R2

Dear Dr. Mukai,

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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Kind regards,

Demetrios G. Vavvas

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: