Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO)

Guanghao Qin; Fang He; Hongda Zhang; Emmanuel Eric Pazo; Guangzheng Dai; Qingchi Yao; Wei He; Ling Xu; Tiezhu Lin

doi:10.1371/journal.pone.0263587

Peer Review History

Original SubmissionJune 6, 2021
14 Dec 2021 Decision Letter - Dario Ummarino, Editor PONE-D-21-18118Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO).PLOS ONE Dear Dr. Lin, 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 been evaluated by two reviewers, and their comments are available below. The reviewers have raised a number of concerns that need attention. They request additional information on methodological aspects of the study and the interpretation of the results. Could you please revise the manuscript to carefully address the concerns raised? Please submit your revised manuscript by Jan 20 2022 11:59PM. 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Kind regards, Dario Ummarino, Ph.D. Senior Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf. 2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] 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: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: Yes Reviewer #2: No ****** 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 ****** 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: Comments to the Author, In the present study, Lin T et al. evaluated the association between the value of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to high-density lipoprotein ratio (MHR) and the development of retinal artery occlusion (RAO) and retinal vein occlusion (RVO). Generally paper is well-written and provides clear explanations for their results. However, I have some important suggestions must be addressed by authors, which contribute to increase the validity of this study as follow; 1) RDW is also one of the important inflammation biomarker. It would be better if authors mention the RDW levels in table 3. 2)Did the authors exclude the patients with anemia? 3) Please add and discuss below references in the discussion part since they are all about your article issue. 1: Kurtul BE, Ozer PA. Neutrophil-to-lymphocyte ratio in ocular diseases: a systematic review. Int J Ophthalmol. 2019 Dec 18;12(12):1951-1958. doi:10.18240/ijo.2019.12.18. PMID: 31850181; PMCID: PMC6901879. 2: Kurtul BE, Çakmak Aİ, Elbeyli A, Özarslan Özcan D, Özcan SC, Cankurtaran V.Assessment of platelet-to-lymphocyte ratio in patients with retinal vein occlusion. Ther Adv Ophthalmol. 2020 Nov 18;12:2515841420971949. doi: 10.1177/2515841420971949. PMID: 33283155; PMCID: PMC7686591. 3: Elbeyli A, Kurtul BE, Ozcan DO, Ozcan SC, Dogan E. Assessment of Red Cell Distribution Width, Platelet/lymphocyte Ratio, Systemic Immune-inflammation Index, and Neutrophil/lymphocyte Ratio Values in Patients with Central Retinal Artery Occlusion. Ocul Immunol Inflamm. 2021 Sep 15:1-5. doi: 10.1080/09273948.2021.1976219. Epub ahead of print. PMID: 34524949. 4) The study would benefit from minor English editing. Reviewer #2: In this paper, Qi et al. compare NLR, PLR and MHR in RAO and RVO. The Authors' findings are interesting; however, there are several issues which need to be addressed, as outlined below. Table 1 - Two recent studies, one assessing NLR and PLR role in RVO (Liu et al. Acta Ophthalmol. 2021 Jul 4. doi: 10.1111/aos.14955) and the other investigating CBC measures in RAO (Pinna et al. Acta Ophthalmol. 2021 Sep;99(6):637-643. doi: 10.1111/aos.14699) are missing. These should be included and commented. - The Table should be displayed in a horizontal view. This makes it easier to read. Methods C-reactive protein and/or erythrocyte sedimentation rate (ESR) are essential to make a diagnosis of arteritic RAO. However, these markers were not analyzed in this paper (line 207). The Authors state that giant cell arteritis was a criterion for exclusion (line 110). How was this exclusion made? If there are no patients with arteritic RAO, all the subjects enrolled in the study had non-arteritic RAO. If so, this has to be clearly stated throughout the manuscript. Indeed, if in the RAO group there are patients with both the arteritic and the non-arteritic form, the higher NLR values associated with arteritic RAO may significantly affect the final overall result. This is a critical point to clarify. Discussion - RAO and RVO are two different vascular retinal disorders with different pathophysiology, risk factors and natural history. What's the rationale for comparing NLR, PLR, and MHR values in these vasculopathies? Please explain. - line 171. Some recent studies suggest lack of association between NLR and PLR and RVO. Conversely, MPV and, to a lesser extent, RDW may be disease biomarkers in RVO (Pinna et al. Ophthalmic Epidemiol. 2021 Feb;28(1):39-47. doi: 10.1080/09286586.2020.1791349). This should be discussed. ****** 6. 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. https://doi.org/10.1371/journal.pone.0263587.r001
Revision 1
10 Jan 2022 Author Response RE: PONE-D-21-18118 Title: Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO). Reviewer #1 comments: 1) RDW is also one of the important inflammation biomarkers. It would be better if authors mention the RDW levels in table 3. Response: We thank the reviewer for the comments. We have added the relevant data about RW and MPV in Table 3, but we didn’t find any significant difference among 3 groups. (page 12, lines 197-200). 2)Did the authors exclude the patients with anemia? Response: We thank the reviewer for the comments. In this study we excluded the patients with any blood disease, including anemia, thrombocytopenia and leukopenia. (pages 6, lines 110). 3) Please add and discuss below references in the discussion part since they are all about your article issue. 1: Kurtul BE, Ozer PA. Neutrophil-to-lymphocyte ratio in ocular diseases: a systematic review. Int J Ophthalmol. 2019 Dec18;12(12):1951-1958. doi:10.18240/ijo.2019.12.18. PMID: 31850181; PMCID: PMC6901879. 2: Kurtul BE, Çakmak Aİ, Elbeyli A, Özarslan Özcan D, Özcan SC, Cankurtaran V.Assessment of platelet-to-lymphocyte ratio in patients with retinal vein occlusion. Ther Adv Ophthalmol. 2020 Nov 18;12:2515841420971949. doi:10.1177/2515841420971949. PMID: 33283155; PMCID: PMC7686591. 3: Elbeyli A, Kurtul BE, Ozcan DO, Ozcan SC, Dogan E. Assessment of Red Cell Distribution Width, Platelet/lymphocyte Ratio,Systemic Immune-inflammation Index, and Neutrophil/lymphocyte Ratio Values in Patients with Central Retinal Artery Occlusion. Ocul Immunol Inflamm. 2021 Sep 15:1-5. doi: 10.1080/09273948.2021.1976219. Epub ahead of print. PMID:34524949. Response: We thank the reviewer for the comments. We have added the reference above in the paper. (references 43,49,50). 4) The study would benefit from minor English editing. Response: We thank the reviewer for the comment. We have done the English editing. Reviewer #2 comments: Table 1 - Two recent studies, one assessing NLR and PLR role in RVO (Liu et al. Acta Ophthalmol. 2021 Jul 4. doi: 10.1111/aos.14955) and the other investigating CBC measures in RAO (Pinna et al. Acta Ophthalmol. 2021 Sep;99(6):637-643. doi:10.1111/aos.14699) are missing. These should be included and commented. - The Table should be displayed in a horizontal view. This makes it easier to read. Response: We appreciate the reviewer's comments. Table 1 has been updated to include the two studies. Additionally, we reoriented Table 1 horizontally. Methods C-reactive protein and/or erythrocyte sedimentation rate (ESR) are essential to make a diagnosis of arteritic RAO. However, these markers were not analyzed in this paper (line 207). The Authors state that giant cell arteritis was a criterion for exclusion (line 110). How was this exclusion made? If there are no patients with arteritic RAO, all the subjects enrolled in the study had non-arteritic RAO. If so, this has to be clearly stated throughout the manuscript. Indeed, if in the RAO group there are patients with both the arteritic and the non-arteritic form, the higher NLR values associated with arteritic RAO may significantly affect the final overall result. This is a critical point to clarify. Response: We thank the reviewer for this great advice. In this study, we have excluded the patients with giant cell arteritis. CRP was tested in only RAO patients. (page 5-6, lines 89-90，109-110). Discussion - RAO and RVO are two different vascular retinal disorders with different pathophysiology, risk factors and natural history. What's the rationale for comparing NLR, PLR, and MHR values in these vasculopathies? Please explain. - line 171. Some recent studies suggest lack of association between NLR and PLR and RVO. Conversely, MPV and, to a lesser extent, RDW may be disease biomarkers in RVO (Pinna et al. Ophthalmic Epidemiol. 2021 Feb;28(1):39-47. doi:10.1080/09286586.2020.1791349). This should be discussed. Response: We thank the reviewer for the comments. Although the pathophysiology of RAO and RVO are not the same, previous studies believed that they were both related to thrombosis and inflammation. Some studies suggest that arterial thrombosis contains more NETs than venous thrombosis. (pages 11, lines 175-184) Although previous studies have shown NLR and/or PLR might be the potential biomarkers in RAO or RVO, we would like to explore if there is some difference between them. We also included the relevant data for RW and MPV in Table 3, but we didn’t find any significant difference among the 3 groups. We speculated that the patients’ race, exclusion criterion and sample size might be responsible for the various results of different studies. (pages 12, lines 197-200). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0263587.r002
14 Jan 2022 Decision Letter - Antonio Pinna, Editor PONE-D-21-18118R1Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO).PLOS ONE Dear Dr. Lin, 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. ACADEMIC EDITOR I participated as a reviewer for the initial evaluation of this manuscriptPlease improve your paper with the suggestions reported below Please submit your revised manuscript by Feb 28 2022 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, Antonio Pinna, M.D. 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. Academic Editor Comments: The manuscript has been revised appropriately and with some minor suggested amendments noted below should be suitable for publication in PLOS ONE. - Please incorporate in the Discussion your response to Reviewer #2 comment: "Although the pathophysiology of RAO and RVO are not the same, previous studies believed that they were both related to thrombosis and inflammation. Some studies suggest that arterial thrombosis contains more NETs than venous thrombosis. Although previous studies have shown NLR and/or PLR might be the potential biomarkers in RAO or RVO, we would like to explore if there is some difference between them." - Line 125: please change "mean SD" into "mean ± standard deviation (SD) - Line 126: please change "normalcy" into "normality" - Line 127: please change "the postmortem test" into "post hoc analysis" - Line 130: please change "to predict" into "predicted" - Line 152: please move the full stop after (Figure 2) - Line 200: please change "virous" into "various" - Line 211: please change "Finally" into "To sum up" - Line 215: please change "may be a potential biomarker for RAO rather than PLR" into "may be a more reliable biomarker for RAO than PLR" - Throughout the test: please do not use the short form of auxiliary verbs. Use "we would" instead of "we'd", "did not find" instead of "didn't find", and so on. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: N/A [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. https://doi.org/10.1371/journal.pone.0263587.r003
Revision 2
15 Jan 2022 Author Response RE: PONE-D-21-18118R1 Title: Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO). Academic Editor comments: 1) Please incorporate in the Discussion your response to Reviewer #2 comment: "Although the pathophysiology of RAO and RVO are not the same, previous studies believed that they were both related to thrombosis and inflammation. Some studies suggest that arterial thrombosis contains more NETs than venous thrombosis. Although previous studies have shown NLR and/or PLR might be the potential biomarkers in RAO or RVO, we would like to explore if there is some difference between them." Response: We thank the editor for the comments. We have added that in the last paragraph. (page 13, lines 215-218). 2) - Line 125: please change "mean SD" into "mean ± standard deviation (SD) - Line 126: please change "normalcy" into "normality" - Line 127: please change "the postmortem test" into "post hoc analysis" - Line 130: please change "to predict" into "predicted" - Line 152: please move the full stop after (Figure 2) - Line 200: please change "virous" into "various" - Line 211: please change "Finally" into "To sum up" - Line 215: please change "may be a potential biomarker for RAO rather than PLR" into "may be a more reliable biomarker for RAO than PLR" - Throughout the test: please do not use the short form of auxiliary verbs. Use "we would" instead of "we'd", "did not find" instead of "didn't find", and so on. Response: We thank the editor for the comments. We have done all the revision above. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0263587.r004
24 Jan 2022 Decision Letter - Antonio Pinna, Editor Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO). PONE-D-21-18118R2 Dear Dr. Lin, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Antonio Pinna, M.D. Guest Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0263587.r005
Formally Accepted
26 Jan 2022 Acceptance Letter - Antonio Pinna, Editor PONE-D-21-18118R2 Neutrophil-to-lymphocyte Ratio (NLR), Platelet-to-lymphocyte Ratio (PLR) are more prominent in retinal artery occlusion (RAO) compared to retinal vein occlusion (RVO) Short title: NLR, PLR and MHR in Retinal Vascular Occlusions Dear Dr. Lin: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Antonio Pinna Guest Editor PLOS ONE https://doi.org/10.1371/journal.pone.0263587.r006

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