Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosis

Gustavo L. Rezende; Marcio Nakanishi; Shirley C. P. Couto; Carmen L. F. S. Martins; André L. L. Sampaio; Lucas F. F. Albuquerque; Selma A. S. Kückelhaus; Maria I. Muniz-Junqueira

doi:10.1371/journal.pone.0267986

Peer Review History

Original SubmissionDecember 20, 2021
24 Mar 2022 Decision Letter - Mrinmoy Sanyal, Editor PONE-D-21-40067Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosisPLOS ONE Dear Dr. Rezende, 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. We believe addressing the reviewer's comments will significantly improve the quality and readability of the manuscript. Please note that the detail comments of Reviewer # 1 are an attachment (Word file). Please download the comments and address them. Please submit your revised manuscript by May 08 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. 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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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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: Partly ******** 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: Yes ****** 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: No ****** 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 findings in the manuscript has been well presented, providing statistical analyses as well as clear explanation of the methods implemented. Overall the manuscript is easy to follow. I have attached my comments for further perusal to help improve the manuscript. Reviewer #2: REVIEW SUMMARY In this study Rezende et al. aims to understand how the innate immune system’s function changes in patients of cystic fibrosis and compared it with a sub-group who have developed chronic rhinosinusitis. This manuscript was assessed for the 7 criteria for publication in PLoS One. Rezende et al. present results of original research that have not been published elsewhere. Experiments performed, statistical analyses meet high technical standard and are described in sufficient detail. The analytical rigor of the authors is demonstrated by the fact that they perform corrections for normally and non-normally distributed data. The authors also adhere to reporting and ethics standards — all volunteers and their parents/guardians signed consent forms. However, there are deficiencies in conclusions drawn from the results, and on article presentation/reporting. The authors over-extend when drawing conclusions from their results. In the introduction section in the abstract, instead of focusing on the gap in knowledge statements about the field of cystic fibrosis is made that is unambiguous and not entirely accurate. In addition, the results section and figure panels are structured in a difficult to interpret manner. As such, in its current form this manuscript cannot be recommended for publication. Detailed comments are below. MAJOR COMMENTS ON CONCLUSION 1. In the introduction section (Page 7, last paragraph), the authors write “… we evaluated whether neutrophiles and monocytes that circulate in the peripheral blood participate directly in inflammatory activity in the paranasal sinuses”. This is incorrect. In vitro assessment of phagocytotic activity and superoxide anion production of neutrophiles and monocytes cannot be used to determine whether these cells participate directly in inflammatory activity in the paranasal sinuses. This is particularly true because these immune cells were isolated from peripheral blood collected in vacuum tubes, presumably through venous blood draw from the arm (Materials and Methods section, Page 9, 3rd paragraph). This conclusion is incorrect. 2. In the highlights section (Page 3, 2nd bullet point), the authors write “Chronic Rhinosinusitis related to Cystic Fibrosis group has impaired leukocytes compared to control group”. This is an over-extension of the results. The authors measure in vitro phagocytotic ability of neutrophiles and monocytes (Y-axis labels, Fig 1 and 2), not for leukocytes that include B-cells, cytotoxic T-cells. Hence this statement is incorrect and does not accurately reflect the results. MAJOR COMMENTS ON ARTICLE PRESENTATION/REPORTING 1. The results section is structured in a difficult to interpret manner. Numbering is not used, and nesting of sub-sections is achieved through italicizing. Also, each paragraph in the “Evaluation of superoxide production by phagocytes” section has its own sub-heading. This is not required and adds unnecessary word count to the manuscript. 2. In the abstract the authors write “The role of leukocytes in the innate immune system of children with cystic fibrosis (CF) is unclear, mainly when associated with chronic rhinosinusitis”. The sentence should be constructed in an unambiguous manner that aligns with the experiments conducted in this paper. As written, the sentence insinuates that the role of leukocytes in pediatric patients of cystic fibrosis is unknown. MINOR COMMENTS ON ARTICLE PRESENTATION/REPORTING 1. Figures are labeled in as A1, B2. The panel naming should be alphabetical. The 3 x 2 grid structure of the figure panels is enough to segment the experimental results and orient the reader. 2. References 17, 18 and 7, 11 in the introduction section (Page 6, 3rd paragraph, first sentence) are misplaced/swapped. This compound statement is supported by two sets of references, which support the opposite halves of the sentence. “The genetic basis of CF has been clearly established, …” should be supported by references 17, 18 and not 7, 11. The opposite is true for the second part of that sentence. “… but no specific mutation is correlated with the impact on the phagocytic activity of neutrophils and monocytes” should be supported by 7, 11 not 17, 18. ****** 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/. 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Revision 1
3 Apr 2022 Author Response Re: Manuscript Ref.: PONE-D-21-40067. “Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosis” Comments from authors We are very grateful to the reviewers for their suggestions, which greatly improved the quality of our manuscript. Reviewer 1 “The findings in the manuscript has been well presented, providing statistical analyses as well as clear explanation of the methods implemented. Overall the manuscript is easy to follow. I have attached my comments for further perusal to help improve the manuscript.” “The article by Gustavo Lara Rezende and colleagues, “Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosis”, offers insights on the role of monocytes and neutrophils in CF +/- CRS+/-NP and importance for the need of more diagnostic and treatments options for this illness. Overall, the study has been well-executed, and the manuscript well written providing explanations and background information to make the manuscript an enjoyable and easy to understand read. I have minor suggestions to improve the manuscript”. Query 1: Materials and Methods Formatting: Pg.9 – ‘In addition, endoscopic signs… meatus or were necessary to define CRS’. The word “OR” should be deleted. Answer 1: Thank you, “OR” was deleted. Query 2: Pg. 10 – Second paragraph… ‘Saccharomyces cerevisiae yeast are phagocytosed via receptors. Phagocytosis…. Align the paragraph accordingly. Answer 2: The paragraph was aligned. Query 3. Table 1: As transplant patients are given immunosuppressive (IS) drugs, it would be nice to mention the # of years post-transplant for the specific subject under the CF+CRS with NP group and clearly specify whether this subject was still on any IS drugs or not to infer that any alterations in this subject’s immune system was not contributed from post-transplant treatment. Answer 3: Thank you for this important observation. It was added: “8th year after liver transplantation because of congenital biliary atresia, without immunosuppressive drugs at the moment.” Please, see in Table 1 Query 4: Figures 1 and 2: It would be better to rename A, B and C as top, middle and bottom panel respectively to avoid confusion with the figure names A1, A2, etc. and as “A, B and C” are not stated on the figures. Answer 4: In the figures 1 and 2, it was included the letter “A” for phagocytosis by molecular patters and “B” for phagocytosis by opsonins. In the legend, the figures were identified by “top” for % of neutrophils involved in phagocytosis, “middle” for number of yeasts ingested by neutrophils and “bottom” for phagocytic index. Please, see in the figures 1 and 2. Query 5: Figure 1A3- under 20 yeasts/neutrophils there is an additional undefined box plot along with a statistical line after CF+CRS without NP. Please clarify. Answer 5: Thank you. This was a mistake that was now removed. Query 6: Supplementary Table 1 & 2: Kindly explain what you mean by ‘values different from their respective control’? Answer 6: It means that the values are p<0,05. It was included in the text. Please, see in S1 e 2 Tables. Query 7: Supplementary Table 2: Both CF+CRS with/without NP have the same number of yeasts ingested by monocytes 2.1 (20 years per cell). Yet a statistical difference is only observed for Ctrl vs CF+CRS with NP and not Ctrl vs CF+CRS without NP. Could you provide some insights on the same? Answer 7: Please, observe in the figure 2B2 that although the median is the same for both patients CP+CRS with or without NP, the box-plot for patients with NP shows the interquartile range and the minimum value below that of patients without NP. In addition, statistical test showed that the number of yeasts ingested by monocytes of control group was higher than that of CP+CRS with NP. However, this difference was not significant for the patients without NP. Reviewer 2 “In this study Rezende et al. aims to understand how the innate immune system’s function changes in patients of cystic fibrosis and compared it with a sub-group who have developed chronic rhinosinusitis. This manuscript was assessed for the 7 criteria for publication in PLoS One. Rezende et al. present results of original research that have not been published elsewhere. Experiments performed, statistical analyses meet high technical standard and are described in sufficient detail. The analytical rigor of the authors is demonstrated by the fact that they perform corrections for normally and non-normally distributed data. The authors also adhere to reporting and ethics standards — all volunteers and their parents/guardians signed consent forms. However, there are deficiencies in conclusions drawn from the results, and on article presentation/reporting. The authors over-extend when drawing conclusions from their results. In the introduction section in the abstract, instead of focusing on the gap in knowledge statements about the field of cystic fibrosis is made that is unambiguous and not entirely accurate. In addition, the results section and figure panels are structured in a difficult to interpret manner. As such, in its current form this manuscript cannot be recommended for publication. Detailed comments are below. MAJOR COMMENTS ON CONCLUSION Query 1 In the introduction section (Page 7, last paragraph), the authors write “… we evaluated whether neutrophiles and monocytes that circulate in the peripheral blood participate directly in inflammatory activity in the paranasal sinuses”. This is incorrect. In vitro assessment of phagocytotic activity and superoxide anion production of neutrophiles and monocytes cannot be used to determine whether these cells participate directly in inflammatory activity in the paranasal sinuses. This is particularly true because these immune cells were isolated from peripheral blood collected in vacuum tubes, presumably through venous blood draw from the arm (Materials and Methods section, Page 9, 3rd paragraph). This conclusion is incorrect. Answer 1: We agree with the reviewer. It was changed the word “directly” to “indirectly”. Please, see in the introduction, last paragraph Query 2: In the highlights section (Page 3, 2nd bullet point), the authors write “Chronic Rhinosinusitis related to Cystic Fibrosis group has impaired leukocytes compared to control group”. This is an over-extension of the results. The authors measure in vitro phagocytotic ability of neutrophiles and monocytes (Y-axis labels, Fig 1 and 2), not for leukocytes that include B-cells, cytotoxic T-cells. Hence this statement is incorrect and does not accurately reflect the results. Answer 2: We agree with the reviewer. For better comprehension, it was changed “leukocytes” to “neutrophils and monocytes”. Please, see in highlights. MAJOR COMMENTS ON ARTICLE PRESENTATION/REPORTING Query 3: 1. The results section is structured in a difficult to interpret manner. Numbering is not used, and nesting of sub-sections is achieved through italicizing. Also, each paragraph in the “Evaluation of superoxide production by phagocytes” section has its own sub-heading. This is not required and adds unnecessary word count to the manuscript. Answer 3: The results section was sub-sectioned again according to the PLOS ONE style templates. We would prefer that remain the sub-heading of subsections to make clearer the topic. These sub-sections were formatted in Level 2 headings, bold type 16pt and Level 3 headings, bold type, 14pt font as style templates instructions. Query 4: 2. In the abstract the authors write “The role of leukocytes in the innate immune system of children with cystic fibrosis (CF) is unclear, mainly when associated with chronic rhinosinusitis”. The sentence should be constructed in an unambiguous manner that aligns with the experiments conducted in this paper. As written, the sentence insinuates that the role of leukocytes in pediatric patients of cystic fibrosis is unknown. Answer 4: Thank you for the observation. The sentence was changed to make clearer: “The role of phagocytes of children with cystic fibrosis (CF) associated with different phenotypes of chronic rhinosinusitis (CRS) is unclear.” Please see in abstract: MINOR COMMENTS ON ARTICLE PRESENTATION/REPORTING Query 5: 1. Figures are labeled in as A1, B2. The panel naming should be alphabetical. The 3 x 2 grid structure of the figure panels is enough to segment the experimental results and orient the reader. Answer 5: The identification in the legends of the figures 1 and 2 were changed “top” for % of neutrophils involved in phagocytosis, “middle” for number of yeasts ingested by neutrophils and “bottom” for phagocytic index. However, we would prefer that the labels A1, A2, etc. remain to facilitate the indication of the figures in the text in results Query 6 2. References 17, 18 and 7, 11 in the introduction section (Page 6, 3rd paragraph, first sentence) are misplaced/swapped. This compound statement is supported by two sets of references, which support the opposite halves of the sentence. “The genetic basis of CF has been clearly established, …” should be supported by references 17, 18 and not 7, 11. The opposite is true for the second part of that sentence. “… but no specific mutation is correlated with the impact on the phagocytic activity of neutrophils and monocytes” should be supported by 7, 11 not 17, 18. Answer 6: Thank you. The order of references was changed in the manuscript. Please, see in the Introduction, 3rd paragraph. Attachments Attachment Submitted filename: Response to Reviewers 3April22.docx* https://doi.org/10.1371/journal.pone.0267986.r002
20 Apr 2022 Decision Letter - Mrinmoy Sanyal, Editor Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosis PONE-D-21-40067R1 Dear Dr. Rezende, 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, Mrinmoy Sanyal, PhD Academic Editor PLOS ONE 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: All comments have been addressed Reviewer #2: All comments have been addressed ******** 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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: Yes Reviewer #2: Yes ****** 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 has addressed all the comments of the reviewer and revised the manuscript as required. Reviewer #2: The authors have addressed the major concerns that were raised. Regarding the points on article presentation/reporting, it would be preferable if the editorial team took that decision since they are more experienced in such decisions. ****** 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 https://doi.org/10.1371/journal.pone.0267986.r003
Formally Accepted
28 Apr 2022 Acceptance Letter - Mrinmoy Sanyal, Editor PONE-D-21-40067R1 Alterations in innate immune responses of patients with chronic rhinosinusitis related to cystic fibrosis Dear Dr. Rezende: 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 Dr. Mrinmoy Sanyal Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0267986.r004

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