Prevalence and aeroallergen sensitization in pediatric Allergic Rhinitis: A population-based study in Jeju, Korea

Min-su Oh; Miok Kim; Jung-Kook Song; Seong-Chul Hong

doi:10.1371/journal.pone.0326070

Peer Review History

Original SubmissionFebruary 13, 2025
13 Feb 2025 Author Response https://doi.org/10.1371/journal.pone.0326070.r001
18 Mar 2025 Decision Letter - Sethu Subha, Editor Dear Dr. Song, 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. Please submit your revised manuscript by May 02 2025 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. 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'. 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We look forward to receiving your revised manuscript. Kind regards, Sethu Thakachy Subha, M.S Academic 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 your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. 3. 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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #1: The data unique to Korea and Jeju were interesting and original. I think it can be a better report if we supplement the data we collect a little more. The conclusions were drawn according to the data, and there is no statistical problem. Reviewer #2: Dr. Song and colleagues reported on the prevalence and aeroallergen sensitization in pediatric allergic rhinitis based on a population-based study in Jeju, Korea. In epidemiological research, unique regional allergy data are valuable as they provide important insights into the onset and increase of allergies. This study uses data from eight years ago, but it would be helpful to explain why it was published at this timing. The results and discussion include findings on Japanese cedar; however, the sensitization rate appears to be lower than that reported in Japanese epidemiological studies. Please consider citing the following paper and discussing the differences: Kiguchi T, et al. Pollen-food allergy syndrome and component sensitization in adolescents: A Japanese population-based study. PLoS One. 2021 Apr 14;16(4):e0249649. Line 34: Since only the odds ratio is presented, please add the 95% confidence interval. Line 50-51: Please remove the terms "in vitro" and "in vivo." Line 57: The term "smaller" is unclear—please specify what it is being compared to. Line 78: Please add the study design at the beginning of the Methods section. Line 131: Should this be a "Table" instead of a "Figure"? Reviewer #3: NO COMMENTS ****** 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 Reviewer #3: 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 Attachments Attachment Submitted filename: KOREAN AR PLOS ONE.docx Attachment Submitted filename: KOREAN AR PLOS ONE (1).docx https://doi.org/10.1371/journal.pone.0326070.r002
Revision 1
27 Mar 2025 Author Response Relevant files have been uploaded. Attachments Attachment Submitted filename: Response to Reviewer_2.docx https://doi.org/10.1371/journal.pone.0326070.r003
15 Apr 2025 Decision Letter - Sethu Subha, Editor Dear Dr. Song, 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. Please submit your revised manuscript by May 30 2025 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. 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 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, Sethu Thakachy Subha, M.S 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #3: Yes ****** Reviewer #1: I think it's data with unique characteristics of Jeju area. Thank you. Let me ask you a few questions. 1. In JC exclusion, AR decreased with age. Is this explained only by the effect of early sensitization of HDM? 2. Why doesn't JC sensitization come out statistically in the AR risk evaluation? JC is likely to be the most important AR risk in Japan, so why is the difference? 3. I'm hoping to add animals (dogs, cats), cockroaches, and Cypress to the SPT. 4. In the geographical data comparison, what if reference goes into places similar to Jeju in the latitude (especially places like Kyushu in Japan). Thank you for your efforts. Reviewer #3: no comments . ****** 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 #3: 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 https://doi.org/10.1371/journal.pone.0326070.r004
Revision 2
21 Apr 2025 Author Response Rebuttal Letter (the Second Review) Dear Reviewer 1, We sincerely appreciate you for the thoughtful and constructive second-round review. Below are our detailed responses to each question and suggestion: 1. "In JC exclusion, AR decreased with age. Is this explained only by the effect of early sensitization of HDM?" Thank you for this insightful question. Indeed, the observed age-related decrease in allergic rhinitis (AR), specifically in Japanese cedar (JC) pollen exclusion, can be explained by multiple interrelated factors: • Differences in lifestyle and environmental exposure: Younger children generally spend more time indoors and in bed, leading to increased exposure to house dust mites (HDM). As children age and engage in more outdoor activities, exposure to indoor allergens decreases while exposure to outdoor allergens such as JC pollen increases. • Age-related changes in immune response: Immune systems in younger children are still maturing, and early hypersensitivity to HDM may evolve as tolerance develops or immune responses change with age. • Natural progression of allergic rhinitis: The "allergic march" concept explains that allergic rhinitis symptoms may naturally improve or even remit over time. Children sensitized to house dust mites (HDM) in early childhood often experience symptom reduction as they age, which could partially explain the observed decrease in HDM-induced AR prevalence among older age groups. We have now clarified and elaborated on these factors explicitly in the discussion section of the manuscript. (line 258~270) The observed age-related decrease in allergic rhinitis (AR), particularly after excluding Japanese cedar (JC) pollen sensitization, can be explained by multiple interrelated factors. First, differences in lifestyle and environmental exposure play a role: younger children generally spend more time indoors and in bed, resulting in greater exposure to indoor allergens such as house dust mites (HDM). As children grow older and engage in more outdoor activities, their exposure to indoor allergens decreases while exposure to outdoor allergens like JC pollen increases. Second, age-related changes in immune responses may contribute; immune systems in young children are still maturing, and early hypersensitivity to HDM may evolve into tolerance or shift as the immune system develops. Third, the natural progression of allergic diseases, often referred to as the "allergic march," suggests that symptoms of HDM-induced allergic rhinitis may naturally improve or even remit over time. Children sensitized to HDM at an early age often experience a reduction in symptoms as they grow, which could partially explain the observed decrease in HDM-related AR prevalence among older age groups. 2. "Why doesn't JC sensitization come out statistically in the AR risk evaluation? JC is likely to be the most important AR risk in Japan, so why is the difference?" Thank you for this important question. Although JC pollen is recognized as a major contributor to AR in Japan, our results suggest that in Jeju, the cumulative allergenic burden (i.e., polysensitization) plays a more critical role in AR development than sensitization to a single allergen. While the sensitization rate to house dust mites was approximately twice as high as that to JC pollen in Jeju (table 1), neither dust mites nor JC pollen remained significant independent predictors after multivariate adjustment. Instead, polysensitization to multiple aeroallergens emerged as the only significant risk factor (table 3). Furthermore, to assess whether multicollinearity between house dust mite (HDM) sensitization and JC pollen sensitization might have affected the statistical results, we examined Cramér's V coefficient between these variables, which was 0.19, indicating a weak association. In addition, the variance inflation factors (VIFs) for the six independent variables included in the multivariate model ranged from 1.003 to 1.388, suggesting that multicollinearity was not a concern. Therefore, the lack of statistical significance for JC pollen sensitization in the multivariate analysis was not attributable to multicollinearity. These findings suggest that, in regions like Jeju, the cumulative allergenic burden — rather than sensitization to a single specific allergen — plays a more critical role in AR development. The differences observed between our results and Japanese studies may reflect variations in environmental exposure, timing of sensitization, host genetic factors, and allergen profiles specific to each region. Further research is needed to clarify the mechanisms underlying these regional differences and to better understand the role of polysensitization in the natural course of allergic diseases. We have added this point to the revised Discussion section. (line 241~250 and 255~270) In our study, JC pollen sensitization did not emerge as an independent risk factor for allergic rhinitis (AR). Although the sensitization rate to house dust mites was approximately twice as high as that to JC pollen, neither dust mite nor JC pollen sensitization remained significant independent predictors after multivariate adjustment. Instead, polysensitization to multiple aeroallergens was the only significant factor associated with AR risk. These findings suggest that in regions like Jeju, the cumulative allergenic burden—rather than sensitization to a single specific allergen—plays a more critical role in AR development. The differences observed between our results and Japanese studies may reflect variations in environmental exposure, timing of sensitization, host genetic factors, and allergen profiles specific to each region. Further research is warranted to clarify the mechanisms underlying these regional differences and to better understand the role of polysensitization in the natural course of allergic diseases. 3. "I'm hoping to add animals (dogs, cats), cockroaches, and Cypress to the SPT." We appreciate the reviewer’s suggestion to include common animals (dogs, cats), cockroaches, and cypress in the SPT panel. In fact, a similar point was raised by another reviewer during the first round of peer review, and we have already incorporated this consideration into our revised manuscript. Specifically, we added a discussion in the Discussion section (line 345~351) noting that our skin prick test panel was limited and did not include certain prevalent allergens. ��This study has several limitations. As a cross-sectional study, it cannot establish causality between allergen exposure and AR development. Additionally, reliance on questionnaire-based definitions introduces the possibility of recall bias [43], and the skin prick test is subject to observer variability [44]. However, the use of a relatively comprehensive allergen panel enhances the reliability of our sensitization estimates. To build upon these findings and address current limitations, future research could benefit from incorporating additional data sources, such as pet allergen sensitization (cats and dogs), detailed environmental exposure measurements (e.g., indoor pollutants and ambient air pollution), and household socioeconomic factors. Including these variables may offer a more comprehensive understanding of the complex interplay between environmental conditions and AR prevalence among children in Jeju. 4. "In the geographical data comparison, what if reference goes into places similar to Jeju in the latitude (especially places like Kyushu in Japan)?" Thank you for this excellent suggestion. We have now included comparative references to geographical regions with similar latitudes and environmental conditions, such as Kyushu, Japan, in the discussion section. 29. Yoshida K, Adachi Y, Akashi M, Itazawa T, Murakami Y, Odajima H, et al. Cedar and cypress pollen counts are associated with the prevalence of allergic diseases in Japanese schoolchildren. Allergy. 2013;68(6):757–763. doi:10.1111/all.12158 Moreover, regions with similar latitude and climatic conditions, such as Kyushu in Japan, may also exhibit allergen sensitization patterns influenced by subtropical environmental factors. A previous study reported that cedar and cypress pollen counts were associated with the prevalence of allergic diseases among Japanese schoolchildren [29], suggesting that pollen exposure patterns in southern Japan could provide a useful comparison for understanding regional differences in allergen sensitization. Your valuable insights and detailed comments have significantly improved the quality of our manuscript. We greatly appreciate your time, effort, and expertise in helping us strengthen our work. We hope that these revisions address all of the reviewer’s concerns. We would also like to sincerely request your consideration regarding the urgency of our situation. Some of the co-authors of this manuscript are currently facing institutional transitions, and if the acceptance of this paper is not confirmed by May 8, their affiliation contracts will unfortunately be terminated. Given these circumstances, we humbly ask for your kind assistance in expediting the review process, if at all possible. We are deeply grateful for the editor's and reviewers' valuable time and thoughtful feedback, which have greatly improved the quality of our manuscript. We remain fully committed to making any additional revisions immediately if needed. Thank you very much for your kind understanding and generous support. Sincerely, Dr. Song and colleagues Attachments Attachment Submitted filename: Response to Reviewer_0421.docx https://doi.org/10.1371/journal.pone.0326070.r005
23 May 2025 Decision Letter - Sethu Subha, Editor Prevalence and aeroallergen sensitization in pediatric allergic rhinitis: A population-based study in Jeju, Korea PONE-D-25-06116R2 Dear Dr. Song, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Sethu Thakachy Subha, M.S Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0326070.r006
Formally Accepted
Acceptance Letter - Sethu Subha, Editor PONE-D-25-06116R2 PLOS ONE Dear Dr. Song, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Sethu Thakachy Subha Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0326070.r007

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