Barriers and promoters to adapting research findings to clinical care in hereditary angioedema in the United States: A qualitative study

Esther L. Langmack; Dana Ravyn; Rob Lowney; Beth Goodwin; William R. Lumry

doi:10.1371/journal.pone.0329585

Peer Review History

Original SubmissionMarch 14, 2025
14 Mar 2025 Author Response Attachments Attachment Submitted filename: HAE-qualitative_PLOS_Response to Reviewers_Resubmit_031325.docx https://doi.org/10.1371/journal.pone.0329585.r001
9 May 2025 Decision Letter - Miquel Vall-llosera Camps, Editor Dear Dr. Langmack, Thank you for submitting your manuscript to PLOS One. Firstly, we would like to apologize for the delay in processing your manuscript. It has been exceptionally difficult to secure reviewers to evaluate your study. We have now received one completed review, which is available below. The reviewer has raised significant scientific concerns about the study that need to be addressed in a revision. Please note that we have only been able to secure a single reviewer to assess your manuscript. We are issuing a decision on your manuscript at this point to prevent further delays in the evaluation of your manuscript. Please be aware that the editor who handles your revised manuscript might find it necessary to invite additional reviewers to assess this work once the revised manuscript is submitted. However, we will aim to proceed on the basis of this single review if possible. Please submit your revised manuscript by Jun 22 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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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. Thank you for uploading your study's underlying data set. Unfortunately, the repository you have noted in your Data Availability statement does not qualify as an acceptable data repository according to PLOS's standards. At this time, please upload the minimal data set necessary to replicate your study's findings to a stable, public repository (such as figshare or Dryad) and provide us with the relevant URLs, DOIs, or accession numbers that may be used to access these data. For a list of recommended repositories and additional information on PLOS standards for data deposition, please see https://journals.plos.org/plosone/s/recommended-repositories. 3. Thank you for stating the following in the Competing Interests section: [I have read the journal's policy and the authors of this manuscript have the following competing interests. Esther L. Langmack, Dana Ravyn, and Beth Goodwin state they have no competing interests to disclose. Rob Lowney discloses that this research was supported by an independent educational grant from Takeda Pharmaceuticals USA, Inc. (Grant IME-007727) to CMEology, West Hartford, CT. William R. Lumry discloses the following: grants or contracts (Astria, BioMarin, CSL Behring, Intellia, Grifols, Ionis, Kalvista, Shire/Takeda); consulting fees (Astria, BioCryst, Biomarin, CSL Behring, Express Scripts/CVS, Fresenius Kabi, Intellia, Kalvista, Magellan, Optum, Pharming, Pharvaris, Shire/Takeda); payments or honoraria for lectures, etc. (BioCryst, CSL Behring, Optinose, Pharming, Shire/Takeda, Grifols, Astra Zeneca, Sanofi/Regeneron, GSK); payment for expert testimony (Vedder-Price, Murphy & King); leadership for fiduciary roles (US Hereditary Angioedema Association Medical Advisory Board).]. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). 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Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. Please update your Data Availability statement in the submission form accordingly. 5. 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? Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes ****** Reviewer #1: In this manuscript by Langmark et al., significant issues related to the translation in clinical practice of research topics related to hereditary angioedema (HAE) management were analyzed by an interview approach with allergy/immunologists practicing in the USA. The scope of the work was to highlight barriers and promoters of such translations. Major barriers that emerged from the interviews were 1) insurance prior authorization for medications, including drugs for long-term prophylaxis of HAE attacks, 2) laboratory testing difficulties for HAE diagnosis, 3) time constraints for physicians and patient care; while promoters of translations were: 1) availability of medications samples, 2) route/frequency of administration (for LTP), and 3) shared-decision making. The study, presented using an overall narrative approach, adds some relevant information on the clinical management of HAE patients. Notwithstanding, it applies to the specific USA healthcare setting, whereby, for example, the issue of insurance prior authorization for medications does not apply in Countries based on a public healthcare system. Based on the mean experience of interviewed physicians, it is clear that they are not HAE specialists. HAE is a true rare disease and is handled in many Countries (especially in Europe) within a network of rare disease centers with HAE specialists who take care of patients. I would therefore suggest to the AA. to recall in the title that the study was carried on in the USA. Also, I would suggest making a comment in the discussion about the specific setting of this study, whereby general allergy specialists or general practitioners participated in the study, therefore, there could be a different scenario if the study had been carried out with HAE specialists. ****** 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: Vincenzo Montinaro ******** [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.0329585.r002
Revision 1
26 May 2025 Author Response RESPONSE TO REVIEWERS Re: PONE-D-25-13647 May 24, 2025 To: Miquel Vall-Illosera Camps Senior Staff Editor PLOS One Thank you for your kind consideration of our manuscript (PONE-D-25-13647). Please be aware that this manuscript now has a new title: Barriers and promoters to adapting research findings to clinical care in hereditary angioedema in the U.S.: a qualitative study. The title was changed in response to a Reviewer #1 comment. We appreciate the editors’ and the reviewer’s constructive suggestions and have made the following changes in response. 1. We modified the manuscript to meet PLOS One’s style requirements. A detailed record of all changes can be viewed in the uploaded Revised Manuscript with Track Changes. 2. We uploaded our de-identified, anonymized data to Harvard Dataverse, a repository recommended by PLOS One. The DOI for our dataset is: https://doi.org/10.7910/DVN/ZBIFEF a. The dataset DOI is mentioned and cited in the Methods section of the paper (Manuscript, Line 109) b. The reference list contains a citation for the dataset (Reference 9, Manuscript, Line 571) c. The Data Availability statement in the submission form now reflects the new dataset repository 3. At the request of the Journal editors, we have added the statement “This does not alter our adherence to PLOS One policies on sharing data and materials” to the Competing Interests statement in our cover letter. Please see the Cover Letter submitted today for the revised Competing Interests statement. 4. We responded to the Reviewer Comments to the Author, as described below. 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 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A 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. AUTHOR RESPONSE: We have uploaded our de-identified, anonymized data to Harvard Dataverse, a repository recommended by PLOS One. The DOI for our dataset is: https://doi.org/10.7910/DVN/ZBIFEF The dataset has been cited in the Methods section of the manuscript (Manuscript, Line 108-109), and a citation for the dataset repository appears in the reference list (Manuscript, Reference 9, Line 571). 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 5. Review Comments to the Author Reviewer #1: In this manuscript by Langmark et al., significant issues related to the translation in clinical practice of research topics related to hereditary angioedema (HAE) management were analyzed by an interview approach with allergy/immunologists practicing in the USA. The scope of the work was to highlight barriers and promoters of such translations. Major barriers that emerged from the interviews were 1) insurance prior authorization for medications, including drugs for long-term prophylaxis of HAE attacks, 2) laboratory testing difficulties for HAE diagnosis, 3) time constraints for physicians and patient care; while promoters of translations were: 1) availability of medications samples, 2) route/frequency of administration (for LTP), and 3) shared-decision making. The study, presented using an overall narrative approach, adds some relevant information on the clinical management of HAE patients. Notwithstanding, it applies to the specific USA healthcare setting, whereby, for example, the issue of insurance prior authorization for medications does not apply in Countries based on a public healthcare system. Based on the mean experience of interviewed physicians, it is clear that they are not HAE specialists. HAE is a true rare disease and is handled in many Countries (especially in Europe) within a network of rare disease centers with HAE specialists who take care of patients. I would therefore suggest to the AA. to recall in the title that the study was carried on in the USA. Also, I would suggest making a comment in the discussion about the specific setting of this study, whereby general allergy specialists or general practitioners participated in the study, therefore, there could be a different scenario if the study had been carried out with HAE specialists. AUTHOR RESPONSE: We agree that clinical practices and challenges associated with HAE care vary around the world and that it is necessary to stipulate that our study involved health care providers located only in the United States. Accordingly, we have made the following changes: a. As suggested by Reviewer #1, we changed the title from “Barriers and promoters to adapting research findings to clinical care in hereditary angioedema: a qualitative study” to “Barriers and promoters to adapting research findings to clinical care in hereditary angioedema in the U.S.: a qualitative study” (Manuscript, Line 1) b. As suggested by Reviewer #1, we specifically acknowledge that U.S. clinical practice characteristics and challenges may differ from those elsewhere in the world in the Discussion (Manuscript, Line 525-530), which has been changed to read as follows (changes are underlined): Potential limitations to this study include the fact that it enrolled a non-random sample of US allergy/immunology health professionals, the majority of whom were general allergy practitioners in group practices, whose perspectives may potentially differ from those of a broader group of providers. Barriers and promoters relevant to research translation into HAE clinical practice may be different outside of the United States, for example in Europe, where many patients with HAE receive care in rare disease centers from HAE specialists rather than general allergy practitioners. Additionally, insurance prior authorization would not be a barrier in countries in which the public healthcare system does not require this type of review. c. We amended the Conclusion to acknowledge that our research relates to HAE clinical care in the United States (Manuscript, Line 541-542), as follows (changes are underlined): This qualitative study revealed a range of barriers to and promoters of research translation into clinical care for patients with HAE in the United States. END of RESPONSE TO REVIEWER DOCUMENT Attachments Attachment Submitted filename: Response to Reviewers_052425.docx https://doi.org/10.1371/journal.pone.0329585.r003
5 Aug 2025 Decision Letter - Miquel Vall-llosera Camps, Editor Dear Dr. Langmack, 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 Sep 18 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, Miquel Vall-llosera Camps Senior Staff Editor PLOS ONE Journal Requirements: 1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 2. 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: Please address Reviewer#2 comments [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 #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The AA. have properly edited the manuscript and addressed the critiques raised to the first submitted version. Reviewer #2: Dear authors, the novelty reported in your paper is limited. As stated also by another reviewer, the experience of the interviewed physician was low; the majority reported following fewer than five patients. For this reason, the insights reported in the interview are all well known to all the physicians with a larger number of HAE patients. The authors have pointed out in their paper that the field of HAE publication is quite saturated; therefore, I believe it may be worth considering whether this paper adds significant value to the existing body of work. ****** 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: Vincenzo Montinaro 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 https://doi.org/10.1371/journal.pone.0329585.r004
Revision 2
25 Aug 2025 Author Response RESPONSE TO REVIEWERS Re: PONE-D-25-13647 August 25, 2025 To: Miquel Vall-Illosera Camps Senior Staff Editor PLOS One Thank you again for your kind consideration of our manuscript (PONE-D-25-13647). We are grateful for both of the Reviewers’ constructive suggestions. We have further revised the manuscript in response to Reviewer #2’s suggestions, as described below. 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? Reviewer #1: Yes Reviewer #2: Yes 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes 4. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: Yes Reviewer #2: Yes 5. Is the manuscript presented in an intelligible fashion and written in standard English? Reviewer #1: Yes Reviewer #2: Yes 6. Review Comments to the Author Reviewer #1: The AA. have properly edited the manuscript and addressed the critiques raised to the first submitted Reviewer #2: Dear authors, the novelty reported in your paper is limited. As stated also by another reviewer, the experience of the interviewed physician was low; the majority reported following fewer than five patients. For this reason, the insights reported in the interview are all well known to all the physicians with a larger number of HAE patients. The authors have pointed out in their paper that the field of HAE publication is quite saturated; therefore, I believe it may be worth considering whether this paper adds significant value to the existing body of work. AUTHOR RESPONSE: Little has been previously published about the clinician experience in HAE care. Most research has focused on the patient experience with HAE. In part because HAE is a rare disease, much less is known about clinician challenges in HAE care compared with a common condition like asthma. We therefore do not consider this area of HAE research (clinician challenges) to be saturated. In fact, we would assert that clinician challenges with HAE need to be more deeply understood before medical care can be improved. Our study, which is novel in its application of qualitative research methods to the topic at hand, provides new information that builds on the findings of previous studies (lines 1031-1042, Track Changes version). It is true that clinicians in our study population treated 5 patients with HAE on average annually. However, our data align closely with previous US surveys showing that the majority (70–74%) of US allergy/immunology clinicians treat only 1 to 5 patients with HAE annually. HAE is a rare disease (estimated prevalence of 1 in 50,000 person). “Physicians with a larger number of HAE patients” practice at HAE subspecialty/referral centers. They would also benefit from knowing more about the specific challenges faced by general allergy practice clinicians like those interviewed in our study. To better explain the value of our findings — and how qualitative research can augment the body of knowledge on clinician perspectives — we have made the following changes. (References have been updated accordingly.) a. We clarified how our study fits within the context of previous studies in the Discussion. Lines 568-579, Track Changes version: The results of this study build and expand upon the findings of quantitative survey studies of allergy/immunology health professionals [20, 21]. One study described challenges related to misdiagnosis of HAE, misinterpretation of test results, and other problems with laboratory testing [20]. Additional challenges were lack of clinician and patient knowledge of HAE, patient inability to afford or access treatment, and difficulties incorporating patient preferences into treatment decisions [20]. Regarding long-term HAE prophylaxis, physicians and patients were previously shown to have differing views of treatment burden [21]. Physicians were more likely than patients themselves to view prophylactic medications administered subcutaneously or intravenously as burdensome, inconvenient, or unpleasant. These findings and those of our study highlight the need for enhanced patient-physician communication and shared decision-making about long-term prophylaxis options. b. We articulated more clearly the strengths of our study in a new paragraph in the Discussion. Lines 609-630, Track Changes version: One strength of this study is that we uncovered several factors not previously reported in quantitative survey studies of allergy/immunology clinicians that may impact delivery of high-quality HAE patient care [20, 21]. Specifically, we detected clinician difficulties with accessing information on HAE, the use of online chat rooms as an information resource, unfamiliarity with HAE clinical practice guidelines, and lack of use of QoL assessment tools as barriers to research translation. Provision of medication samples and pharmaceutical representative detailing were identified as facilitators of care delivery in our study but not previous quantitative survey studies [20, 21]. In translational health research, qualitative methods are increasingly recognized as valuable ways to reveal stakeholder attitudes, perceptions, and experiences that escape detection using quantitative approaches [23]. Additionally, this study is the first, to our knowledge, to use contemporary qualitative research methods including computer-assisted thematic analysis to examine the experiences of allergy/immunology clinicians related to HAE patient care. Recent qualitative research on HAE has focused on patients rather than clinicians [3, 22, 24,25]. However, the experiences and perspectives of allergy/immunology clinicians, particularly those in general allergy/immunology practices (where most of our respondents worked), also need to be more fully recognized if treatment is to improve for all HAE patients, not just those who receive care in HAE subspecialty centers. c. We added this statement about the number of patients with HAE treated annually to the Discussion. Lines 640-643, Track Changes version: Although clinicians in our study reported seeing an average of only 5 patients with HAE annually, this number is consistent with previous surveys of US physicians treating patients with HAE, in which the majority (70–74%) reported treating 1 to 5 patients with HAE in the past year [26]. 7. Do you want your identity to be public for this peer review? Reviewer #1: Yes: Vincenzo Montinaro Reviewer #2: No END of RESPONSE TO REVIEWER DOCUMENT Attachments Attachment Submitted filename: Response to Reviewers_082525.docx https://doi.org/10.1371/journal.pone.0329585.r005
23 Sep 2025 Decision Letter - Miquel Vall-llosera Camps, Editor Barriers and promoters to adapting research findings to clinical care in hereditary angioedema in the U.S.: a qualitative study PONE-D-25-13647R2 Dear Dr. Langmack, 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. For questions related to billing, please contact billing support . 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, Miquel Vall-llosera Camps Staff Editor PLOS One Additional Editor Comments: We consider that the previous concerns have been sufficiently addressed. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: (No Response) Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #2: No ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: the manuscript has significantly improved in its present form. The AA. have answered to all comments made to the original version Reviewer #2: Dear Authors, the number of papers published about HAE is increasing, and most of these papers have not significantly contributed to HAE knowledge. If you search on PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=hereditary+angioedema&sort=date In the first eight months of the year, 181 papers were published. ****** 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: Vincenzo Montinaro Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0329585.r006
Formally Accepted
Acceptance Letter - Miquel Vall-llosera Camps, Editor PONE-D-25-13647R2 PLOS ONE Dear Dr. Langmack, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. 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. PLOS Manuscript Reassignment Staff Editor PLOS ONE https://doi.org/10.1371/journal.pone.0329585.r007

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .