Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: An observational study

Andrea Zanichelli; Mario Ghezzi; Ivan Santicchia; Romualdo Vacchini; Marco Cicardi; Antonella Sparaco; Girolamo Donati; Vito Ranìa; Alberto Busa

doi:10.1371/journal.pone.0230128

Peer Review History

Original SubmissionJuly 24, 2019
27 Nov 2019 Decision Letter - Girijesh Kumar Patel, Editor PONE-D-19-20853 Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: an observational study PLOS ONE Dear Dr zanichelli, 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 would appreciate receiving your revised manuscript by Jan 11 2020 11:59PM. When you are 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. 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 follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests Additional Editor Comments (if provided): [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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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: 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: I think this paper can only be accepted if the author's add and answer the following points in the current submission. It needs more statistical analysis to be done with statistical software packeges. 1. Kindly add co-relation of patient age with the disease pattern. In current article patients age 8-85 years are added, which is a wide range. 2. Add some more statistical data analysis as well as some statistical graph in this article. 3. Add some more discussion to correlate the immunological effect of the disease process as well as therapeutic approach. 4. Kindly add some more current relevant references. 5. Add some pictures to show the Angioderama and clarify the scoring process with more supporting images in the current population of the patient. Reviewer #2: The authors present data from a study on the management of dental procedures in patients with HAE or AAE due to C1-Inhibitor deficiency. It is adequately written and the conclusions presented are appropriately supported by the data. Although most of the conclusions reached by the authors are not novel, they do provide experimental support to previously reported observations with important implications for the management of these patients. Because of dealing with a rare pathology, the relatively small number of individuals recruited for this study is not to be considered a substantial limitation in its design. Minor points: - Lines 175-176: The manuscript states that “….Most patients recruited in this study had a moderate-to-high score for the severity of oral pathology”. However, according to Table 1, most of the patients studied (20/27) had a Mild to Moderate phenotype. - Lines 179-180: The amelioration of the patients’ HAE course after dental care is a reasonable conclusion. Though, significant improvement of HAE was observed in as little as 20% of the studied cases. Wouldn’t it be expectable to find a general improvement in the cohort after dental management? Were these 4 patients showing amelioration of HAE those exhibiting worse oral pathological scores?; that is, is there any correlation between the oral disease score and the beneficial effect of dental care on HAE? Can the authors speculate in the discussion section on the hypothetical causes of the lack of response in an 80% of cases? - Line 223: Previous studies have also shown that pdC1INH prophylaxis is less effective for AAE-C1INH as compared to HAE-C1INH (reviewed for example in Cicardi et al, 2014). This observation is coherent with the increased C1INH catabolism characteristic of AAE-C1INH patients and may be influenced by the presence or absence of anti-C1INH autoantibodies in the patient, as suggested by the authors’ data. However, most experts recommend antifibrinolytic agents for the prophylaxis of AAE-C1INH; why were the two AAE-C1INH patients receiving pdC1INH instead? The reason of this treatment choice should be clear in the manuscript. ****** 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: Yes: Dr. Moumita Roy 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 to be viewed.] 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. 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Revision 1
9 Dec 2019 Author Response REVIEWER Reviewer #1: I think this paper can only be accepted if the author's add and answer the following points in the current submission. It needs more statistical analysis to be done with statistical software packeges. 1. Kindly add co-relation of patient age with the disease pattern. In current article patients age 8-85 years are added, which is a wide range. 2. Add some more statistical data analysis as well as some statistical graph in this article. AUTHORS As required by Reviewer #1, we performed more statistical analyses. We investigated the possible correlation between age and oral disease severity and between age and angioedema severity. We added two paragraphs and one figure in the Results section. REVIEWER 3. Add some more discussion to correlate the immunological effect of the disease process as well as therapeutic approach. 4. Kindly add some more current relevant references. AUTHORS We added a more thorough explanation about the relationship between infections and occurrence of angioedema attacks in the Discussion section and we circumstantiated these data with appropriate bibliographic references. REVIEWER 5. Add some pictures to show the Angioderama and clarify the scoring process with more supporting images in the current population of the patient. AUTHORS We showed our scoring systems, adding Table 1 and Table 2 in the Methods section (see “Severity of oral and angioedema disease” paragraph). REVIEWER Reviewer #2: The authors present data from a study on the management of dental procedures in patients with HAE or AAE due to C1-Inhibitor deficiency. It is adequately written and the conclusions presented are appropriately supported by the data. Although most of the conclusions reached by the authors are not novel, they do provide experimental support to previously reported observations with important implications for the management of these patients. Because of dealing with a rare pathology, the relatively small number of individuals recruited for this study is not to be considered a substantial limitation in its design. AUTHORS We thank the Reviewer for appreciating this work. REVIEWER Minor points: - Lines 175-176: The manuscript states that “….Most patients recruited in this study had a moderate-to-high score for the severity of oral pathology”. However, according to Table 1, most of the patients studied (20/27) had a Mild to Moderate phenotype. AUTHORS The intended meaning was that the sum of patients with moderate and severe oral pathology is greater than 50%. In order to avoid misunderstandings, we changed the sentence indicating the precise percentage (59.25%). REVIEWER - Lines 179-180: The amelioration of the patients’ HAE course after dental care is a reasonable conclusion. Though, significant improvement of HAE was observed in as little as 20% of the studied cases. Wouldn’t it be expectable to find a general improvement in the cohort after dental management? Were these 4 patients showing amelioration of HAE those exhibiting worse oral pathological scores?; that is, is there any correlation between the oral disease score and the beneficial effect of dental care on HAE? Can the authors speculate in the discussion section on the hypothetical causes of the lack of response in an 80% of cases? AUTHORS We thank the Reviewer, as our manuscript would certainly benefit from further deepening of this topic. We eliminated a possible trigger of angioedema attack, but, as it not possible to eradicate the underlying pathology, we did not expect an improvement in all the patients. No one worsened and 4 improved: we added in the Discussion section a thorough analysis of the severity of oral pathology. The average oral pathology score was slightly worse in the subpopulation who experienced an amelioration compared with the other patients (4.75 vs 4). This finding indicates that the subpopulation who benefits most from dental procedures has more severe oral pathology. REVIEWER - Line 223: Previous studies have also shown that pdC1INH prophylaxis is less effective for AAE-C1INH as compared to HAE-C1INH (reviewed for example in Cicardi et al, 2014). This observation is coherent with the increased C1INH catabolism characteristic of AAE-C1INH patients and may be influenced by the presence or absence of anti-C1INH autoantibodies in the patient, as suggested by the authors’ data. However, most experts recommend antifibrinolytic agents for the prophylaxis of AAE-C1INH; why were the two AAE-C1INH patients receiving pdC1INH instead? The reason of this treatment choice should be clear in the manuscript. AUTHORS We thank the Reviewer for this comment. There is no evidence from randomized clinical trials that antifibrinolytic agents are effective for STP in AAE-C1INH. These agents are contraindicated in some categories of patient, such as those receiving antiplatelet or anticoagulant therapy and those with procoagulant condition. This was the case of our patients and the reason why we chose pdC1INH for STP. We clarified the reason of the treatment choice in the manuscript in the Discussion section. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0230128.r002
24 Feb 2020 Decision Letter - Girijesh Kumar Patel, Editor Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: an observational study PONE-D-19-20853R1 Dear Dr. Zanichelli, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. 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With kind regards, Girijesh Kumar Patel, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #2: All comments have been addressed Reviewer #3: (No Response) ******** 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 #2: Yes Reviewer #3: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: (No Response) ****** 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 #2: Yes Reviewer #3: (No Response) ****** 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 #2: Yes Reviewer #3: (No Response) ****** 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 #2: The authors have succesfully addressed all the questions and comments. No further reviewing is required on my part. Reviewer #3: Your raising of awareness with regards to a highly neglected disease in Dentistry is a rewarding addition to health and science. Following past reviewer comments has greatly enhanced the content of this paper and made it more valuable, however, there are a few minor corrections (added as comments) I have pointed out on the context of your PDF document article (provided as an attachment) that I recommend you amend as a final aspect. ****** 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 #2: Yes: Alberto López Lera Reviewer #3: No https://doi.org/10.1371/journal.pone.0230128.r003
Formally Accepted
28 Feb 2020 Acceptance Letter - Girijesh Kumar Patel, Editor PONE-D-19-20853R1 Short-term prophylaxis in patients with angioedema due to C1-inhibitor deficiency undergoing dental procedures: an observational study Dear Dr. zanichelli: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Girijesh Kumar Patel Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0230128.r004

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