Identification of distinct phenotypes related to benralizumab responsiveness in patients with severe eosinophilic asthma

Hideyasu Yamada; Masayuki Nakajima; Masashi Matsuyama; Yuko Morishima; Naoki Arai; Norihito Hida; Taisuke Nakaizumi; Hironori Masuko; Yohei Yatagai; Takefumi Saito; Nobuyuki Hizawa

doi:10.1371/journal.pone.0248305

Peer Review History

Original SubmissionDecember 3, 2020
3 Feb 2021 Decision Letter - Stelios Loukides, Editor PONE-D-20-37996 Identification of distinct phenotypes related to benralizumab responsiveness in patients with severe eosinophilic asthma PLOS ONE Dear Dr. Yamada, Thank you for submitting your manuscript to PLOS ONE. We apologise for the delay. 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. Both reviewers raised some concenrs. These concerns are mainly related to low number of patients, to the way that introduction and discussion are presented and fnally to some methodological issues which may affect the interpretation of the results. Please submit your revised manuscript by Mar 20 2021 11:59PM. 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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: N/A 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: Hideyasu Yamada et al, tried to indentify distinct phenotypes related to benralizumab responsiveness in patients with severe eosinophilic asthma on a real world basis study and found 5 phenotypes according to FEV1 responsiveness. Although it is an interesting study with clinical significance regarding every day clinical practice, there are issues that have to be clarified: 1. The study population section is incomplete as basic characteristics are missing even from the Table 1. It is not clarified if patients have received other kind of biological in the past. What was the number of exacerbations in the previous 1 or 2 years? Besides allergic rhinitis, did they have nasal polyposis as well, and in what percentage? 2. The cut off value of 173 IU/mL for IgE is rather arbitrary and high, as there are many references of 100 IU/mL as normal values. Furthermore, no information is provided about positive skin prick or Rast tests in order to better characterize the phenotype of severe allergic asthma. 3. There is no reference regarding changes in OCS use as almost 18 of the patients were under this treatment. OCS sparing is a major parameter of responsiveness to a biologic agent besides FEV1 improvement. The same applies for the number of exacerbations which should be included in the final analysis. 4. Authors should make a comment comparing their results to those based on pool data of the initial phase III studies of Benralizumab (Bleecker ER, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018; 52: 1800936) as there are both similarities and differences. 5. The conclusion should be more clear about which phenotypes relate to benralizumab responsiveness. Minor comments 1. Reference 1 does not support the first paragraph of the introduction section and the same applies for reference 7 2. References 24, 25 at the end of the first paragraph of introduction should be omitted 3. PSL abbreviation in Table 2 is not explained 4. Table 3 is rather confusing and most of the comparisons are not statistically significant, so it is suggested to be omitted. Table 5 could be omitted as Figure 3 is more informative 5. Statistical significant p values lower than 0,05 would better be written as p<0,001 instead of e.g. 3,1 x10-5 Reviewer #2: Thank you for asking me to review this paper. Cluster analysis was used to investigate benralizumab’ treatment response in a small real-world data set. The study deals with an interest aspect of severe asthma management for a tailored therapy. The paper is well written and easy to follow. My main concerns are the small sample size and the low generalizability of the results. Comments: 1) Abstract: The paper is about identifying clusters of benralizumab treatment response. However, the Results summary does not clearly define which clusters were identified. 2) Introduction is very generical and not informative. I would emphasize the importance of identifying clusters responding to benralizumab treatment outside clinical trials and to have information from real world settings. 3) Methods: Why not taking into account airway reversibility and post-bronchodilator FEV1? Please specify 4) Results: Table 2 please describe all the abbreviations 5) Discussion needs improvements. Please discuss in detail the published literature in light of the results of your research. 6) Discussion: tables and figures should not be referenced in the Discussion section 7) Discussion: I would suggest adding a paragraph developing the potential usefulness of the study results and their generalizability. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0248305.r001
Revision 1
11 Feb 2021 Author Response Responses to the reviewers’ comments Reviewer: #1 COMMENT 1 The study population section is incomplete as basic characteristics are missing even from the Table 1. It is not clarified if patients have received other kind of biological in the past. What was the number of exacerbations in the previous 1 or 2 years? Besides allergic rhinitis, did they have nasal polyposis as well, and in what percentage? RESPONSE 1 Thank you for the comment. In the revised manuscript, we have added the number of patients who had previous administration of other biologics at Table 1. We are afraid that information about previous exacerbation and nasal polyps is not available in this real-world cohort. COMMENT 2 The cut off value of 173 IU/mL for IgE is rather arbitrary and high, as there are many references of 100 IU/mL as normal values. Furthermore, no information is provided about positive skin prick or Rast tests in order to better characterize the phenotype of severe allergic asthma. RESPONSE 2 Thank you for the comment. According to the suggestion, in the revised manuscript, we have reanalyzed our data using the cut off value of 100 IU/mL, which showed no significant changes in the result. We agree that information about allergen specific IgE responses is important to better characterize each cluster of severe eosinophilic asthma; however, insufficient information about this in this real-world cohort did not allow us to do so. COMMENT 3 There is no reference regarding changes in OCS use as almost 18 of the patients were under this treatment. OCS sparing is a major parameter of responsiveness to a biologic agent besides FEV1 improvement. The same applies for the number of exacerbations which should be included in the final analysis. RESPONSE 3 Thank you for the comment. Although this study focused on the initial 4-month after starting benralizumab in a real-world setting, small but significant reduction in doses of maintenance OCS was noted during this period (Table 2). In terms of exacerbation, insufficient information about exacerbation history before starting benralizumab did not allow us to evaluate the effect of benralizumab. COMMENT 4 Authors should make a comment comparing their results to those based on pool data of the initial phase III studies of Benralizumab (Bleecker ER, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018; 52: 1800936) as there are both similarities and differences. RESPONSE 4 Thank you for the comment. We have added a following sentence to the discussion in the revised manuscript. “Pooled data analysis from the Phase III studies (SIROCCO and CALIMA) identified oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis as baseline factors that influenced benralizumab efficacy (E1). In addition, the real-world effectiveness study of benralizumab also highlighted higher eosinophil counts, nasal polyposis, and adult-onset asthma as baseline characteristics associated with a superior response to benralizumab (E2). In the current study, in addition to elevated type-2 markers, lower FEV1 or OCS use appeared to be related to increased FEV1 response to benralizumab, which is in line with the previous studies. In contrast, age at disease onset was not related to the responsiveness in our study, which may be attributed to the rather older disease onset (57.8 years old) observed in our cohort.” E1. Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018 Oct 18;52(4):1800936. doi: 10.1183/13993003.00936-2018. E2. Joanne EK, Andrew PH, Jaideep D, Gráinne d'A, Abdel D, Cris R, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. Online ahead of print. DOI: https://doi.org/10.1016/j.chest.2020.08.2083 COMMENT 5 The conclusion should be more clear about which phenotypes relate to benralizumab responsiveness. RESPONSE 5 Thank you for the comment. At the 1st paragraph of the discussion, we have now described clearly that the greatest response was found in the distinct phenotype of severe eosinophilic asthma, which was characterized by modest increases in total IgE and FeNO relative to blood eosinophils with least exposure to smoking. MINOR　COMMENT 1. Reference 1 does not support the first paragraph of the introduction section and the same applies for reference 7 2. References 24, 25 at the end of the first paragraph of introduction should be omitted 3. PSL abbreviation in Table 2 is not explained 4. Table 3 is rather confusing and most of the comparisons are not statistically significant, so it is suggested to be omitted. Table 5 could be omitted as Figure 3 is more informative 5. Statistical significant p values lower than 0,05 would better be written as p<0,001 instead of e.g. 3,1 x10-5 RESPONSE to minor comment The above has been corrected as appropriate. In the revised manuscript, we omitted Table 5, but not Table 3. We believe that Table 3 has some importance of showing the baseline predictive factors for FEV1 improvement in response to 4-month benralizumab. Reviewer: #2 COMMENT 1 Abstract: The paper is about identifying clusters of benralizumab treatment response. However, the Results summary does not clearly define which clusters were identified. RESPONSE 1 Thank you for the comment. In the result section of abstract, we have now described clearly that the greatest response was found in the distinct phenotype of severe eosinophilic asthma, which was characterized by modest increases in total IgE and FeNO relative to blood eosinophils with least exposure to smoking. COMMENT 2 Introduction is very generical and not informative. I would emphasize the importance of identifying clusters responding to benralizumab treatment outside clinical trials and to have information from real world settings. RESPONSE 2 Thank you for the comment. We have revised the introduction accordingly. COMMENT 3 Methods: Why not taking into account airway reversibility and post-bronchodilator FEV1? Please specify RESPONSE 3 Thank you for the comment. We are afraid that we do not have sufficient information about airway reversibility and post-bronchodilator FEV1 in this cohort. COMMENT 4 Results: Table 2 please describe all the abbreviations RESPONSE 4 Thank you for the comment. We have revised Table 2 accordingly. COMMENT 5 Discussion needs improvements. Please discuss in detail the published literature in light of the results of your research. RESPONSE 5 We have added a following sentence to the 4th paragraph of the discussion in the revised manuscript. “Pooled data analysis from the Phase III studies (SIROCCO and CALIMA) identified oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis as baseline factors that influenced benralizumab efficacy (E1). In addition, the real-world effectiveness study of benralizumab also highlighted higher eosinophil counts, nasal polyposis, and adult-onset asthma as baseline characteristics associated with a superior response to benralizumab (E2). In the current study, in addition to elevated type-2 markers, lower FEV1 or OCS use appeared to be related to increased FEV1 response to benralizumab, which is in line with the previous studies. In contrast, age at disease onset was not related to the responsiveness in our study, which may be attributed to the rather older disease onset (57.8 years old) observed in our cohort.” E1. Bleecker ER, Wechsler ME, FitzGerald JM, Menzies-Gow A, Wu Y, Hirsch I, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018 Oct 18;52(4):1800936. doi: 10.1183/13993003.00936-2018. E2. Joanne EK, Andrew PH, Jaideep D, Gráinne d'A, Abdel D, Cris R, et al. Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma. Chest. Online ahead of print. DOI: https://doi.org/10.1016/j.chest.2020.08.2083 COMMENT 6 Discussion: tables and figures should not be referenced in the Discussion section RESPONSE 6 Thank you for your comment. We have revised the manuscript accordingly. COMMENT 7 Discussion: I would suggest adding a paragraph developing the potential usefulness of the study results and their generalizability. RESPONSE 7 Thank you for your comment. Accordingly, we have added a sentence as the 3rd paragraph of the Discussion. Attachments Attachment Submitted filename: Response to reviewer ver.1.docx https://doi.org/10.1371/journal.pone.0248305.r002
24 Feb 2021 Decision Letter - Stelios Loukides, Editor Identification of distinct phenotypes related to benralizumab responsiveness in patients with severe eosinophilic asthma PONE-D-20-37996R1 Dear Dr. Yamada, 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, Stelios Loukides 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 #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: Although there are missing data to further supportthe final conclusion, the required questions have been answered and all responses meet formatting specifications Reviewer #2: The authors addressed all the points raised. The manuscript adds interesting information in the field. I have no further comments. ****** 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.0248305.r003
Formally Accepted
3 Mar 2021 Acceptance Letter - Stelios Loukides, Editor PONE-D-20-37996R1 Identification of distinct phenotypes related to benralizumab responsiveness in patients with severe eosinophilic asthma Dear Dr. Yamada: 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. Stelios Loukides Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248305.r004

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