Low-dose theophylline in addition to ICS therapy in COPD patients: A systematic review and meta-analysis

Tiankui Shuai; Chuchu Zhang; Meng Zhang; Yalei Wang; Huaiyu Xiong; Qiangru Huang; Jian Liu

doi:10.1371/journal.pone.0251348

Peer Review History

Original SubmissionJanuary 22, 2021
12 Feb 2021 Decision Letter - Walid Kamal Abdelbasset, Editor PONE-D-21-02298 Adding Low-dose Theophylline to ICS therapy on COPD: a systematic review and meta-analysis PLOS ONE Dear Dr. Liu, 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 Mar 29 2021 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. 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The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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. Reviewer #1: No 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: No 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: Paper titled (Adding Low-dose Theophylline to ICS therapy on COPD: a systematic review and meta-analysis) discussed the valued of adding theophylline to the traditional ICS therapy to COPD patients. ALthough the manuscript has merit but many recommendations can be follwoed before consideration for publication. Title: on COPD should be in COPD patients or cases Abstract: man abbreviations appeared without definition at the first appearance. I believe Plos one is a multidisciplinary journal and clarifications of these terms before use is mandatory. Abstract: first line (It has been reported that there was synergism...) can be replaced by (a synergism has been reported)'' The conclusion is not useful (by the way it is exactly the same as that written after discussion) and cannot give the reader what was the outcome of using theophylline whether good or bad. whether will be recommended or not Also (There were several studies explored) can be , Sevral studies explored............ Kindly revise the whole manuscript for similar non-perfect terms and sentences. I recommend if authors seek help from a naive speaker or editing services. Resolution of all images should be 300 dpi as minimal (or better 600 dpi). Reviewer #2: 1. Line 132 Studies that did not exclude patients who used drugs that interact with theophylline should be excluded. 2. Lines 126, 127 Please check (The subjects included who had been predominantly diagnosed with COPD: ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) <0.7) as the presence of post bronchodilator (FEV1/FVC) <0.7 confirms the presence of airflow limitation and COPD diagnosis. 3. Table (1) There is no equality in intervention therapies between selected studies as well as study of 2007 did not mention the used standard therapy which makes your hypothesis not accurate. 4. Selected studies did not afford data about exact dosage of theophylline and the dosage might influence the pharmacological action of theophylline .Also there is no available data about duration of treatment as variability in dose and duration increase heterogeneity. 5. Line 242 Select a study you refer in this sentence (there was a study that indicated Theophylline as add-on therapy to ICS improved lung function of COPD). ****** 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:** Sawsan A. Zaitone 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.0251348.r001
Revision 1
28 Mar 2021 Author Response We have studied the valuable comments from you, the assistant editor and reviewers carefully, and tried our best to revise the manuscript. The point-to-point response to the reviewers and editor are listed as following: Respond to reviewer’s comments: Reviewer#1: Paper titled (Adding Low-dose Theophylline to ICS therapy on COPD: a systematic review and meta-analysis) discussed the valued of adding theophylline to the traditional ICS therapy to COPD patients. Although the manuscript has merit but many recommendations can be followed before consideration for publication. Title: on COPD should be in COPD patients or cases Thanks for the reviewer’s suggestion. The title of the article has been revised as following: “Low-dose theophylline in addition to ICS therapy in COPD patients: a systematic review and meta-analysis”. I have corrected it in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). Abstract: many abbreviations appeared without definition at the first appearance. I believe Plos one is a multidisciplinary journal and clarifications of these terms before use is mandatory. Thanks for the reviewer’s suggestion. I have added the definitions of abbreviations at the first appearance in abstract and highlighted with yellow mark in the revised manuscript with track changes (supporting information). Abstract: first line (It has been reported that there was synergism...) can be replaced by (a synergism has been reported) Thanks for the reviewer’s suggestion. The corresponding part of the article has been revised as following: “A synergism has been reported between theophylline and corticosteroids, wherein theophylline increases and restores the anti-inflammatory effect of inhaled corticosteroids (ICS) by enhancing histone deacetylase-2 (HDAC) activity”. I have revised it in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). The conclusion is not useful (by the way it is exactly the same as that written after discussion) and cannot give the reader what was the outcome of using theophylline whether good or bad. whether will be recommended or not Thanks for the reviewer’s suggestion. The corresponding part of the article has been revised as following: “Based on current evidence, low-dose theophylline as add-on therapy to ICS did not reduce the exacerbation rate. Instead, the hospitalization rate and mortality increased with theophylline. Thus, we do not recommend adding low-dose theophylline to ICS therapy in COPD patients”. I have revised it in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). Also (There were several studies explored) can be , Several studies explored............ Thanks for the reviewer’s suggestion. The corresponding part of the article has been revised as following: “Several studies have explored the efficacy of low-dose theophylline plus ICS therapy on chronic obstructive pulmonary disease (COPD) but the results are discrepant”. I have corrected it in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). Kindly revise the whole manuscript for similar non-perfect terms and sentences. I recommend if authors seek help from a naive speaker or editing services. Thanks for reviewer’s comment. I have invited a native English-editor to help me correct the grammar and style errors. The version with track changes of editing agency and the certification of editing has been uploaded to the journal. Resolution of all images should be 300 dpi as minimal (or better 600 dpi). Thanks for reviewer’s comment. I have corrected the resolution of the image and uploaded the correct version. Reviewer #2: 1. Line 132 Studies that did not exclude patients who used drugs that interact with theophylline should be excluded. Thanks for reviewer’s comment. I have added one exclusion criteria as following: “studies that used drugs with the potential to influence plasma theophylline concentration”. Also, I have rechecked the included studies, none of which met the exclusion criteria. 2. Lines 126, 127 Please check (The subjects included who had been predominantly diagnosed with COPD: ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) <0.7) as the presence of post bronchodilator (FEV1/FVC) <0.7 confirms the presence of airflow limitation and COPD diagnosis. Thanks for reviewer’s comment. The corresponding part of the article has been revised as following: “Studies with subjects including individuals who had been predominantly diagnosed with COPD: a post-bronchodilator ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) < 0.7”. I have corrected it in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). 3. Table (1) There is no equality in intervention therapies between selected studies as well as study of 2007 did not mention the used standard therapy which makes your hypothesis not accurate. Thanks for reviewer’s comment. The included studies in this meta-analysis did exist inconsistencies in the basic therapy regimens. And we listed the detailed medication of each studies in table1 (“Intervention”). Also, we tried to perform subgroup analysis based on medication type. But there were so few studies of each treatment regimen that there is only one study in a subgroup. Therefore, the subgroup analysis did not address the issue very well. This is indeed a source of heterogeneity for our meta-analysis. Thus, we describe it in the discussion section (line 289-293): “the intervention following in the exposure group of included studies was not exactly the same; other than theophylline and ICS, LABA and ipratropium were also included in some studies. The difference in interventions may have caused the different effect on COPD patients. Accordingly, this could be a possible source of high heterogeneity”. 4. Selected studies did not afford data about exact dosage of theophylline and the dosage might influence the pharmacological action of theophylline. Also, there is no available data about duration of treatment as variability in dose and duration increase heterogeneity. Thanks for reviewer’s comment. The included studies provided the specific dosage or the dosage ranges of the theophylline. Based on the information from included researches, we added the dosage of theophylline to the Table 1. And we conducted the subgroup analysis based on the theophylline dosage (Fig 2), indicating that the dosage might be a source of heterogeneity. Furthermore, we have described it in the discussion section (line 288, 289): “the exact dosage of theophylline was different in the included studies and the dosage may influence the pharmacological effect of theophylline in vivo”. Meanwhile, as the reviewer considered, the included studies in this meta-analysis did exist inconsistencies in the duration. And we listed the duration of each studies in table1 (“Duration”). Considering the dose-time-effect, individual differences, and the fact that most studies did not continuously monitor theophylline concentrations in plasma, we believe it is also part of the source of heterogeneity. we have described it in the discussion section (line 294-296): “the duration of study varied from 60 days to 4 years. We believe that the duration may influence the effect of theophylline on COPD; accordingly, it was also regarded as a source of heterogeneity”. 5. Line 242 Select a study you refer in this sentence (there was a study that indicated Theophylline as add-on therapy to ICS improved lung function of COPD). Thanks for reviewer’s comment. I have added the study in manuscript and highlighted with yellow mark in the revised manuscript with track changes (supporting information). Attachments Attachment Submitted filename: Response to reviewers.docx* https://doi.org/10.1371/journal.pone.0251348.r002
26 Apr 2021 Decision Letter - Walid Kamal Abdelbasset, Editor Low-dose theophylline in addition to ICS therapy in COPD patients: a systematic review and meta-analysis PONE-D-21-02298R1 Dear Dr. Liu, 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, Walid Kamal Abdelbasset, Ph.D. 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 #3: 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 #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 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 #3: 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 #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The revised version of Paper titled (Low-dose theophylline in addition to ICS therapy in COPD patients: a systematic review and meta-analysis) was adequately revised by the authors. Thanks for the authors for addressing the recommendations. Reviewer #3: (No Response) ****** 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: Yes:** Sawsan A. Zaitone Reviewer #3: No https://doi.org/10.1371/journal.pone.0251348.r003
Formally Accepted
14 May 2021 Acceptance Letter - Walid Kamal Abdelbasset, Editor PONE-D-21-02298R1 Low-dose theophylline in addition to ICS therapy in COPD patients: a systematic review and meta-analysis Dear Dr. Liu: 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. Walid Kamal Abdelbasset Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251348.r004

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