Effects of additional oral theophylline with inhaled therapy in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysis

Qiang Yang; Pingxiu Tang,; Xunyan Zhang

doi:10.1371/journal.pone.0321984

Peer Review History

Original SubmissionAugust 14, 2024
14 Aug 2024 Author Response https://doi.org/10.1371/journal.pone.0321984.r001
12 Nov 2024 Decision Letter - Shailza Singh, Editor PONE-D-24-33914Effects of additional oral theophylline with inhaled therapy in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysisPLOS ONE Dear Dr. Yang, 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 Dec 27 2024 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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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: Yes 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: The manuscript by Yang et al presented a systematic review and meta-analysis on the effects of additional oral theophylline in conjunction with inhaled therapy in stable COPD patients. The topic is an interesting one in clinical relevance as theophylline is applied in COPD for very long time. The study is well-structured, follows the PRISMA guidelines, and uses standard meta-analysis techniques. However, there are areas that require clarification and further major revision before it get accepted for publication. - The abstract should mention the increased adverse reactions observed to avoid overstating the potential benefits of theophylline. - The manuscript addresses an important question regarding the role of theophylline as adjunct therapy in COPD, but the introduction should provide more justification for this research, considering known risks of theophylline. - Significant heterogeneity was observed in key outcomes (e.g., symptom scores, adverse reactions). The manuscript should address potential sources and perform subgroup analyses to explore this further. - The manuscript needs to better discuss the clinical risks posed by the high rate of adverse reactions, particularly in the context of theophylline’s known narrow therapeutic window. - The non-significant results for FEV1/FVC% and symptom scores should be more clearly interpreted to guide clinicians on their clinical relevance. - More details on how comorbidities were handled in the included studies are necessary for transparency in the methodology. - The lack of allocation concealment in some studies should be thoroughly discussed as a limitation that could affect the robustness of the findings. - The discussion should be expanded to clarify where, if at all, theophylline should fit in current COPD treatment guidelines, especially given the availability of more effective therapies. - The conclusion should highlight specific research gaps, such as the need for studies on long-term outcomes or focusing on different COPD phenotypes. Reviewer #2: 1. What are the inclusion and exclusion criteria for patients with COPD with/without other complications? Needs to be well defined 2. Table 2 needs to be re-looked into. There are mismatches between cardiovascular and neurological adverse reactions. Besides these common symptoms, adverse reactions, and drug-drug interactions may be included. 3. Many times, COPD patients are treated with other drugs, including antibiotics. Such complications can be discussed in the discussion. ****** 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.0321984.r002
Revision 1
7 Jan 2025 Author Response Reviewer #1: The manuscript by Yang et al presented a systematic review and meta-analysis on the effects of additional oral theophylline in conjunction with inhaled therapy in stable COPD patients. The topic is an interesting one in clinical relevance as theophylline is applied in COPD for very long time. The study is well-structured, follows the PRISMA guidelines, and uses standard meta-analysis techniques. However, there are areas that require clarification and further major revision before it get accepted for publication. (1) The abstract should mention the increased adverse reactions observed to avoid overstating the potential benefits of theophylline. Respond: thank you for reviewer's comments. We have added the mention in abstract. (2) The manuscript addresses an important question regarding the role of theophylline as adjunct therapy in COPD, but the introduction should provide more justification for this research, considering known risks of theophylline. Respond: thank you for reviewer's comments. Indeed, emphasizing the risks of theophylline is very important and could further illustrate the importance of our research. So, we have added relevant content in the introduction. (3) Significant heterogeneity was observed in key outcomes (e.g., symptom scores, adverse reactions). The manuscript should address potential sources and perform subgroup analyses to explore this further. Respond: thank you for reviewer's comments. I am so sorry for my mistake that I mistakenly labeled the meta-analysis figure of adverse reactions. I have corrected it in manuscript and there was no Significant heterogeneity in adverse reactions. Indeed, there was Significant heterogeneity in symptom scores. The symptom scores were subjectively evaluated and recorded by researchers and there were differences between different studies that may lead to significant heterogeneity. It is difficult to perform subgroup analyses because of that It is difficult to classify the included literature. (4) The manuscript needs to better discuss the clinical risks posed by the high rate of adverse reactions, particularly in the context of theophylline’s known narrow therapeutic window. Respond: thank you for reviewer's comments. We have added the discussion in manuscript about the clinical risks posed by the high rate of adverse reactions as following: The therapeutic window of theophylline is relatively narrow (520 g/ml) and show high rate of adverse reactions even though within the therapeutic window (1520 g/ml) such as nausea、vomiting、irritability and insomnia. When the serum concentration exceeds 20g/ml, tachycardia and arrhythmia may occur. Fever、dehydration、convulsions and even death caused by respiratory and cardiac arrest may occur when serum concentration exceeds 40g/ml. In addition, many factors could affect the serum concentration of theophylline, such as age、medication and disease. Therefore, clinician need to be in cautions when prescribing theophylline and it is recommended to monitor the serum concentration. (5) The non-significant results for FEV1/FVC% and symptom scores should be more clearly interpreted to guide clinicians on their clinical relevance. Respond: Thank you for reviewer's comments. Our meta-analysis indicated non-significant results for FEV1% pred、FEV1/FVC% and symptom scores. FEV1% pred and FEV1/FVC% were important index to evaluate lung function and the effectiveness of medication therapy. Theophylline is a weak acting bronchodilator and adding theophylline on the basis of potent inhaled bronchodilators may do not produce additional effects, inducing no improvement in FEV1% pred and FEV1/FVC%. Symptoms scores are closely related to lung function and non-significant FEV1% pred and FEV1/FVC% improvements result non-significant symptom scores. The above content was added into the discussion of the manuscript. (6) More details on how comorbidities were handled in the included studies are necessary for transparency in the methodology. Respond: Thank you for reviewer's comments. Indeed, comorbidities may affect the effectiveness of COPD treatment. The included studies excluded patients with comorbidities that could affect the evaluation of treatment efficacy, such as bronchiectasis、tuberculosis、cancer、heart failure and infections. For some comorbidities, such as hypertension、osteoporosis, it is expected that they will not obviously affect the evaluation of treatment efficacy and have not been excluded, and there is no baseline characteristic difference between the treatment group and the control group. (7)The lack of allocation concealment in some studies should be thoroughly discussed as a limitation that could affect the robustness of the findings. Respond: Thank you for reviewer's comments. Allocation concealment is an important step in randomized controlled trials, aimed at ensuring the confidentiality of the randomization process and preventing researchers from predicting the grouping of subjects before allocation, thereby reducing selection bias. If no allocation concealment scheme, researchers may make subjective judgments during randomization, leading to certain subjects being preferentially assigned to specific groups and resulting in selection bias. The results of meta-analysis depend on the quality of the included studies and the reliability of the randomization process. The lack of allocation concealment schemes in the original research would affect the objectivity and accuracy of the meta-analysis. The above content was added into the discussion of the manuscript. (8)The discussion should be expanded to clarify where, if at all, theophylline should fit in current COPD treatment guidelines, especially given the availability of more effective therapies. Respond: Thank you for reviewer's comments. Our Meta analysis results show that adding theophylline to inhalation therapy can reduce the risk of acute exacerbation in patients with COPD. Therefore, the theophylline may be more suitable for patients who have a high risk of acute exacerbation especially when have already been treated with ICS+LABA+LAMA. (9)The conclusion should highlight specific research gaps, such as the need for studies on long-term outcomes or focusing on different COPD phenotypes. Respond: Thank you for reviewer's comments. We have added relevant contents in the conclusion of the manuscript. Reviewer #2: 1.What are the inclusion and exclusion criteria for patients with COPD with/without other complications? Needs to be well defined. Respond: Thank you for reviewer's comments. The inclusion criteria included:(1) stable COPD; (2) age>18 years old; (3) RCTs; (4) no limitations in gender, age, ethnicity, or treatment duration. (5) without bronchiectasis、tuberculosis、cancer、heart failure and infections. Exclusion criteria included: (1) non-stable COPD; (2) non-RCTs; (3) Valid ending data unable to be extracted; (4) Full text of the study is not available. (5) with bronchiectasis、tuberculosis、cancer、heart failure and infections. We have added in the manuscript. 2.Table 2 needs to be re-looked into. There are mismatches between cardiovascular and neurological adverse reactions. Besides these common symptoms, adverse reactions, and drug-drug interactions may be included. Respond: Thank you for reviewer's comments. I am so sorry for my mistake of mismatching between cardiovascular and neurological adverse reactions. We have corrected it in the manuscript. Theophylline is metabolized by cytochrome P450 mixed function oxidases. Many other drugs can modify theophylline. For example, macrolides and quinolones could decline the clearance of theophylline and may lead to an increase of serum concentration, rising the risk of adverse reactions of theophylline. The content above was added in the discussion of the manuscript. 3.Many times, COPD patients are treated with other drugs, including antibiotics. Such complications can be discussed in the discussion. Respond: Thank you for reviewer's comments. Stable COPD generally does not require antibiotics. When COPD patients experience acute exacerbation, short-term use of antibiotics is possible and is not expected to have a significant impact on research. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0321984.r003
6 Feb 2025 Decision Letter - Shailza Singh, Editor PONE-D-24-33914R1Effects of additional oral theophylline with inhaled therapy in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysisPLOS ONE Dear Dr. Yang, 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 23 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. Please include the following items when submitting your revised manuscript: 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. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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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 revise as per reviewer’s suggestions [Note: HTML markup is below. Please do not edit.] 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: 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 #2: (No Response) Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: (No Response) Reviewer #3: No ****** 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: (No Response) 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 #2: (No Response) 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 #2: (No Response) Reviewer #3: The authors have addressed most of the comments and significant improvement in the manuscript. However, I request the authors further clarify and refine before its get accepted for publication. − The author have acknowledged heterogeneity in symptom scores, the justification for not performing subgroup analyses could be expanded. If subgroup analyses are truly infeasible, please consider alternative approaches, such as sensitivity analyses or meta-regression, to explore the sources of heterogeneity. − It has been mentioned difficulties in classifying literature for subgroup analysis. It would be helpful to elaborate on these difficulties in the methods or discussion section. For example, were there inconsistencies in study design, population characteristics, or outcome measures that prevented meaningful subgroup comparisons? − The authors have improved the discussion regarding the non-significant changes in lung function parameters (FEV1/FVC%), further elaboration on the clinical implications would be beneficial. How should clinicians interpret these findings in the context of COPD management, particularly in patients who are already receiving triple therapy? − The authors have acknowledged the lack of allocation concealment in some studies as a potential limitation, which is appreciated. However, a brief discussion on how this might have influenced your results (e.g., overestimation of theophylline’s benefits) would further enhance transparency. − The conclusion has added the research gaps. However, adding more specific recommendations (e.g., the need for long-term studies assessing cardiovascular risks or theophylline's role in different COPD phenotypes) would make the conclusion and manuscript for further improvement. ****** 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: No Reviewer #3: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0321984.r004
Revision 2
10 Mar 2025 Author Response Reviewer#3: The authors have addressed most of the comments and significant improvement in the manuscript. However, I request the authors further clarify and refine before its get accepted for publication. (1) The author has acknowledged heterogeneity in symptom scores, the justification for not performing subgroup analyses could be expanded. If subgroup analyses are truly infeasible, please consider alternative approaches, such as sensitivity analyses or meta-regression, to explore the sources of heterogeneity. Respond: thank you for reviewer's comments. When conducting a meta-analysis of symptom scores, only three studies were included, making subgroup analysis difficult. Sensitivity analysis using Stata14 software revealed that after excluding the Subramanian2015 study, the heterogeneity was significantly reduced, yet there remained no significant difference in symptom scores between the two groups (MD = -0.14, 95% CI: -0.44 to 0.15, p = 0.35, I² = 37%). The study of Subramanian2015 specifically reported night symptom scores, which may explain the heterogeneity compared to the other two studies. We have added the content in the discussion section in manuscript. (2)It has been mentioned difficulties in classifying literature for subgroup analysis. It would be helpful to elaborate on these difficulties in the methods or discussion section. For example, were there inconsistencies in study design, population characteristics, or outcome measures that prevented meaningful subgroup comparisons. Respond: thank you for reviewer's comments. Indeed, meaningful subgroup analyses were not conducted due to challenges in classifying the literature with regard to inconsistencies in study design, population characteristics, and medication regimens.We have added the content in the discussion section in manuscript. (3)The authors have improved the discussion regarding the non-significant changes in lung function parameters (FEV1/FVC%), further elaboration on the clinical implications would be beneficial. How should clinicians interpret these findings in the context of COPD management, particularly in patients who are already receiving triple therapy? Respond: thank you for reviewer's comments. FEV1/FVC%<70% serves as a key diagnostic criterion for COPD. A persistent decline in FEV1/FVC% during follow-up monitoring of COPD also indicates progressive deterioration of lung function. Meta-analysis findings demonstrate that the addition of theophylline to inhaled therapy do not significantly improve FEV1/FVC%. Although theophylline exhibits bronchodilatory effects, its efficacy is relatively modest. When combined with novel potent bronchodilators (e.g., LABA and LAMA) in COPD treatment regimens, theophylline may not exhibit additional bronchodilation and therefore fails to improve pulmonary function parameters. However, meta-analyses have demonstrated that adjunctive theophylline therapy may reduce acute exacerbation risks, primarily attributable to its anti-inflammatory properties rather than bronchodilatory mechanisms. Therefore, theophylline is recommended for patients with high risk of acute exacerbations, particularly for those already on triple therapy, but is not recommended for pulmonary function enhancement in COPD management. (4)The authors have acknowledged the lack of allocation concealment in some studies as a potential limitation, which is appreciated. However, a brief discussion on how this might have influenced your results (e.g., overestimation of theophylline’s benefits) would further enhance transparency. Respond: thank you for reviewer's comments. The absence of allocation concealment in primary studies may systematically compromise the validity of meta-analysis, particularly through inflated treatment effect estimates (e.g., overestimation of theophylline’s benefits) . We have added relative content in the manuscript according to reviewer's suggestion. (5)The conclusion has added the research gaps. However, adding more specific recommendations (e.g., the need for long-term studies assessing cardiovascular risks or theophylline's role in different COPD phenotypes) would make the conclusion and manuscript for further improvement. Respond: thank you for reviewer's comments. We have added relative content in the manuscript according to reviewer's suggestion. Attachments Attachment Submitted filename: Response to Reviewers_.docx https://doi.org/10.1371/journal.pone.0321984.r005
17 Mar 2025 Decision Letter - Shailza Singh, Editor Effects of additional oral theophylline with inhaled therapy in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysis PONE-D-24-33914R2 Dear Dr. Yang, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Shailza Singh, Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0321984.r006
Formally Accepted
Acceptance Letter - Shailza Singh, Editor PONE-D-24-33914R2 PLOS ONE Dear Dr. Yang, 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 If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Shailza Singh Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0321984.r007

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