PONE-D-21-13798

Incidence of Long-term Post-acute Sequelae of SARS-CoV-2 Infection Related to Pain and Other Symptoms: A Living Systematic Review and Meta-analysis

PLOS ONE

Dear Dr. Shiga,

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 address the issues and revise accordingly.

Please submit your revised manuscript by Nov 20 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.

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. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for stating the following financial disclosure: "NO"

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. 

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

3. Thank you for stating the following in your Competing Interests section: "NO"

Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now 

 This information should be included in your cover letter; we will change the online submission form on your behalf.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

5. Please remove all personal information, ensure that the data shared are in accordance with participant consent, and re-upload a fully anonymized data set. 

Note: spreadsheet columns with personal information must be removed and not hidden as all hidden columns will appear in the published file.

Additional guidance on preparing raw data for publication can be found in our Data Policy (https://journals.plos.org/plosone/s/data-availability#loc-human-research-participant-data-and-other-sensitive-data) and in the following article: http://www.bmj.com/content/340/bmj.c181.long.

[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: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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 read with interest about this comprehensive systemic review of post-acute COVID-19 symptoms. Generally, the article was well written with adequate meta-analyses. I still had some concerns about this study.

1. At least some important studies were not included in the current study. I suggest authors include these studies and re-analyze your results.

a. Chopra, V., Flanders, S. A. & O’Malley, M. Sixty-day outcomes among patients hospitalized with COVID-19. Ann. Intern. Med. (2020).

b. Garrigues, E. et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J. Infect. 81, e4–e6 (2020).

2. The last literature research was performed on January 15, 2021. The post-acute COVID-19 symptoms had been reported more in detail after that time. Since this study is aimed to be a living meta-analysis, is it feasible for authors to include newer publised studies after Jan 2021. At least the following should be considered:

a. Huang L, Yao Q, Gu X, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021; 398(10302):747-758. →Updated results from reference 31.

b. Moreno-Pérez, O. et al. Post-acute COVID-19 syndrome. Incidence and risk factors: a Mediterranean cohort study. J. Infect. (2021)

Reviewer #2: The authors use a living systematic review and meta-analysis to depict the incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms. They defined long-term complications as symptoms from which patients suffered for more than one month after onset of the first COVID-19 symptoms or after discharge from hospital. There are several concerns as follows:

Major concern 1: From the results, pain-related symptoms are much less frequently noticed compared to the secondary outcome, symptoms relevant to pain such as fatigue, insomnia, dyspnea, weakness. I am wondering whether the clinical setting could be a source of selection bias. For example, a patient underwent invasive treatment might be highly sedative. The pain would be masked initially, and its related symptoms may flair up in later disease courses.

Major concern 2: Theoretically, all symptoms should be thoroughly observed from estimated onset of the disease. It would be better to have a consistent format for checking up each symptom with daily bases. Since the available published data bear witness to a high heterogeneity, I suggest the authors make a summary table to show the common symptoms according to individual report.

Major concern 3: The authors smartly described “post intensive care syndrome” or “ICU-acquired weakness" in Discussion Section. However, the sensitivity analyses based on ICU and Non-ICU patients are lacking in present draft. If the authors can provide this assessment, it would be also helpful to clarify the Major concern 1.

Minor concern, Line 216: COVID-19 survivors were multifarious with "an" incidence of 5-17%.

**********

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: Wei-Chih Chen

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.

PONE-D-21-13798R1Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms:A systematic review and meta-analysisPLOS ONE

Dear Dr. Shiga,

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 Nov 26 2022 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. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Miquel Vall-llosera Camps

Senior Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

I would like to sincerely apologise for the delay you have incurred with your submission. As mentioned previously, during our final internal checks on this submission, we noticed a potential concern regarding the quality of the peer review process. To ensure that your work received a thorough and objective evaluation at PLOS ONE, we considered necessary to invite additional reviewers. We have now received their completed reviews; the comments are available below.

Although the previous reviewers are happy with your response to their previous comments, the additional reviewers some raised scientific concerns about your study. In particular, reviewer#5 raised concerns that the literature search of your manuscript is out of date. We acknowledge that this concern has been raised previously during this peer review and that you responded that due to the high volume of publications rewriting the manuscript would not be possible. In consideration of your response, to address this concern we would request including in your manuscript a discussion on research published after the search was complete and discussion of your study in the context of the recent published literature.

Please revise the manuscript to address reviewer#5 and #6 comments in a point-by-point response. Please note that the revised manuscript might need to undergo further review, but if you can address these comments satisfactorily the manuscript will be ready to move forward.

[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 #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

Reviewer #6: 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

Reviewer #4: Yes

Reviewer #5: No

Reviewer #6: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: 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

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: 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

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: 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 authors addressed reviewer's comment and revised the manuscript accordingly. I suggest the current study accepted for publication.

Reviewer #3: The authors submitted a revised version of the article along with thorough explanation of the way by which the changes and corrections were made. I have no serious flaws to the article in its revised version.

Reviewer #4: The authors submitted a revised version of the paper along with the clear explanation if the ways by which the corrections were made. I have no serious flaws to the article in its revised version.

Reviewer #5: This meta analysis is totally out of date. The last search was January 2021, now we are September 2022. One year in COVID-19 research implies that several papers and MA about post-COVID pain have been published. This paper does not add nothing to the literature and does not include most updated data.

Reviewer #6: This manuscript describes a systematic review and meta-analysis to estimate the incidence rate for pain and other symptoms due to “long COVID.”

This study used several large electronic databases (including MediRxiv and BioRxiv) to search articles before Jan 15, 2021. In total, 1290 articles were identified in the literature search, and finally, 35 studies were included in the study after a rigorous screening and selection process. The analyses followed a PRISMA standard for meta-analysis, and the inter-study heterogeneity was assessed using I^2 statistics. In addition, the authors investigated the potential source of heterogeneity using meta-regression with a mixed-effects model. Furthermore, the publication bias was assessed by Egger’s P statistics and funnel plots.

Overall, the study method is solid and rigorous. This study provides comprehensive results for long COVID related pain and other symptoms.

I have two questions just for curiosity.

1. The result “every one month of follow-up corresponds to an increase of 1.45 units (45% increase) in prevalence in patients who developed neuralgia after acute COVID-19 infection” indicate the longer follow-up time is associated high incidence rate of neuralgia. Is that because neuralgia will take time to develop, so the studies with short follow-up time can not detect the development of neuralgia?

2. Will different regions of study (e.g. Europe, US and China) be a potential factor contributing to the heterogeneity, as people from different regions may have different tolerances or thresholds of pain?

**********

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 #3: Yes: Alexander E Berezin, FESC, Professor of Medicine, MD, PhD, DSci

Reviewer #4: No

Reviewer #5: No

Reviewer #6: 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.

Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms:A systematic review and meta-analysis

PONE-D-21-13798R2

Dear Dr. Shiga,

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,

Huzaifa Ahmad Cheema

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Due to the long delay associated with this manuscript, I believe it should be expedited for publication as soon as possible. I believe the comments of the authors have been suitably addressed and their are no major concerns.

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

Reviewer #5: (No Response)

Reviewer #6: 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

Reviewer #5: No

Reviewer #6: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #5: No

Reviewer #6: 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

Reviewer #5: No

Reviewer #6: 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

Reviewer #5: Yes

Reviewer #6: 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 manuscript addressed reviewers' and editor's suggestion adequately. I suggested this manuscript accepted for publication.

Reviewer #3: The authors gave comprehensive responces to reviewers' comments and deeply changed the manuscript. I am satisfied about the revised version of the paper.

Reviewer #5: this reviewer understand the situation that the authors comment about their manuscript but publishing a meta-analysis conducted in 2021 in 2023 is not feasible. I apologize, my opinion is the same, authors must update the review and focus only on pain symptoms.

Reviewer #6: (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: Wei-Chih Chen

Reviewer #3: No

Reviewer #5: No

Reviewer #6: No

**********