PONE-D-20-22733

Re: Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

PLOS ONE

Dear Dr. Townsend,

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 Oct 19 2020 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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We look forward to receiving your revised manuscript.

Kind regards,

Giordano Madeddu

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

Dear authors,

I have received comments on your article from two independent reviewers. They suggest minor revisions to improve the manuscript.

however, I have noticed that the number of authors is excessive (26) and many of them do not follow the ICMJE criteria. The authors' list should be reduced to those fullfilling ICMJE criteria.

Best regards

Giordano Madeddu

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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: This is a very interesting paper on the pivotal issue of post-COVID 19 fatigue.

It is a very well written manuscript and I really appreciate the way it is structured and analyzed.

I have one question/request:

analysis and results = please provide and weight, if possible, any stratification of the timing of patients presentation >=6 weeks after acute infection, e.g. within 8 weeks, within 12 weeks etc.

Reviewer #2: Liam Townsend, with his coauthors, wrote an interesting paper about SARS-CoV-2 infection and persistent fatigue. The manuscript is well written and very interesting. However, some issues are present:

Introduction:

The introduction is well structured. I only suggest expanding the first part, adding the general symptomatology of COVID-19, both the major symptoms such as fever and dyspnea (10.26355/eurrev_202007_22291, https://doi.org/10.1016/S0140-6736(20)30183-5) and the minor such as anosmia and ageusia (https://doi.org/10.1002/hed.26269, https://doi.org/10.1002/hed.26204).

The authors wrote, “Similarly, prominent post-viral fatigue syndromes have been reported following Epstein-Barr Virus (EBV), Q-Fever and Ross River Virus (RRV) infections (16-19)." Q-fever is not caused by a virus. I suggest reformulating the sentence, and substitute ”post-viral fatigue ”with post-infection fatigue”, adding some other infectious disease such as Rickettsiosis, present in a recent review of the literature that should be added in the reference: https://doi.org/10.4084/mjhid.2020.056

Methods

The authors wrote, “Descriptive statistics are reported as means with standard deviations (SD) and interquartile ranges (IQR) as appropriate”. Please, modify the sentence with “Descriptive statistics are reported as means with standard deviations (SD) and median with interquartile ranges (IQR) as appropriate”.

I suggest to explicit the range of physical and psychological fatigue score (0 to …)

Results

I suggest deleting (See Table 1). At the end of the paragraph, the authors already wrote Baseline characteristics are detailed in Table 1.

The sentence “This is reflective of the overall demographics of Irish data and our institution, where 50% of positive SARS-CoV-2 cases involved healthcare workers (38).” should be moved in the Discussion.

It is not unclear, why the authors decide to adjust the regression model for age. Please comment.

No data are available about medical treatment. Do the authors know if these patients have been treated with hydroxychloroquine, steroids, or other drugs? Otherwise I suggest adding this lack in the limits of the study.

About the tables, it seems that some columns are missing; please fix it; otherwise, I will not be able to evaluate it.

Some percentage seems wrong. Please, recheck the tables (examples, Required Hospital Admission n people with severe fatigue: 35/67. The correct percentage is 52.2 and not 52.4; Required Critical Care/ICU in people with severe fatigue 8/67. The correct percentage is 11.9 and not 13.1).

Other issues

Some typos are present in the manuscript. Please recheck carefully and fix them.

In some reference the number of pages is missing.

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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: Stefano Rusconi

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-20-22733R1

Re: Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

PLOS ONE

Dear Dr. Townsend,

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 08 2020 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Giordano Madeddu

Academic Editor

PLOS ONE

[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 #2: All comments have been addressed

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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: (No Response)

Reviewer #2: Liam Townsend et al. re-submitted the manuscript, "Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection". The authors have modified the article, as suggested in the previous revisions.

I have carefully reread the manuscript, and some issues are present.

The authors added that 41 patients received treatment with hydroxychloroquine. Have the authors checked if there are significant differences between the two groups (fatigued vs. non-fatigue)?.

Have the authors verified if people admitted to the hospital have were related to chronic fatigue?

In table one, the difference in BMI between the two groups had a p-value slightly above the cut-off of significance. Have the authors verified if having an obesity condition was associated with the development of chronic fatigue? Different studies about chronic fatigue in people with cancer showed how overweight people and, in particular, obese people had an increased risk to have chronic fatigue (https://doi.org/10.1007/s00520-019-04953-4, https://doi.org/10.1186/1471-2407-10-453)

In table one, the percentage should be rechecked. For example, the sum of the percentage in the row “Interval from COVID-19 Symptoms to Fatigue Assessment” about “people with fatigue” is 100.1%.

In table one, in the row “Interval from COVID-19 Symptoms to Fatigue Assessment”, the interval seems wrong because ten days are missing (56-69; 79-83)

In the subtitle of table one, the abbreviation “CFQ” should be explained.

In the subtitle of table two, the abbreviation “CI” “CRP” and “IL” should be explained. The abbreviation “OR” is reported two times.

There are some typos; please check all the manuscript; for example, in the discussion, the authors wrote “These finding are independent of ageing effects” instead of “These findings are independent of ageing effects”; “Given that this cohort have no enduring evidence of active infection” instead of “Given that this cohort has no enduring evidence of active infection”.

The word “multidisciplinary” one times was written with the hyphen, one time without it.

In the introduction, the authors changed “post-viral fatigue” with “post-infection fatigue” as suggested. The sentence now is “Similarly, prominent post-infectious fatigue syndromes have been reported following Epstein-Barr Virus (EBV), Q-Fever and Ross River Virus (RRV) infections.” In my opinion, three important infectious disease are missing: HIV infection (https://doi.org/10.1016/j.jpainsymman.2015.02.006), HHV-6 infection (https://doi.org/10.1155/1993/414602), and rickettsiosis (https://doi.org/10.4084/mjhid.2020.056). I suggest adding them.

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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: Stefano Rusconi

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.

Re: Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

PONE-D-20-22733R2

Dear Dr. Townsend,

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.

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Kind regards,

Giordano Madeddu

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: