PONE-D-20-29085

Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release storm; a retrospective propensity matched control study

PLOS ONE

Dear Dr. Kamran,

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.

Reviewers' suggest several major revisions. Please, amend your manuscript and resubmit.

Please submit your revised manuscript by Dec 27 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,

Prof. Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

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3. We noted that you refer to this study as an "interventional retrospective" cohort study. Since your study was retrospective, in order to avoid confusion we would suggest that you change the wording in your manuscript and avoid referring to this study as interventional.

4. We note that UNICEF is described as a study sponsor on your clinical trial registration. If any authors are affiliated to UNICEF, please state this on your manuscript cover page and in the online submission form. Additionally, if any funding was received from UNICEF, please state this in the Financial Disclosure field on the online submission form. Review the submission guidelines for detailed requirements.

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Additional Editor Comments:

The article is potentially interesting. Provided you revise your article according to reviewers' suggestions we will be happy to reconsider your work.

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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

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

Reviewer #1: 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: 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

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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: The correct terminology in English for CRS is cytokine release syndrome. This should be corrected throughout the text.

This study looks at whether TPE may be a useful treatment option for COVID-19 disease. In order to appropriately segregate the patient population, the authors utilized as PSM study design. While this is an design, it ended up with a much reduced population of only 90 out of 280 patients. This reduced comparison led to some issues not addressed by the authors:

1) Primarily, it led to only a single female patient. This was not addressed by the authors other than that there were "primarily" males in the cohort (line 295-296). Due to the extreme differences between males and females, particularly in inflammation and inflammatory cytokine production, as well as susceptibility to more extreme forms of inflammatory disorders, this study should either be repeated using all of the 6 females with appropriate matches, or the single female should be excluded and the conclusions reported for male patients only.

2) The lymphocyte count in Table 1 is strange in that the difference in the count went from 45 without PSM to 90 with PSM even though the p-value increased to just outside of significance.

3) The IL-6 levels flipped following PSM restriction. Without the PSM, the TPE treated group had a higher median IL-6 level suggestive of more severe disease. With the PSM, the non-TPE treated group had a higher median IL-6 level, that was now nearing significance, suggestive of more severe disease. If the non-TPE group had more severe disease within each category of moderate, severe, critical, compared with the TPE group, the non-TPE group would be expected to do worse than the TPE group despite the TPE treatment.

The authors present better survival in the TPE treated group which is encouraging in Fig 2-3, though this is a bit confusing. There are 4 lines listed in the figure legend but only 2 on the graph. It doesn't look like the lines lie on top of each other, but if they do, you should offset the lines so that they can both be seen. If there are only 2 lines with censored data points then either remove the top 2 legends without the censor points, or change the symbol on the bottom 2 legends to just a + sign without the connecting line.

Figure 4 is incomplete and makes no sense. The label is just 1 and 2 and not TPE vs non-TPE. The axes are labeled normalizationCRS and cumulative normalizationCRS which are the same thing. I would think that this graph is supposed to show time to normalization of CRS. The data table also doesn't make since as it shows fewer patients at risk (either of CRS or normalization of CRS, I can't tell). If this is # of patients, then you should change the data table title.

The authors report that the study "demonstrates better results of TPE when used earlier during the course of infection" (line 275-276) but there is no data to show that. The survival curves demonstrate that TPE is better than not for less severe disease, but that is NOT the same thing as earlier in infection.

Also, the manuscript needs an overall editing to be consistent throughout in verbiage, abbreviations, etc.

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Reviewer #1: 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-20-29085R1

Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release syndrome; a retrospective propensity matched control study

PLOS ONE

Dear Dr. Kamran,

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.

The manuscript is potentially interesting, but some concerns should be addressed before we can reconsider for peer review again.

Please submit your revised manuscript by Jan 28 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Prof. Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The manuscript is potentially interesting but some concerns should be addressed.

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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: (No Response)

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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: Partly

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

Reviewer #1: 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

**********

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

**********

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: Due to the single female patient in the TBE-treated group, it is unacceptable to state that "female gender was less represented in this study...therefore results of this trial cannot be generalized on females and gender based comparative analysis cannot be done."

Those 4 patient need to be removed from the entire analyses. Since this is a retrospective study, this can be easily done by removing the data points for those individuals.

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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: 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.

Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release syndrome; a retrospective propensity matched control study

PONE-D-20-29085R2

Dear Dr. Kamran,

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,

Prof. Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

amended manuscript is acceptable

Reviewers' comments: