Dear Dr Pottegaard,

Thank you for submitting your manuscript entitled "Adverse Outcomes and Mortality in Users of Non-Steroidal Anti-Inflammatory Drugs tested positive for SARS-CoV-2: A Danish Nationwide Cohort Study" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Artur Arikainen,

Associate Editor

PLOS Medicine

Dear Dr. Pottegaard,

Thank you very much for submitting your manuscript "Adverse Outcomes and Mortality in Users of Non-Steroidal Anti-Inflammatory Drugs tested positive for SARS-CoV-2: A Danish Nationwide Cohort Study" (PMEDICINE-D-20-02753R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. 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 us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Jul 21 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Emma Veitch, PhD

PLOS Medicine

On behalf of Clare Stone, PhD, Acting Chief Editor,

PLOS Medicine

plosmedicine.org

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Requests from the editors:

*In the last sentence of the Abstract Methods and Findings section, please include a brief note regarding any key limitation(s) of the study methods overall.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*As noted by one reviewer, it would be good to include in the Discussion a more explicit and thorough discussion of the main limitations of the study methods to answer the question of interest.

*As the paper reports analyses of data from a cohort study, it would be good to ensure that the study is reported according to the STROBE guideline; if doing this please include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (SChecklist)." The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/. When completing the checklist, please use section and paragraph numbers, rather than page numbers.

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Comments from the reviewers:

Reviewer #1: I greatly enjoyed reading this manuscript, which is very neatly written with the entire emphasis on solid statistical evaluation, as I would expect. Some of the English is cumbersome and sloppy (eg. abstract: "matched to up to...") but on the whole it is an excellent paper, and a useful addition to the literature.

Considering the methods used and the 'solidity' of the database I have some suggestions, and I am deliberately keeping this brief:

1. It would be helpful if statins could be studied too, using almost identical methods. The title would need to be changed to reflect this.

2. In view of the RECOVERY data on dexamethasone, can steroids be looked at too? These data should at least be mentioned. As per 1.

3. It was disappointing not to see a paragraph or 2, in the introduction and discussion, on mechanisms here that may be relevant and operational, leading the authors to study this as more than a simple correlation ie. is there any suggestion that the potential association may have been causative and problematic, based on the first line of the abstract? This is not expanded upon anywhere in the text and I do not see clinicians concerned any more about NSAID use (this is an old story as the authors know).

4. There is no substantial limitations paragraph with the usual dose, duration etc discussion.

J Stebbing

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Reviewer #2: I confine my remarks to statistical aspects of this paper. These were very well done and I recommend publication.

Peter Flom

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Reviewer #3: This is an interesting and relevant observational study to estimate if there is any effect on patients who obtained a prescription for NSAIDs 30 days prior to a positive SARS-CoV-2 PCR test on mortality within 30 days (primary outcome) or hospitalisation, ICU admission, ventilation or acute renal replacement therapy within 14 days. This has been the subject of much debate during the current COVID-19 outbreak so represents a valuable contribution to the field and will likely impact on clinical management or public health policy.

The set of baseline covariates were defined (age, gender, comorbidities, use of other selected medications plus phase of the outbreak) and the methodology is appropriate. Propensity scores were used to ensure that the 'treated' subjects are similar in their baseline covariates to 'untreated' subjects (matched 1: 4 in this case) in order to provide an unbiased estimate of the relative risk of NSAIDs on the measured outcomes. Additional stratification looked at age (<65y; >65y), gender, cardiovascular disease and non-healthcare worker.

The analyses do not indicate that NSAIDs presented an increased risk of mortality or morbidity in the COVID-19 population in Denmark.

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Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Pottegaard,

Thank you very much for re-submitting your manuscript "Adverse Outcomes and Mortality in Users of Non-Steroidal Anti-Inflammatory Drugs tested positive for SARS-CoV-2: A Danish Nationwide Cohort Study" (PMEDICINE-D-20-02753R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by 1 reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jul 16 2020 11:59PM.

Sincerely,

Artur Arikainen,

Associate Editor

PLOS Medicine

plosmedicine.org

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Requests from Editors:

1. When completing the STROBE checklist, please use section and paragraph numbers, rather than page numbers.

2. The Data Availability Statement (DAS) requires revision. If the data are owned by a third party, please provide contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

3. Abstract:

a. Line 35: please correct to: “…use of NSAIDs was…”

b. Line 48: please include basic cohort demographics (age and sex).

c. Please quantify all results with both 95% CIs and p values.

d. Line 53 (and throughout the text): please correct to: “…ICU admission…” (no hyphen)

4. Author Summary:

a. Line 71: please spell out NSAIDs.

5. Results:

a. Please quantify all results in the text and tables with both 95% CIs and p values.

b. Lines 232-233: Please give absolute numbers as well as percentages.

6. All tables and figure: Please define all abbreviations (eg. RT-PCR, IQR, SMD, COPD, ICU, NSAIDs) in the legend or footnote.

7. Lines 397-418: Please remove these sections on Funding, Competing Interests, and Author Contributions, and ensure the information is instead filled in on the submission form.

8. Lines 420-424: Please move details on ethical approval to the Methods section.

9. Re: reference 30 listed as under review, papers cannot be listed in the reference list until they have been accepted for publication or are otherwise publically accessible (for example, in a preprint archive). The information may be cited in the text as a personal communication with the author if the author provides written permission to be named. Alternatively, please provide a different appropriate reference.

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Comments from Reviewers:

Reviewer #1: excellent answers, lovely paper, congratulations, justin stebbing

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Pottegaard,

On behalf of my colleagues and the academic editor, Dr. Anne C Cunningham, I am delighted to inform you that your manuscript entitled "Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs tested positive for SARS-CoV-2: A Danish nationwide cohort study" (PMEDICINE-D-20-02753R3) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Artur Arikainen,

Associate Editor

PLOS Medicine

plosmedicine.org