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PONE-D-20-34816

Predictors of infection, symptoms’ development, and mortality in people with SARS-CoV-2 living in retirement nursing homes.

PLOS ONE

Dear Dr. De Vito,

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 Feb 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'.
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We look forward to receiving your revised manuscript.

Kind regards,

Andrea Calcagno

Academic Editor

PLOS ONE

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2. In the Methods section and in the online submission please specify the name of the local IRB institute which approved the study and please include a copy of the original ethics documents and an English translated version as "Supporting" file.

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We will update your Data Availability statement on your behalf to reflect the information you provide

Additional Editor Comments (if provided):

Dear authors,

I have received the comments of 2 reviewers and they suggest major revision.

I agree with them that some caution may be used in interpreting the data and that some may be further discussed.

I also agree that hydroxycholoroquine data should be taken with caution given the study design and the results from randomized studies.

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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: No

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: No

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 paper reports on rates of SARS-CoV-2 positivity in ‘retirement nursing homes’ experiencing outbreaks in Italy during April/May 2020 and comments on symptoms as well as clinical outcomes. The study also looks at the associations of different putative treatments and their relationship to outcomes. A substantial number (382) of patients are included in the study. This is an important topic and looks at a critically high risk group which is not easy to study.

Unfortunately however there is sufficient detail in the methods for me to be able to recommend this paper for publication, and I am concerned that the conclusions, particularly with respect to recommending treatments, stray to far from the limitations of the data.

Specific comments:

1. The patient population is not well defined. Although this may be an English language translation issue. The entity referred to in the manuscript is ‘retirement nursing homes’. It is unclear if this refers to people in sheltered care/ warden controled accommodation who require very little support; or residential Care home residents (requiring support with some activities of daily living) or nursing home residents (requiring nursing care specifically, ie. a high degree of dependency).

2. I am not convinced that the background literature review is sufficiently rigorous / critical. For example the paper implies that there is ‘debate’ around the efficacy of hydroxychloroquine (HCQ). On the contrary there are plenty of very well designed randomised trials which do not show efficacy and I am concerned that framing this as debate could give the wrong impression.

3. The description of the study could and should be much clearer. This would allow readers to interpret the findings in the right context. Given that the authors wish to comment on the efficacy of putative treatments should this be framed as a ‘retrospective non-randomised non-blinded cohort study’?

4. It is unclear who was given which treatment, at what dose, and why.

5. The testing methodology is unclear. Was this one off? What prompted testing? What was the timing? Were people tested repeatedly?

6. How were symptoms ascertained? Were patients who had no symptoms reassessed to see if they were truly asymptomatic, vs pre-symptomatic? The authors comment on clinical symptoms and signs “at admission”. Does this mean the patient were hospiasllied ? The rest of the paper makes this sound as though patients were managed in the community. This would need clarification. It is suggested that several asymptomatic patients died - did they really develop no symptoms prior to death, even in their final hours?

7. Were there any adverse events related to treatment, such as but not limited to bleeding or QTc elongation ?

8. Are comparisons corrected for multiple comparisons? The full range of possible comorbidities examined is confusing. In earlier tables neurological syndromes are lumped together and later hypokinetic disease appears separately.

9. The interpretation of these findings is generous. It is probably not appropriate to say ‘protective factors were’ in the results section. All that can be commented on was an association (protection suggests causality). I do not regard this as sufficient evidence to support giving LMWH to patients in this setting and I think the authors should be careful about doing so, or make a clearer justification of why they think this should be done.

Reviewer #2: This is an interesting research on a timely and important topic. While I cannot recommend the publication of the research as of now, I would like to give the authors a chance to respond to my comments below.

General. I don’t see any reason to explain why the authors are so concise when they describe their measures. For example, patient compliance is defined on lines 87-89, but it is not obvious that it is related to general medical advices given that the reader is aiming to read a very specific study on COVID-19. At first, I understood that compliance was about the COVID-19-related treatments. Hence, the results for those who did not contract COVID-19 did not make much sense. Another example: mental disorders, which is labelled as psychiatric disorders in the text. What does it mean? It can be very brief, but a little bit of details would be appreciated.

There is something incredibly interesting about autonomy and mortality rates. Among 83 observations with a value on ‘autonomy’, 81/83 survived. This is probably the most interesting result of the study, but it is not discussed. First, and again, the variable should be detailed in greater length. What does it mean (‘any daily activity’ is not that obvious)? Second, what are the implications? Is it simply a confounding factor measuring something else? It is *very* a strong predictor of surviving, which is very important, so what should we make out of this finding?

Statistical analysis section. First, the mention of ‘univariate analysis’ seems wrong: it’s always bivariate or multivariate. For example, the variables are break down by positivity/negativity (Table 1), Symptomatic or not (Table 2) and death/survival (Table 3). That’s not univariate. Second, there is no need to say anything about the ‘established p-values’ as the authors show the exact p-value instead of using asterix (which is the right thing to do). However, there is a mention that only the variable where p<.2 where included. This is ad hoc and needs a rationale. I am still unsure what it means and what happened, and it should be justified.

On the data: we have no idea about the location. I appreciate ethical concerns, but it seems that mentioning the country would be the minimum. It makes little sense that it is absent from the manuscript, but I failed to find such important. There is a mention of a ‘province…’ I might have missed something here.

The findings for cancer entail way too uncertainty to be taken seriously. The number of observations is too low (26) and the distributions make it worse (12 v/s 14 in Table 2; 4 v/s 22 in Table 3).

The authors should mention the studies by Daoust (2020) in PLOS One about elderly people and their response to COVID-19. Among others, it is relevant for the discussion section.

Line 160: the comparison for the effect of age is ad hoc, using the cut-off of 80 years with no justification. There is no need for such a dichotomization.

On hydroxychloroquine: The authors cannot claim that it is ‘probably due to the fact that the subjects that started the treatments had severe disease’ as it would be misleading given what we now know about this treatment. It seems simply not effective. See, among others, the meta-analysis and systematic review by Fiolet et al. (2020, in CMI).

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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: 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.

PONE-D-20-34816R1

Predictors of infection, symptoms’ development, and mortality in people with SARS-CoV-2 living in retirement nursing homes.

PLOS ONE

Dear Dr. De Vito,

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 26 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,

Andrea Calcagno

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Thanks for addressing all the reviewers's comments. I believe the manuscript has singifiafcntly improved. One of the reviewer has still a question about p values that I ask you to address before accepting it for publication.

[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

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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 #2: Yes

**********

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

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 #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 #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 #2: The authors have addressed all my concerns except one, that is, the second consideration of my third point: "Second, there is no need to say anything about the

'established p-values' as the authors show the exact p-value instead of using asterix

(which is the right thing to do). However, there is a mention that only the variable where

p<.2 where included. This is ad hoc and needs a rationale. I am still unsure what it

means and what happened, and it should be justified."

I am still puzzled after reading the authors' responses and the new version of the manuscript.

**********

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

[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.

Predictors of infection, symptoms’ development, and mortality in people with SARS-CoV-2 living in retirement nursing homes.

PONE-D-20-34816R2

Dear Dr. De Vito,

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,

Andrea Calcagno

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thanks for addressing the last concerns from one of our reviewers. I think the manuscript can now be accepted for publication.

Reviewers' comments: