PONE-D-22-23300Clinical progression, disease severity, and mortality among adults hospitalized with COVID-19 caused by the Omicron and Delta SARS-CoV-2 variants: A population-based, matched cohort studyPLOS ONE

Dear Dr. Casper Roed,

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ACADEMIC EDITOR: the paper was revised by me and two reviewers. It requires minor revisions that need to be addressed. Please respond properly to reviewer comments.

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PLOS ONE

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Additional Editor Comments (if provided):

I revised the paper entitled "Clinical progression, disease severity, and mortality among adults hospitalized with COVID-19 caused by the Omicron and Delta SARS-CoV-2 variants: A population-based, matched cohort study". It was a cohort study aimed to evaluate differences in clinical outcomes between hospitalized patients with delta and omicron sars-cov-2 variant.

I want to congratulate with Authors for the excellent work. THe study was well conducted, the methodology was strong and deeply described.

I have only some minor observations:

- Did Authors considered the re-infection status? If yes, how it was handled in the analysis?

- was IperImmune Plasma therapy performed in Denmark?

- Among discussion, Author should better highlight that Omicron variant patients more frequently has three doses of vaccine, so it can strongly influence hospital outcomes;

- Did Authors considered to subanalyze by type of vaccination performed?

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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: Yes

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: Dear Authors:

I have read with interest the manuscript entitled "Clinical progression, disease severity, and mortality among adults hospitalized with COVID-19 caused by the Omicron and Delta SARS-CoV-2 variants: A population based, matched cohort study" for PlosOne to which I would like to make the following comments:

1. The manuscript the manuscript compares the virulence of the severe acute respiratory syndrome SARS-CoV-2 omicron variant with the delta variant in hospitalized adults with COVID-19 in the Capital Region of Copenhagen, Denmark.

2. The abstract summarizes well the characteristics and results of the study. Perhaps it could be emphasized in the conclusions section that the results have demonstrated the protective effect of vaccines by reducing the severity of the infection.

3. The introduction is correct, the characteristics of the Omicron variant and its differences with the Delta variant are exposed, since Omicron has a lower risk of hospitalization, intensive care unit (ICU) admission, and death compared to Delta. Through a cohort retrospective study, the differences between them are studied in hospitalized patients.

4. The methodology is correctly designed, the study design (retrospective, multicenter, matched cohort study) well explained, as well as the setting and data collection. The selection of patients, the variables, including the vaccination status, and the statistical analysis are correct. Ethical considerations are included.

5. The results are well expressed with the support of the 4 tables and figure 1. Table 4 and figure 1 should be highlighted as they make clear both the influence of vaccination (3 doses) and the risks of severe hypoxemia during admission and death at 30 and 60 days

6. The discussion is correct and highlights the results obtained, the limitations of the study are included. The conclusion: "the finding that infection with the Omicron variant was associated with reduced mortality in hospitalized COVID-19 patients who had received three doses is reassuring for planning vaccination strategies. Our results underline the importance of global public health efforts to achieve equity in access to COVID-19 vaccination in countries with low vaccination uptake", marks the direction of the path to follow emphatically.

7. The bibliographical references are adequate

Reviewer #2: This Danish multicentre observational study with a very high number of patients describes the difference in disease severity between the Delta and Omikron waves. The data are neatly presented and the manuscript is very well written, with the exceptions mentioned below. The observed effect of vaccination (with Omikron only one effect after three vaccinations) is, in my opinion, based on the effect observed in many other studies (including this Danish multicentre observational study with a very large number of patients). The data are neatly presented and the manuscript is very well written, with the exceptions mentioned below. The observed effect of vaccination (with Omikron only one effect after three vaccinations) is, in my opinion, based on the substantial effect of booster vaccination described in many other studies (including immunogenicity data). This should be emphasised more strongly.

1. Was the Sars-CoV-2 variant known in the patients? Some laboratories indicate the Sars-CoV-2 variant (at least Delta or Omicron) even without sequencing based on the PCR melting points. Please answer clearly in the text.

2. Due to the continuous transition from Delta to Omikron, a wash-out period of 2-4 weeks would have been necessary in my view. Why did the authors not do this? Please justify. This is a limitation.

3. This sentence from the abstract it's not clear to me, pls rephrase: „Omicron patients exhibited decreased aHR for 30-day mortality (aHR, 0.61; 0.39–0.95) and when given three vaccine doses (aHR, 0.31;0.16–0.59), but not two doses (aHR, 0.86; 0.41–1.84) or 0–1 dose (aHR, 0.94; 0.49–1.81).“ - To what does the vaccine status refer? Mortality within the Omicron patients?

4. The same applies to figure one. What does the grey area refer to? Is that the comparison of vaccine effectiveness (against mortality )within the Delta and within the Omikron patients? Was there no effect within the Delta group or was the effect within the Delta group set as reference?

5. Table 1: Why was the time since the last vaccination longer in the Delta group than in the Omikron group? At the time of Omikron, most patients should have received their third vaccination some time ago.

6. Table 2: The increased proportion of positive blood cultures in the Omikron group compared to Delta in critically ill patients is remarkable in my view. The proportion of bacterial co- infections in COVID-19 is increasing according to our experience. This is probably because the typical respiratory pathogens are returning and Sars-CoV-2 behaves the same as any other respiratory virus: bacterial co- infections are common and come in with increased severity. Was this increase significant? In any case, this aspect should be addressed in the discussion, as it has implications for future management.

7. Tab. 3: why did the critically ill patients with Omikron receive steroids less often than the critically ill patients under Delta?

8. Table 4: When comparing Omikron versus Delta by vaccination status, was the time elapsed since the last vaccination also taken into account?

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Reviewer #1: No

Reviewer #2: Yes: Mathias Pletz

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Clinical progression, disease severity, and mortality among adults hospitalized with COVID-19 caused by the Omicron and Delta SARS-CoV-2 variants: A population-based, matched cohort study

PONE-D-22-23300R1

Dear Dr. Casper Roed,

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,

Giuseppe Di Martino

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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: Dear Authors: Your manuscript is well written, with interesting results, and can be published in its present form

Reviewer #2: You have nicely addressed my issues. I encourage you to take a deeper look into the bacterial co-infections.

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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

Reviewer #2: No

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