PONE-D-24-05103

Factors associated with prolonged hospitalizations for COVID-19 during the first three waves of the pandemic: evidence from a Southeastern state of Brazil

PLOS ONE

Dear Dr. Lopes-Júnior,

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André Ricardo Ribas Freitas

Academic Editor

PLOS ONE

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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

The current manuscript is outstanding but needs to improve in some ways. Even so, there are some questions.

Introduction

The authors of the current manuscript could briefly describe complications of prolonged hospitalization due to COVID-19, such as long-term COVID-19.

Materials and Methods

In the second paragraph, what do the authors mean about 19?... in the second paragraph, what do authors mean about 19...

The 138 adopted inclusion criterion was confirmation of the diagnosis of COVID-19, with 6 139 laboratory confirmations by RT-PCR and hospitalization in Espírito Santo due to this 140 diagnosis.

Measures

The authors must report the types and places of hospitalized patients with COVID-19, such as wards or intensive care units.

Could the authors report outcomes, such as the need for mechanical ventilation, dialysis, or even mortality, to compare the different waves of the COVID-19 pandemic?

Results

Was there any statistical difference in the distribution of hospitalizations between the three waves?

Authors need to write better about significant comorbidities, comparing each wave to help understand any changes in comorbidities across these waves.

Again, were the authors able to determine outcomes related to length of hospital stay?

Was there a longer length of hospital stay in intensive care units in which wave of the COVID-19 pandemic?

Discussion

The authors could describe molecular and pathophysiological mechanisms evident in the literature and explain why some comorbidities are related to a higher risk of prolonged hospitalization due to COVID-19. For example, in the elderly, is a reduced innate immunity predisposed to more severe SARS-CoV-2 infection?

It is crucial to underscore the potential for a prolonged hospitalization period related to outcomes, as this highlights the severity of the disease and the significant need for hospital support, including oxygen and ventilatory support or vasoactive drugs. As the authors have noted, "an estimated 15% of patients may develop severe symptoms that necessitate oxygen support, and about 5% may progress to the critical form of the disease with complications necessitating hospital support".

Furthermore, the authors have carried out their research with the utmost ethical standards, ensuring the integrity and reliability of the data. This commitment to ethical research practices should instill confidence in the audience about the validity of the findings.

Reviewer #2: Thank you for investing time and efforts studying this topic. The topic is very important that should augment global efforts to improve preparedness for upcoming pandemic. Please consider the following:

1- Define the level of support the state had offered in the acknowledgement section

2- Revise English

3- Improve the introduction section; shed light on Brazilian COVID-19 experience and Brazilian pandemic mitigation strategies

4- Reflect on the rationale of the study.

5- Revise the discussion section. Link the results to the pandemic management protocol

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Reviewer #1: Yes:  Miguel Angelo Goes

Reviewer #2: Yes:  WEAM Mohammed BANJAR

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PONE-D-24-05103R1Factors associated with prolonged hospitalizations for COVID-19 during the first three waves of the pandemic: evidence from a Southeastern state of BrazilPLOS ONE

Dear Dr.  Lopes-Júnior,

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 Sep 03 2025 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Ivan Filipe de Almeida Lopes Fernandes, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The manuscript “Factors associated with prolonged hospitalizations for COVID-19 during the first three waves of the pandemic: evidence from a Southeastern state of Brazil” presents a retrospective observational study analyzing factors associated with short and prolonged hospitalizations due to COVID-19. Using data from Espírito Santo state in Brazil, the manuscript classified hospitalizations as short or prolonged based on a 7-day threshold. They conducted bivariate analyses using chi-square tests and employed logistic regression models to explore associations between clinical and sociodemographic factors and hospitalization duration across the first three pandemic waves. The study’s main finding is that prolonged hospitalizations were more frequent in the first wave. In contrast, shorter stays predominated in the second and third waves, with older age, obesity, symptom burden, and comorbidities associated with prolonged hospitalization.

Given that I have assumed editorial responsibility after prior rounds of peer review, and considering the manuscript has already addressed comments from previous reviewers, I will request only a limited set of fundamental revisions before the manuscript can be considered for acceptance. If these changes are fully addressed, the manuscript will be approved for publication.

1) Empirical Testing of the Main Hypothesis: the manuscript’s argument regarding differences in the proportion of prolonged hospitalizations across the three waves is presented emphatically. Still, it lacks formal statistical testing to support the conclusion. I request the authors to perform two additional analyses:

First, a logistic regression model using hospitalization duration (short vs. long) as the dependent variable and the pandemic wave as the key independent variable for the full dataset, composed of the three waves. A second model using hospitalization duration in days as a continuous dependent variable, preferably applying an appropriate regression model to compare the mean duration across waves. These analyses are essential to substantiate the claim that the profile of hospitalization duration significantly changed across waves. The conclusions about differences between waves should only be presented after conducting and reporting these tests.

2) Throughout the manuscript, the authors redundantly report the confidence level (95% CI) and the alpha level (5%) when describing statistical results. It is unnecessary to state both, as a 95% confidence interval inherently implies an alpha of 5%. Please standardize the reporting and remove redundant mentions of the alpha level where confidence intervals are already presented.

3) Definition of Long vs. Short Hospitalizations: the use of 7 days as the threshold to define short and prolonged hospitalizations needs further justification. The current explanation that it corresponds to the median of the second wave is insufficient. Please elaborate on why the second wave median was chosen as the cutoff and discuss its clinical relevance. Additionally, as a robustness check, I recommend testing alternative thresholds (e.g., 6 days or 10 days) and reporting whether the main associations remain consistent.

4) Standardization of Regression Tables: The presentation of regression results should follow a more conventional format. Specifically, remove the reference category rows (“Ref.”) as a separate line in the table. Present only the Odds Ratios (OR) and their standard errors. Confidence intervals and p-values should be omitted from the table body, and p-values should be indicated using conventional asterisks (*p<0.05; **p<0.01; ***p<0.001). Consider eliminating the crude (unadjusted) models from the main regression tables and moving them to a statistical appendix if necessary. In the main text, I recommend presenting only the adjusted models, using a clearer layout to improve readability.

MINNOR COMMENTS

a) Page 2, line 62:

From: “Subsequently, the Odds/Odds Ratio and their respective 95% confidence intervals”

To: “Subsequently, the Odds Ratios and their respective 95% confidence intervals”

b) Page 3, line 81:

Please clarify what is meant by “distinct patterns,” as the results across the waves do not appear markedly discrepant. Consider rephrasing to reflect better the observed differences, which seem subtle rather than pronounced.

c) Page 5, line 138:

From: The adopted inclusion criterion was confirmation of the diagnosis for COVID-19 19 with laboratory confirmation by RT-PCR ...

To: The adopted inclusion criterion was confirmation of the diagnosis for COVID-19 with laboratory confirmation by RT-PCR ...

d) Page 14, line 242

From: the likelihood of prolonged hospitalization in elderly patients

To: the chance of prolonged hospitalization in elderly patients

d)Page 20, line 292-300:

Consider expanding the discussion regarding the vulnerabilities of older adults. While the current text highlights their susceptibility to psychological effects, it is important to emphasize that older adults are also at greater risk for a wide range of physical health complications. Beyond mental health issues, elderly individuals often experience other deteriorating body functions that may exacerbate COVID-19 outcomes. Deepening this analysis would provide a more comprehensive understanding of why age is consistently associated with prolonged hospitalizations and worse clinical outcomes.

I look forward to reviewing the revised version incorporating these essential modifications.

Regards,

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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: 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: Dear authors,

You have conducted association research that aligns with the local context at the time. Additionally, you have addressed all the questions raised by the reviewer and improved the manuscript accordingly. There are no further questions.

Reviewer #2: Thank you for taking the time to address reviewers comments and concerns. The manuscript had been substantially improved.

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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:  Miguel Angelo Goes, MD, PhD, FASN

Reviewer #2: Yes:  WEAM BANJAR

**********

[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.

<p>Factors associated with prolonged hospitalizations for COVID-19 during the first three waves of the pandemic: evidence from a Southeastern state of Brazil

PONE-D-24-05103R2

Dear Dr. Lopes-Júnior,

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,

Ivan Filipe de Almeida Lopes Fernandes, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: