PONE-D-22-17138Clinical characteristics and severity prediction of Adenovirus pneumonia in immunocompetent adultsPLOS ONE

Dear Dr. Jiang,

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.

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ACADEMIC EDITOR: See comments below.

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Please submit your revised manuscript by November 6th, 2022. 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.

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Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

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Additional Editor Comments:

Please review comments made by the reviewers and provide point by point response in your revised manuscript. Specifically please address study methodology and criteria used to define immunocompetent adults.

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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: Partly

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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: thank you for the opportunity to review this manuscript

after reading it there are several doubts and questions that arise.

1) a study period comprising the first year of the covid pandemic was chosen: are the periods before covid and during covid comparable? was the hospital management similar? were the diagnostic studies performed the same? were there no changes that would make the two time periods not comparable?

2)The use of the term "immunocompetent adults" is strongly emphasized, considering that there are diabetics (whose level of metabolic control is unknown) and also patients with chronic obstructive pulmonary disease (COP).

in one of the tables it is mentioned that a significant number of patients have use of sterioids (26 patients), it is not clear if they were used as part of the treatment of pneumonia or were drugs used prior to admission.

3)also in the definition of immunocompetent, was HIV co-infection studied on admission of the patients? no mention is made of whether this was ruled out.

4)The high rate of infection with agents that are not part of the usual community pneumonias is striking. 34% of infection with Acinetobacter spp, also Tuberculosis, even fungal pneumonias (aspergillus which exists almost exclusively in immunocompromised patients). How can this rate of infection be explained?

Reviewer #2: Main points

Abstract

Lines 40-42 Adding all the co-infections (by bacterial, viruses and fungi), could be useful to find differences between ICU and non-ICU patients? It would be interesting to assess.

Methods

Lines 78-81. Include some characteristic of the hospital, such as the total number of hospital admissions per year, number of beds, and ICU.

In line 264 they wrote it is a regional respiratory center, put this also in the methods.

Lines 83-84. Do NGS or PCR are standardized to perform in all adults who are admitted because a pneumonia process? Please clarify.

lines 109-117. Also, searching for other pathogens, antibodies, bacterial cultures, are performed in all patients with low respiratory infections?

Results

Lines 133-134:…23 (46%) were admitted to or moved to the ICU. It should be interesting to know the number of patients who were admitted directly to the ICU, and how many moved later, including the mean time to admission to the ICU.

Lines 144-146. They describe the main results in the laboratory parameters. Should be interesting to comment something about monocytes, because included monocytopenia as a potential predictor in the background (line 59).

Line 148. The two patients who died the cause was directly related with the pneumonia? Another co-infection? septic shock? Please clarify.

Linea 150-151. The cost of hospitalization in ICU were higher. Including costs, and defining how they had calculated, must be included in the methods.

Line 169-170. The abbreviation next to the full name for Epstein-Barr must be first (exchange line 170 with 169). The common abbreviation is EBV, not EB, lines 170 and 277. EBV, should be included in the methods in the part of pathogen detection (lines 109-112)

Line. 170. Do IFA should be IFV? Or what does IFA mean?

Lines 173-175 and table 3. Add the whole gender and specie: Acinetobacter spp, Mycoplasma spp or pneumoniae? Streptococcus spp, Pseudomonas aeruginosa or spp?

Lines 179-187. The searching of lymphocyte subgroups should be added in the methods.

Figure 2 legend is very difficult to read. Describe also, the meaning of the different colors used.

Minor

I suggest the title should establish the severity prediction will be based in a previous score used for pneumonia patients. So maybe could be: “Clinical characteristics and severity prediction score of…….”

Introduction:

Lines 52-53: … with inadequate immunity, such as newborns and organ transplant recipients”. These infections are very common in hematopoietic stem cell transplants. I suggest to add these too.

Methods

line 113. Describe the abbreviations for IFA, or it should be IFV?

Results

Line 134. Approximately 89.96% (20/23) of patients who required ICU…. Approximately? Consider to eliminate the word

Eliminate the two decimals (.00) and leave the whole number

Tables

IN the first column, you can leave the number, example (n=23, %). And eliminate all the symbol % in all the rest of the lines.

Typo

Line 235. Should be pathogens, nor parthenogens

Reviewer #3: Authors evaluated the applicability of severity score in predicting intensive care unit admission of Adenovirus pneumonia such as PSI, CURB-65, SMART-COP, and PaO2/FiO2. The study brought out few important data. The manuscript may be accepted with following few corrections in manuscript:

1. Abstract should have the sample size used for the study.

2. End of the manuscript (line 262) mentioned in there that 56 patients, this needs to be clarified in the methodological section appropriately.

3. Methodological details regarding RT-PCR or NGS should be given - at least some minimal details need to be given.

4. When the manuscript focuses immunocompetent individuals, including some diseased/clinical conditions such as Diabetes and Pregnancy may not be appropriate.

5. Table 3: All the bacteria terms should be initialized.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Pachamuthu Balakrishnan

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Attachments

Attachment

Submitted filename: PONE-D-17138 Pneumonia adenovirus immunocompetern sep 2022.docx

PONE-D-22-17138R1Clinical characteristics and severity prediction score of Adenovirus pneumonia in immunocompetent adultsPLOS ONE

Dear Dr. Jiang,

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 December 15, 2022. 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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

Additional Editor Comments:

Please review comments made by the reviewers and provide your response in the revised manuscript.

[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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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

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: (No Response)

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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

**********

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: Given the high rate of co-infection with other agents, it is very difficult to assert that a score can predict the severity of adenovirus pneumonia when in reality it is mostly co-infection with multiple agents.

In the conclusions it is stated: "In conclusion, adenovirus pneumonia is not uncommon in immunocompetent adult patients who are prone to coinfection with multiple agents."

This part of the conclusion, in my opinion, if it is possible to extract from the study done.

However, the second part of the conclusion: "Our data suggest that the initial SMART-COP score is a valid predictive assessment of ICU admission in adult non-immunocompromised patients hospitalized with adenovirus pneumonia" does not seem to me to be drawn from the reported study.

Reviewer #2: All the suggestions were made.

It is only important to correct the names of the bacteria: if it has a gender and specie, it is no longer necessary to include spp. (eg. Klebsiella pneumoniae). If it is only the genus without species, must include spp (species), example: Acinetobacter spp. Run lines 204, 205, table 3, and everything that corresponds

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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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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-22-17138R2Clinical characteristics and severity prediction score of Adenovirus pneumonia in immunocompetent adultsPLOS ONE

Dear Dr. Jiang,

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.

==============================

ACADEMIC EDITOR: Reviewer has one final comment. Please address it at your earliest convenience" in my opinion the separate results for co-infected versus non co-infected should be included and highlight that there was no significant difference, implying that co-infections do not affect the validity of the SMART-COP score."

==============================

Please submit your revised manuscript by 01-15-2023. 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,

Muhammad Adrish, MD, MBA, FCCP, FCCM

Academic Editor

PLOS ONE

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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.

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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

**********

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: in my opinion the separate results for co-infected versus non co-infected should be included and highlight that there was no significant difference, implying that co-infections do not affect the validity of the SMART-COP score.

Reviewer #2: The authors made the changes according to the recommendations made in the previous version. I consider it can be published.

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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

**********

[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.

Clinical characteristics and severity prediction score of Adenovirus pneumonia in immunocompetent adults

PONE-D-22-17138R3

Dear Dr. Jiang,

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.

"Please add  IRB/ethics submission and approval in the methodology"

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Muhammad Adrish, MD, MBA, FCCP, FCCM

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

**********

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

**********

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: the requested corrections have been made

the only concern is that in the latest version the mention of the ethics committee that evaluated the project and the informed consent waiver was removed,

I am not sure if I did not find the file, but the IRB/ethics submission and approval must appear in the methodology.

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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

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