PONE-D-20-31950

The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT

PLOS ONE

Dear Dr. Chen,

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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Giordano Madeddu

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

**********

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: 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: Dear Authors,

First, I would like to thank you for the paper you submitted. After the great interest grown in the scientific community in the first months of the year toward the acute phase of COVID-19 and its possible treatments, now it is the time to ask us what will happen after the infection, and if these modifications will affect survivors for the rest of their lives. In the wake of the outcomes of SARS-CoV and MERS-CoV pneumonia, many papers investigating on the possible long-time effects of COVID-19 have been published in the past few months, but, by now, the follow-up timing is too short to establish a permanent effect. During 2020 numerous studies investigated toward the role of AI in the diagnosis of COVID-19 pneumonia, but this is possibly the first paper published on the use of AI in the evolution of pneumonia after the clinical healing and its role in predicting fibrosis, even if there are many limitations, that you correctly identified.

However, I have a few concerns I will enlist you as follow.

Minor concerns:

- In the abstract, you repeated the phrase “IL-6 and albumin are independent risk factors for pulmonary fibrosis” twice.

- Page 4, line 66: there is a typo, for it is written “SARA-CoA-2” instead of “SARS-CoV-2”.

- Page 5, line 88: milliampere-second is written in one word.

- Page 6, line 99: “anterior endobasal segment” is not a term commonly used in the anatomy of lung segments. Did you mean medial segment of the lower lobe? Please, correct.

- Page 8, line 149: you say that 248 patients were enrolled, clearly a refuse.

Major concerns:

- Page 3, line 33-34: there is an imprecision that I would suggest you to correct. In fact, you correctly reported that SARS-CoV-2 is similar for the 85% of genome to a bat coronavirus, but after that you included on parenthesis SARS-CoV: SARS-CoV-2, instead, share 85% of its genome with bat coronavirus bat-SL-CoVZC45 (Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, Wang Y, Guo X. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses. 2020 Feb 22;12(2):244. doi: 10.3390/v12020244. PMID: 32098422; PMCID: PMC7077191).

- Page 6, line 95-96: you used the term “shadow” to describe many CT findings associated with COVID-19 pneumonia. This term it is not used by other radiologists in an international setting: I suggest you to change it with the common used “linear opacities” and honeycombing. I did not understand the term “mesh shadows”: could you explain it better?

- In page 6, line 104, you cited a score for lung fibrosis proposed by Camiciottoli, followed by an apex “1”. You didn’t cite the relative paper.

- In page 8, line 150 you say that patients with pulmonary fibrosis were 239, while in the rest of the text you say 237. I suggest you to correct the refuse.

- Page 9, paragraph “The relationship between the degree of pulmonary fibrosis and the clinical classification”: I suggest you to write again the initial part of the paragraph where you enlist the amount of patients with fibrosis for each group, because as it is written by now it is confusing and it is necessary to look at table 1 to understand what you meant.

- In the study, you found a statistical association with the elevation of AST and severity of fibrosis. A recently published study showed a peculiar association between AST/ALT ratio, known also as de Ritis ratio, and hospital mortality in COVID-19 patients, tied also to a larger pneumonia (Zinellu A, Arru F, De Vito A, Sassu A, Valdes G, Scano V, Zinellu E, Perra R, Madeddu G, Carru C, Pirina P, Mangoni AA, Babudieri S, Fois AG. The De Ritis ratio as prognostic biomarker of in-hospital mortality in COVID-19 patients. Eur J Clin Invest. 2020 Oct 11:e13427. doi: 10.1111/eci.13427. Epub ahead of print. PMID: 33043447; PMCID: PMC7646002). I suggest you to read this work and evaluate if de Ritis ratio was also associated with more severe pulmonary fibrosis. Moreover, another study found an association with others laboratory findings and combined indexes, and I suggest you to have a look for a comparison: Paliogiannis P, Zinellu A, Scano V, Mulas G, De Riu G, Pascale RM, Arru LB, Carru C, Pirina P, Mangoni AA, Fois AG. Laboratory test alterations in patients with COVID-19 and non COVID-19 interstitial pneumonia: a preliminary report. J Infect Dev Ctries. 2020 Jul 31;14(7):685-690. doi: 10.3855/jidc.12879. PMID: 32794454.

- It is a great pity that after all the good analysis you conducted you didn’t specify the category of patients who underwent CT at 30, 60 and 90 days from discharge: it would be very interesting to know if they were all severe cases or belonged to different groups. I suggest you to specify it. I would also like to know why only few patients had a new CT scan: were they symptomatic? Did symptoms mismatch CT findings? Why you suggest the use pf antibiotics in patients showing residual interstitial abnormalities after 90 days?

The abstract is concise and it is representative of the full article, and discussion and conclusion are coherent with the study and data shown.

The paper is generally well-written, but there are many phrase constructions atypical for English grammar which probably reflects a literal translation from your native language. I suggest an overall revision of the language, preferably from a mother tongue one.

Reviewer #2: General comments

The paper entitled “The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT” by Chen and Co-wokers is aimed at evaluating a possible role of artificial intelligence applied to chest CT in order to provide an important basis for the clinical diagnosis, treatment and prognosis of COVID-19 pulmonary fibrosis. The aim is clear and the topic is interesting and innovative. The paper is well written. Some shortcomings need to be addressed; in particular, the retrospective nature of this study and the relative high number of missed CT could affect the inference of the results.

Detailed comments

Introduction:

- “Pulmonary fibrosis is a serious complication of viral pneumonia, which often leads to dyspnea and impaired lung function”: I suggest “pulmonary fibrosis can occur as a serious …”

- Line 43: I suggest: “Chest x-rays and high-resolution-CT (citing Severity of lung involvement on chest X-rays in SARS-coronavirus-2 infected patients as a possible tool to predict clinical progression: an observational retrospective analysis of the relationship between radiological, clinical, and laboratory data. Baratella E, Crivelli P, Marrocchio C, Bozzato AM, Vito A, Madeddu G, Saderi L, Confalonieri M, Tenaglia L, Cova MA. J Bras Pneumol. 2020 Sep 21;46(5):e20200226. doi: 10.36416/1806-3756/e20200226. eCollection 2020).

- Methods:

- Chest CT protocol: Authors could better explain the mean radiation dose exposure during CT.

- Chest CT image analysis: Authors could better clarify the years of experience on chest CT images.

- “… striated shadow or mesh shadow…” Authors could explain the mean of these words.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-20-31950R1

The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT

PLOS ONE

Dear Dr. Chen,

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 28 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,

Giordano Madeddu

Academic Editor

PLOS ONE

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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 #2: All comments have been addressed

Reviewer #3: 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

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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 revised manuscript is well written, the topic is original and Clear. Authors responded correctly to the requested reviews

Reviewer #3: The paper was revised in the correct way, although no article is mentioned in support of important laboratory prognostic indices in particular on liver function (https://doi.org/10.1111/eci.13427).

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Reviewer #2: Yes: Paola Crivelli

Reviewer #3: 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.

The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT

PONE-D-20-31950R2

Dear Dr. Chen,

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,

Giordano Madeddu

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 #2: All comments have been addressed

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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: All comments bave been addressed. The paper is well written, the topic is original and the aim i clear. For the anice-mentionned reatina, The paper can ne published. I suggest pubblication of this paper.

Reviewer #3: (No Response)

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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 #2: Yes: Paola Crivelli

Reviewer #3: No