Impact of body composition on patient prognosis after SARS-Cov-2 infection

Takayuki Yamamoto; Kazushi Sugimoto; Syuhei Ichikawa; Kei Suzuki; Hideki Wakabayashi; Kaoru Dohi; Norihiko Yamamoto

doi:10.1371/journal.pone.0289206

Peer Review History

Original SubmissionJanuary 16, 2023
23 Feb 2023 Decision Letter - Jun Mori, Editor PONE-D-23-01341Impact of body composition on patient prognosis after SARS-Cov-2 infectionPLOS ONE Dear Dr. Yamamoto, 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 Apr 09 2023 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. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following in your Competing Interests section: "The author(s) received no specific funding for this work." Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state ""The authors have declared that no competing interests exist."", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. 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Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. Additional Editor Comments: The authors assess the body composition and the degree of sarcopenia between severe and non-severe patients with COVID-19. They concluded that Intra-muscular adipose tissue content (IMAC) could be a useful predictor of disease severity for patients with COVID-19. The data is somewhat interesting, but I have the following concerns. 1. Non-severe patients group includes young patient such as 20 years age, even though mean age was not different between severe and non-severe groups. In general, younger people tend to be less severe with COVID-19 infection compared to older people. I'm wondering why this young patient was admitted and CT scan was performed. You should show the patient's age for both groups in detail. 2. There are many risk factors of severity of COVID-19 other than obesity and T2DM, e.g. hypertension, hyperlipidemia, chronic lung disease, chronic kidney disease, tobacco habits. What are your thoughts on the involvement of these other risk factors? 3. Do you have the data of waist circumference, which is also an index of visceral fat mass? Measuring waist circumference is much easier to evaluate VFA by CT, thus it is useful in the clinical setting. 4. In Fig 1, IMAC in severe group is higher in Obesity group 0. Is there difference in age between non-severe and severe groups in Obesity group 0? 5. In table 2, the authors show that IMAC is higher in severe group compared to non-severe group. However, in Fig 1, IMAC in group 1 and group 2-4 is not different between severe and non-severe groups. Could you elaborate the reason why there is no difference? [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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Reviewer #1: No ****** 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: I read the manuscript entitled “ Impact of body composition on patient prognosis after SARS-Cov-2 infection”. I think that this study is impressive, and important to understand the relationship between obesity/adiposity and the risk factors, prognosis and severity of COVID19 infection. I have some questions on the current manuscript. I would like to refer to Methods and Study population. (Page11) This study cohort is thought to be a retrospective observational study. I wonder if computed tomography (CT) scanning was performed on all the admitted patients with COVID19. Exclusion criteria from the study was equivocated or might not be written in the manuscript. The author should totally explain the study design, and illustrate a figure including the flowchart to sum up the method of recruiting and enrolling the patients and collecting their data. I should mention about data collection in the study. (Page11-12) The authors compared the differences of clinical parameters between the intubated patients and the non-intubated patients with COVID19. I wonder if there were patients with mild phenotype among the non-intubated patients, who did not need oxygen administration. I assume that most of the patients the author enrolled required oxygenation therapy: moderate type. I wonder if the data of patients without oxygenation (i.e., mild type) were involved. I thought that comparison between the patients with severe type and those with mild type is necessary. The author should refer to the methods of measurement on the blood parameters, including equipment. The CT device they used should be precisely written. The author should indicate the source of reference on the severity of COVID19 patients, the definition of obesity, and the classification of obesity. Did the author apply the guidelines for the Management of Obesity Disease 2022, which was published by Japanese Society of the Study of Obesity (JASSO) to the study design? The data of IMAC are interesting. Figure 1(Page 28) indicates that ectopic adiposity in the muscle (i.e., myosteatosis) can affect the prognosis of COVID19 patients in non-obese population. I consider that myosteatosis can have a bigger influence on the severity of COVID19 infection compared with sarcopenia. What is its mechanism? The author may mention what they considered about that, even if it was speculation. In the abstract (Page 7), the influence of SARS-CoV2 mutation for the severity of COVID19 does not matter in the context. A native English speaker may correct grammatical problems in the current manuscript. And, the paper was organized again. ****** 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 ******** [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". 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Revision 1
6 Apr 2023 Author Response Professor Jun Mori Academic Editor PLOS ONE PONE-D-23-01341 Impact of body composition on patient prognosis after SARS-Cov-2 infection Dear Prof. Jun Mori We appreciate your positive response and the opportunity to address the reviewer’s and editor’s comments regarding our submitted manuscript (PONE-D-23-01341). We would also like to take this opportunity to thank the reviewer for the time and insightful suggestions. We have modified our manuscript according to the reviewer’s and editor’s suggestions. As requested, a point by point response to each of the issues raised by the reviewer and editor now follows: Reviewer #1 # I would like to refer to Methods and Study population. (Page11) This study cohort is thought to be a retrospective observational study. I wonder if computed tomography (CT) scanning was performed on all the admitted patients with COVID19. Exclusion criteria from the study was equivocated or might not be written in the manuscript. The author should totally explain the study design, and illustrate a figure including the flowchart to sum up the method of recruiting and enrolling the patients and collecting their data. We appreciate this comment. We basically performed CT scan for all the cases unless the patient had any problem for taking CT scan (for example, pregnancy), and patients who lacked CT images were excluded for further analysis. Totally, 93 patients were admitted in the study period. Of these, 17 patients were excluded from the study, for eight patients were pregnant and CT scans of abdomen were not performed, required area for anthropometric measurements were not captured in eight patients, and clear image was not obtained in one patient. This information was added in the Result section and we also added the flowchart of the patient enrollment as Figure 1. # I should mention about data collection in the study. (Page11-12) The authors compared the differences of clinical parameters between the intubated patients and the non-intubated patients with COVID19. I wonder if there were patients with mild phenotype among the non-intubated patients, who did not need oxygen administration. I assume that most of the patients the author enrolled required oxygenation therapy: moderate type. I wonder if the data of patients without oxygenation (i.e., mild type) were involved. I thought that comparison between the patients with severe type and those with mild type is necessary. We agree this comment. However, all the patients admitted to our hospital had underlying disease and certain risks for disease severity of COVID-19, and hence all of the patients enrolled to this study needed oxygenation. Therefore, though we also think it is very important to compare the clinical and anthropometric parameters between severe and mild cases as the reviewer mentioned, we could not make this comparison for the reason described above. # The author should refer to the methods of measurement on the blood parameters, including equipment. The CT device they used should be precisely written. All the blood tests were performed at the Clinical Laboratory of Mie University Hospital using LABOSPECT 008 (Hitachi High-Tech Corporation, Tokyo, Japan) for blood chemistry, XN-3000 (Sysmex, Kobe, Japan) for complete blood count, and CS-5100 (Sysmex) for blood coagulation tests. CT scans were performed using Discovery CT750 HD (GE Health Care, Tokyo, Japan). We added this information to the Methods section of the text. # The author should indicate the source of reference on the severity of COVID19 patients, the definition of obesity, and the classification of obesity. Did the author apply the guidelines for the Management of Obesity Disease 2022, which was published by Japanese Society of the Study of Obesity (JASSO) to the study design? 　We apologize for the lack of the source of obesity classification. As the reviewer mentioned, we classified obese patients into four grades by BMI according to the Guidelines for the Management of Obesity Disease 2022 by Japanese Society for the Study of Obesity. We added this information to Methods section. In addition, we classified the patient who needed intubation and mechanical ventilation as severe cases. The indication for intubation and mechanical ventilation followed the “Clinical Management of Patients with COVID-19: A guide for front-line healthcare workers” by the Ministry of Health, Labour and Welfare, Japan. We also included this information in Method section. # The data of IMAC are interesting. Figure 1(Page 28) indicates that ectopic adiposity in the muscle (i.e., myosteatosis) can affect the prognosis of COVID19 patients in non-obese population. I consider that myosteatosis can have a bigger influence on the severity of COVID19 infection compared with sarcopenia. What is its mechanism? The author may mention what they considered about that, even if it was speculation. We greatly appreciate this comment. The mechanism regarding the association between IMAC and disease severity of COVID-19 is still unclear. Furthermore, though it is possible that myosteatosis may have a bigger influence of the COVID-19 prognosis than sarcopenia as the reviewer suggested, we do not have enough evidences to fully explain this mechanism yet. However, we can speculate some explanations. Recent study by Yi et al. showed thoracic myosteatosis was related to progression of COVID-19, which is comparable with our results. They suggested that muscle adiposity causes systemic muscle weakness and diminished effort for coughing which is crucial for protection against respiratory infection, and leads to disease progression. We also agree their speculation. We can assume myosteatosis may have bigger effect on muscle weakness than sarcopenia. The other possible mechanism is the changes in myokines. It has been elucidated that skeletal muscle secrets several hundreds of myokines. Myokines have multiple effects on modulating immunological, metabolic and physiological activities of human body. We can speculate that muscle adiposity may change the myokine profiles and causes alterations in their metabolic or immunomodulating effects, which results in disease severity. However, these effects by myokines may become less remarkable as the patients get obese, because the effects of the larger amount of inflammatory adipokines secreted by visceral adipose tissue become more prominent. We added these descriptions to the Discussion section. # In the abstract (Page 7), the influence of SARS-CoV2 mutation for the severity of COVID19 does not matter in the context. We agree this suggestion. Following this comment, we eliminated the descriptions regarding SARS-Cov-2 mutation from the text and rewrote conclusion in Abstract. # A native English speaker may correct grammatical problems in the current manuscript. And, the paper was organized again. We have had our manuscript proofread by a professional English editing service to correct errors in the text. Additional Editor Comments: The authors assess the body composition and the degree of sarcopenia between severe and non-severe patients with COVID-19. They concluded that Intra-muscular adipose tissue content (IMAC) could be a useful predictor of disease severity for patients with COVID-19. The data is somewhat interesting, but I have the following concerns. 1. Non-severe patients group includes young patient such as 20 years age, even though mean age was not different between severe and non-severe groups. In general, younger people tend to be less severe with COVID-19 infection compared to older people. I'm wondering why this young patient was admitted and CT scan was performed. You should show the patient's age for both groups in detail. In total, eight patients were in their 20s. Among them, 6 patients were pregnant and abdominal CT scans were not performed, therefore, they were excluded from the study. The remaining two patients were included to the study. One was 22 years old female who had obesity (BMI; 32.8) and T2DM, and the other was 26 years old male who had obesity (BMI; 37). Both of them became severe ill after admission and intubated and on mechanical ventilation. We have also reanalyzed the data and made a comparison of age between non-severe and severe group in each obesity grade. We will describe this result more in detail in the response to editor’s comment 4. 2. There are many risk factors of severity of COVID-19 other than obesity and T2DM, e.g. hypertension, hyperlipidemia, chronic lung disease, chronic kidney disease, tobacco habits. What are your thoughts on the involvement of these other risk factors? We think all those factors the editor mentioned are also very crucial for severity of COVID-19. However, most of the patients in this study were transferred from the other regional hospitals and many of them had not attended any medical institution regularly before COVID-19. Therefore, we regret to say we did not have enough patients’ information regarding those risk factors other than obesity and T2DM which could be assessed after admission to our hospital. 3. Do you have the data of waist circumference, which is also an index of visceral fat mass? Measuring waist circumference is much easier to evaluate VFA by CT, thus it is useful in the clinical setting. We do not have the data of waist circumference. We agree measuring waist circumference is easier and less expensive way to assess visceral fat mass. However, it sometimes varies by the body posture or the measurers. Therefore, we used CT scan as a more precise and objective method to evaluate VFA in this study. 4. In Fig 1, IMAC in severe group is higher in Obesity group 0. Is there difference in age between non-severe and severe groups in Obesity group 0? We greatly appreciate this comment. To respond to this query, we made comparison of the age between non-severe and severe patients in each obesity group and found non-severe patients were younger than severe patients in obesity grade 0, while no difference of age was observed between non-severe and severe patients in obesity grade 1, 2-4 groups. As non-obese individuals are less likely to have other metabolic-associated risk factors, these results may suggest that high IMAC may be more crucial for COVID-19 severity in this group. In addition, we can also speculate non-obese younger patients had more favorable disease courses because they had less muscle adiposity compared to non-obese older patients. We added these results in Table 4 as a new Table for the revision version and our interpretation in the discussion. 5. In table 2, the authors show that IMAC is higher in severe group compared to non-severe group. However, in Fig 1, IMAC in group 1 and group 2-4 is not different between severe and non-severe groups. Could you elaborate the reason why there is no difference? In the bottom of Table 2, it is shown that IMAC was not different between non-severe and severe groups. We think this result is consistent with Figure 1. Once again, we would like to thank you and the reviewer for your positive suggestions. We believe our manuscript has been much improved as a result of incorporation of these useful suggestions and hope you will now find it acceptable for publication in PLOS ONE. Norihiko Yamamoto M.D., Ph.D. Department of General Medicine Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Tel: +81-59-231-5290 Fax: +81-59-232-5289 E-mail: kotetsu@med.mie-u.ac.jp Attachments Attachment Submitted filename: Response to Reviewer (1).docx https://doi.org/10.1371/journal.pone.0289206.r002
2 May 2023 Decision Letter - Jun Mori, Editor PONE-D-23-01341R1Impact of body composition on patient prognosis after SARS-Cov-2 infectionPLOS ONE Dear Dr. Yamamoto, 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 Jun 16 2023 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, Jun Mori Academic Editor PLOS ONE Journal Requirements: 1. 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 authors responded to all my comments. I have no further concerns. The authors should respond the additional reviewer's comments. [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 ******** 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: I must refer to the discussion. The author must precisely read the references you used, especially Ref.31 written by Bay ML. He precisely described that anti-inflammatory effects are induced by the muscle through physical exercise. The author inserted new discussion, using the review article ( Ref.31). That article shows many kinds of myokine induced by physical exercise. Unfortunately, author’s description in the discussion was equivocal. I understand that the muscle-derived (md) IL-6 increases by exercise, and mdIL6 suppresses TNF-alfa production, through that review article. Certainly, mdIL6 is anti-inflammatory cytokine. Exercise may be protective to inflammation, or COVID19 pneumonia. This context that the author wrote would be correct. However, I wonder if intramuscular hyperadiposity, which means high IMAC in the muscle, could lead to inflammatory excitement in the lung or immune system in patients with COVID19 pneumonia. This discussion matters. Moreover, I would like to know whether intramuscular adipocyte specifically secrets inflammatory cytokines and adipokines. Or I would like to know whether there could be crosstalk between the muscle and the adipocytes in muscle in immune response. Such discussion is of importance, and should be added, and be written concretely. Discussion should be more profound and meaningful. ****** 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 ******** [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. https://doi.org/10.1371/journal.pone.0289206.r003
Revision 2
10 Jun 2023 Author Response Professor Jun Mori Academic Editor PLOS ONE PONE-D-23-01341R1 Impact of body composition on patient prognosis after SARS-Cov-2 infection Dear Prof. Jun Mori We appreciate your positive response and the opportunity to address the reviewer’s and editor’s comments regarding our submitted manuscript (PONE-D-23-01341R1). We would also like to take this opportunity to thank the reviewer for the time and insightful suggestions. We have modified our manuscript according to the reviewer’s suggestions. As requested, a point by point response to the issue raised by the reviewer now follows: Reviewer #1: I must refer to the discussion. The author must precisely read the references you used, especially Ref.31 written by Bay ML. He precisely described that anti-inflammatory effects are induced by the muscle through physical exercise. The author inserted new discussion, using the review article (Ref.31). That article shows many kinds of myokine induced by physical exercise. Unfortunately, author’s description in the discussion was equivocal. I understand that the muscle-derived (md) IL-6 increases by exercise, and mdIL6 suppresses TNF-alfa production, through that review article. Certainly, mdIL6 is anti-inflammatory cytokine. Exercise may be protective to inflammation, or COVID19 pneumonia. This context that the author wrote would be correct. However, I wonder if intramuscular hyperadiposity, which means high IMAC in the muscle, could lead to inflammatory excitement in the lung or immune system in patients with COVID19 pneumonia. This discussion matters. Moreover, I would like to know whether intramuscular adipocyte specifically secrets inflammatory cytokines and adipokines. Or I would like to know whether there could be crosstalk between the muscle and the adipocytes in muscle in immune response. Such discussion is of importance, and should be added, and be written concretely. Discussion should be more profound and meaningful. We greatly appreciate this comment. We agree our discussion about myokines is equivocal, therefore, we focused on IL-6 in the revised version, for it is one of the most important and well-studied inflammatory myokine. It is reported that increased level of IL-6 is produced by the muscle tissues with fatty regeneration (Addison O, et al.). As the reviewer pointed out, muscle-derived IL-6 has some anti-inflammatory effect. However, IL-6 has two-way signal transductions by the differed receptors. One signaling (classic signaling) induces generative and protective responses to small subset of cells (hepatocytes and leucocytes), the other signaling (trans-signaling) induces proinflammatory responses to all cells in the body. Moreover, it is reported that IL-6 plays a crucial role for the pathogenesis of cytokine release syndrome which leads disease severity of COVID-19. In muscle cells, though IL-6 has some beneficial effects for muscle growth, myogenesis or energy metabolism, it also has negative effects such as inducing muscle atrophy or wasting that could affect COVID-19 prognosis. We added these things concisely and modified discussion section to make it less equivocal and more profound. We also replaced Ref 31 to another references (Ref. 31, 32, 33) which more adequately support our description. Once again, we would like to thank you and the reviewer for the positive suggestion. We believe our manuscript has been further improved as a result of incorporation of the reviewer’s suggestion and hope you will now find it suitable for publication in PLOS ONE. Attachments Attachment Submitted filename: Resonse to Reviewers.docx https://doi.org/10.1371/journal.pone.0289206.r004
25 Jun 2023 Decision Letter - Jun Mori, Editor PONE-D-23-01341R2Impact of body composition on patient prognosis after SARS-Cov-2 infectionPLOS ONE Dear Dr. Yamamoto, 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 Aug 09 2023 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. 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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: All comments have been addressed. [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 ******** 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 ****** 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: Obesity can also predict the severity of COVID19 pneumonia in Japan as well as in the United States and European countries. In Japan, the population of severe obesity is fewer than in the United States and European countries. The current study suggests that IMAC might be predictive for the severity of COVID19 pneumonia in non-obese Japanese patients. In that context, to discover a predictor on the severity of COVID19 pneumonia is greatly meaningful in Japan. The finding that the author discovered on IMAC in this study is interesting to me. However, IMAC does not look different in the Japanese obese patients with COVID19 pneumonia. So, IMAC may not be useful to predict the severity of COVID19 pneumonia as well as mortality in Japan. The author should modify the conclusion in the abstract in order to avoid misunderstanding. ****** 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 ******** [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. https://doi.org/10.1371/journal.pone.0289206.r005
Revision 3
29 Jun 2023 Author Response Professor Jun Mori Academic Editor PLOS ONE PONE-D-23-01341R2 Impact of body composition on patient prognosis after SARS-Cov-2 infection Dear Prof. Jun Mori We appreciate your positive response and the opportunity to address the reviewer’s and editor’s comments regarding our submitted manuscript (PONE-D-23-01341R2). We would also like to take this opportunity to thank the reviewer for the time and insightful suggestions. We have modified our manuscript according to the reviewer’s suggestions. As requested, a point by point response to the issue raised by the reviewer now follows: Reviewer #1: Obesity can also predict the severity of COVID19 pneumonia in Japan as well as in the United States and European countries. In Japan, the population of severe obesity is fewer than in the United States and European countries. The current study suggests that IMAC might be predictive for the severity of COVID19 pneumonia in non-obese Japanese patients. In that context, to discover a predictor on the severity of COVID19 pneumonia is greatly meaningful in Japan. The finding that the author discovered on IMAC in this study is interesting to me. However, IMAC does not look different in the Japanese obese patients with COVID19 pneumonia. So, IMAC may not be useful to predict the severity of COVID19 pneumonia as well as mortality in Japan. The author should modify the conclusion in the abstract in order to avoid misunderstanding. We agree this comment. Our description in the Abstract may cause misunderstanding. As the reviewer stated, our data showed IMAC was different between severe and non-severe COVID-19 cases in non-obese patients. And it does not predict disease course in obese patients or disease mortality in any obesity grade. We modified the conclusion in the Abstract to make these points clearer according to the reviewer’s suggestion. Once again, we would like to thank you and the reviewer for the positive suggestion. We believe our manuscript has been further improved as a result of incorporation of the reviewer’s suggestion and hope you find it meet PLOS ONE’s publication criteria now. Norihiko Yamamoto M.D., Ph.D. Department of General Medicine Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Tel: +81-59-231-5290 Fax: +81-59-232-5289 Attachments Attachment Submitted filename: Response to Reviewer (1).docx https://doi.org/10.1371/journal.pone.0289206.r006
14 Jul 2023 Decision Letter - Jun Mori, Editor Impact of body composition on patient prognosis after SARS-Cov-2 infection PONE-D-23-01341R3 Dear Dr. Yamamoto, 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. 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, Jun Mori Academic Editor PLOS ONE Additional Editor Comments (optional): The authors responded to the reviewer's comments correctly. 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 modificaton the author has done is acceptable to me. It is worth publishing the current 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 #1: No ******** https://doi.org/10.1371/journal.pone.0289206.r007
Formally Accepted
20 Jul 2023 Acceptance Letter - Jun Mori, Editor PONE-D-23-01341R3 Impact of body composition on patient prognosis after SARS-Cov-2 infection Dear Dr. Yamamoto: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Jun Mori Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0289206.r008

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