Predicting the aggravation of coronavirus disease-19 pneumonia using chest computed tomography scans

Yukitaka Yamasaki; Seido Ooka; Shin Matsuoka; Hayato Tomita; Masanori Hirose; Tomonori Takano; Shotaro Suzuki; Mitsuru Imamura; Hiroshi Handa; Hiroki Nishine; Mumon Takita; Ayu Minoura; Kenichiro Morisawa; Takeo Inoue; Masamichi Mineshita; Kimito Kawahata; Hiromu Takemura; Shigeki Fujitani; Hiroyuki Kunishima

doi:10.1371/journal.pone.0276738

Peer Review History

Original SubmissionNovember 29, 2021
27 Dec 2021 Decision Letter - Wen-Wei Sung, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-21-37765Predicting the aggravation of coronavirus disease-19 using chest computed tomography scansPLOS ONE Dear Dr. Seido Ooka, 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. I invited two experts in the field of chest medicine to review this article. The comments are constructive and reasonable. Please revise the MS accordingly or discuss in the proper section if revision was not possible. Please submit your revised manuscript by JAN 31, 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'. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. 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: Partly ******** 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: No ****** 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 ****** 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: Summary Goal of this paper is trying to identify predictors for COVID-19 aggravation in a retrospective clinical analysis. Chest CT scan done by 15 days after disease onset is the key target for this study. 189 candidates were enrolled and divided into SPG(n=76) and NSPG(n=113) groups. It is concluded that the degree of lung damage detected by chest CT scanning in the early stage (3 days after onset) could serve as a predictor for disease aggravation. Major Issues (1) Line 108 : “The severe pneumonia group (SPG) included patients with intubation or respiratory management and those who died.” ----- 1. The definition of “respiratory management” is not precise enough. Does it include oxygen therapy, conventional ventilator therapy, NIPPV, HFNC, prone therapy and/or ECMO? 2. In addition to severe pneumonia with acute respiratory failure, COVID-19 victims may also die of sepsis, cardiac dysfunction, thrombosis or other comorbidities. These cases will be recruited into the SPG group despite their lungs are less damaged, and that will distort the results of chest CT analysis. (2) Line 129 : “Analysis of chest CT scans” -----In this study the methodology of chest CT analysis adopted a scoring system from Muller NL (ref 10) which was specifically for pulmonary sarcoid analysis in 1989. The details of estimation method was not given in this paper. Nevertheless, new expert consensus and chest CT scoring system specifically for COVID -19 infections were available in 2020, which will be more specific and updated for your analysis. Ref: # Marco Francone, Franco Iafrate, Giorgio Maria Masci, et al. Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis. European Radiology 2020;30(12):6808-6817. # Feng Pan, Tianhe Ye, Peng Sun, et al. Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology 2020; 295:715–721. # Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH, Chung M, Henry TS, Kanne JP, Kligerman S, Ko JP, Litt H. Radiological Society of North America expert consensus statement on reporting chest CT findings related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA - secondary publication. J Thorac Imaging 2020;35:219-27. # Geoffrey D. Rubin, Christopher J. Ryerson, Linda B. Haramati, et al. The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society. Radiology 2020; 296:172–180. (3) Line 202-224 : “Analysis according to site”, “…..in terms of the area with damage combining GGO and consolidation in the upper, middle, and lower lobes (Fig 3A).” -----According to your methodology the so called “the upper, middle, and lower lobes” in this study actually are not the same the terminology of upper, middle, and lower lobes in lung anatomy. Readers will get confused if your “lobe” is actually not a lobe, but a region in the lung. Minor Issues Line 225-232 : “Clinical course analysis” “Figure 4A” ----- Simple linear regressions were conducted separately for both SPG and NSPG for different CT lesions. Please specify the Y and X variables in the liner regression equation. Other Comment Line 73: “several pneumonia phases” ----- “severe pneumonia” or “several pneumonia” ? Line 93 : “As our institution receives patients with moderate to severe pneumonia caused by COVID-19, factors that can predict aggravation from moderate to severe illness in patients who demonstrate the same were examined.” ----- “who demonstrate the same” ??? Line 98 : “was qualitatively examined.” ----- qualitatively or quantitatively or semi-quantitatively examined in this study? Line 123 : “KL6 levels” ----- KL6 is not a popular abbreviation. Please provide full name in front of abbreviation. Line 124: “and the use of non-inhaled steroids, including favipiravir and remdesivir” ----- Favipiravir and remdesivir are actually anti-viral agents, not non-inhaled steroids. Line 290 : “It has been highlighted that COVID-19 is an asymptomatic infection” ----- ??? Reviewer #2: This is a retrospective study. Although 277 COVID-19 patients were accessed initially, 65 patients were excluded because they had no computerized tomography, 8 patients were excluded because they had no pneumonia presented at chest CT scans. Fifteen patients were excluded due to clinical courses were unclear, so only 189 patients were included for course analysis. Given the study designs are not prospective cohort setting, there are some concerns for the interpretation of the results: Major concern 1: “Age” is an aggravation factors for most of the critical illness, according to existing reports, there was an insignificant difference between the SPG and NSPG in terms of age. The authors should address further analysis of the interaction between age factor and the presence or absence of underlying illnesses. Figure 5 separately analyzes the individuals who were more than 65 years old, with significant differences. The readers must also request to see this comparison in younger group. Major concern 2: There should be other chest computerized tomography image findings, such as interstitial infiltration, septal thickening, cavitating lung lesions, or pneumothorax, etc. The author should try their bet to evaluate possible prognosticator among them. Major concern 3: Compared to COVID-19 patients with NSPG, those with SPG overall had higher GGO and consolidation scores; however, their values were overlapping seriously. This makes the results only provide us some insight in realizing pneumonia degree and extension correlate with clinical severity. It will be more practical to develop a chest computerized tomography scoring system to predict clinal outcomes. Please refer to the published paper “Chest CT Severity Score: An Imaging Tool for Assessing Severe COVID-19” at Radiology: Cardiothoracic Imaging Volume 2: Number 2, 2020. Minor concern 1: Since the 65 patients without CT scans and the 8 patients without pneumonia presented at chest CT scans were excluded, the title should be verified as “The aggravation of coronavirus disease-19 pneumonia in chest computed tomography scans”. Minor concern 2: Figure 2 to Figure 5 should annotate the longitudinal axis meaning to indicate what kind of percentage. Figure 2A lacks horizontal bar to indicate mean values. ****** 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 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. https://doi.org/10.1371/journal.pone.0276738.r001
Revision 1
8 Apr 2022 Author Response Response to Reviewers' comments: 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: Summary Goal of this paper is trying to identify predictors for COVID-19 aggravation in a retrospective clinical analysis. Chest CT scan done by 15 days after disease onset is the key target for this study. 189 candidates were enrolled and divided into SPG(n=76) and NSPG(n=113) groups. It is concluded that the degree of lung damage detected by chest CT scanning in the early stage (3 days after onset) could serve as a predictor for disease aggravation. ⇒We thank the reviewer for the advice. Major Issues (1) Line 108 : “The severe pneumonia group (SPG) included patients with intubation or respiratory management and those who died.” ----- 1. The definition of “respiratory management” is not precise enough. Does it include oxygen therapy, conventional ventilator therapy, NIPPV, HFNC, prone therapy and/or ECMO? ⇒The definition of "respiratory management" is ventilator management. Therefore, the definition of "severe pneumonia" in this study is ventilator management or death. It is described in lines 143-144. The severe pneumonia group (SPG) included patients with intubation and conventional ventilator therapy or death. 2. In addition to severe pneumonia with acute respiratory failure, COVID-19 victims may also die of sepsis, cardiac dysfunction, thrombosis or other comorbidities. These cases will be recruited into the SPG group despite their lungs are less damaged, and that will distort the results of chest CT analysis. ⇒ "Myocardial infarction" and "pulmonary embolism" are excluded in this study. It is described in lines 145-146. Patients who were intubated for conditions other than pneumonia were excluded from the evaluations. It is described in lines 186-188. Intubation was performed for myocardial infarction in 3 patients, pulmonary embolism in 4 patients, and gastrointestinal perforation in 1 patient, and thus these patients were excluded from this study. (2) Line 129 : “Analysis of chest CT scans” -----In this study the methodology of chest CT analysis adopted a scoring system from Muller NL (ref 10) which was specifically for pulmonary sarcoid analysis in 1989. The details of estimation method was not given in this paper. Nevertheless, new expert consensus and chest CT scoring system specifically for COVID -19 infections were available in 2020, which will be more specific and updated for your analysis. Ref: # Marco Francone, Franco Iafrate, Giorgio Maria Masci, et al. Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis. European Radiology 2020;30(12):6808-6817. # Feng Pan, Tianhe Ye, Peng Sun, et al. Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology 2020; 295:715–721. # Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH, Chung M, Henry TS, Kanne JP, Kligerman S, Ko JP, Litt H. Radiological Society of North America expert consensus statement on reporting chest CT findings related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA - secondary publication. J Thorac Imaging 2020;35:219-27. # Geoffrey D. Rubin, Christopher J. Ryerson, Linda B. Haramati, et al. The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society. Radiology 2020; 296:172–180. ⇒The CT severity scoring of 2020 is had scoring of for each lobe. Therefore the right middle lobe of approximately 10% of total lung is actually estimated as 20% by CT severity scoring. As CT severity scoring was not exact for an area, we chose a standard method. However, in consideration of the need of the on-site physician who used CT severity scoring, we wrote score jointly. It is described in lines 171-175. CT severity scoring [11] was calculated per each of the 5 lobes considering the extent of involvement, as follows: 0, no involvement; 1, < 5% involvement; 2, 5-25% involvement; 3, 26-50% involvement; 4, 51-75% involvement; and 5, > 75% involvement. The CT severity score was the sum of each individual lobar score (0 to 25). It is described in lines 226-227. The ROC curve for CT severity score demonstrated a sensitivity of 83.3%, specificity of 62.8%, and cut-off value of 9. It is described in lines 287-289. In the ROC curve for CT severity score, the sensitivity, specificity, and cut-off values were 70.6%, 75.0%, and 6 in the T2 period; 76.4%, 67.1%, and 9 in the T3 period; and 90.9%, 83.3%, and 10 in the T4 period. (3) Line 202-224 : “Analysis according to site”, “…..in terms of the area with damage combining GGO and consolidation in the upper, middle, and lower lobes (Fig 3A).” -----According to your methodology the so called “the upper, middle, and lower lobes” in this study actually are not the same the terminology of upper, middle, and lower lobes in lung anatomy. Readers will get confused if your “lobe” is actually not a lobe, but a region in the lung. ⇒The expression "lobe" and “site” has been changed to "regions". Minor Issues Line 225-232 : “Clinical course analysis” “Figure 4A” ----- Simple linear regressions were conducted separately for both SPG and NSPG for different CT lesions. Please specif the y Y and X variables in the liner regression equation. ⇒In Figure 4a, we added Y = 2.822 × X + 20.18 as SPG and Y = 1.353 × X + 11.93 as NSPG. In Figure 5b, we added Y = 2.750 × X + 23.27 as SPG and Y = 1.139 × X + 13.51 as NSPG Other Comment Line 73: “several pneumonia phases” ----- “severe pneumonia” or “several pneumonia” ? ⇒The expression " several pneumonia" has been changed to " severe pneumonia” in line 107 Line 93 : “As our institution receives patients with moderate to severe pneumonia caused by COVID-19, factors that can predict aggravation from moderate to severe illness in patients who demonstrate the same were examined.” ----- “who demonstrate the same” ??? ⇒In 126, we added “Therefore, since our institution accepts patients with moderate to severe pneumonia by COVID-19, we investigated what predictors of severe disease were present in patients who consequently transitioned from moderate to severe disease.” Line 98 : “was qualitatively examined.” ----- qualitatively or quantitatively or semi-quantitatively examined in this study? In line132, we changed as “was examined qualitatively and quantitatively.”migi Line 123 : “KL6 levels” ----- KL6 is not a popular abbreviation. Please provide full name in front of abbreviation. ⇒In line156, we changed as “sialylated carbohydrate antigen KL-6” Line 124: “and the use of non-inhaled steroids, including favipiravir and remdesivir” ----- Favipiravir and remdesivir are actually anti-viral agents, not non-inhaled steroids. Inlind157, we added “The history of use of inhaled steroids including Ciclesonide, non-inhaled steroids, favipiravir, and remdesivir was evaluated as factors affecting the severe pneumonia group.” Line 290 310: “It has been highlighted that COVID-19 is an asymptomatic infection” ----- ⇒In Line 349, we changed to “It has been highlighted that COVID-19　is often asymptomatic and is difficult to control.” Reviewer #2: This is a retrospective study. Although 277 COVID-19 patients were accessed initially, 65 patients were excluded because they had no computerized tomography, 8 patients were excluded because they had no pneumonia presented at chest CT scans. Fifteen patients were excluded due to clinical courses were unclear, so only 189 patients were included for course analysis. Given the study designs are not prospective cohort setting, there are some concerns for the interpretation of the results: ⇒We thank the reviewer for the advice. Major concern 1: “Age” is an aggravation factors for most of the critical illness, according to existing reports, there was an insignificant difference between the SPG and NSPG in terms of age. The authors should address further analysis of the interaction between age factor and the presence or absence of underlying illnesses. Figure 5 separately analyzes the individuals who were more than 65 years old, with significant differences. The readers must also request to see this comparison in younger group. ⇒In line 220, we added “Patients 65 years or older were more frequent of associated disease than younger patients (90.3% vs 65.2%).” In line 299, we added “As data under 65 years old, there was not a significant difference observed in the chest CT scans in the SPG and NSPG,” In line 304, we added “The data under 65 years old did not significantly have linear regression in the SPG and NSPG.,” Major concern 2: There should be other chest computerized tomography image findings, such as interstitial infiltration, septal thickening, cavitating lung lesions, or pneumothorax, etc. The author should try their bet to evaluate possible prognosticator among them. ⇒ These findings were rare and did not make a significant difference. Therefore the extent of consolidation and GGO was measured, and the mean was calculated. Major concern 3: Compared to COVID-19 patients with NSPG, those with SPG overall had higher GGO and consolidation scores; however, their values were overlapping seriously. This makes the results only provide us some insight in realizing pneumonia degree and extension correlate with clinical severity. It will be more practical to develop a chest computerized tomography scoring system to predict clinal outcomes. Please refer to the published paper “Chest CT Severity Score: An Imaging Tool for Assessing Severe COVID-19” at Radiology: Cardiothoracic Imaging Volume 2: Number 2, 2020. ⇒The CT severity scoring of 2020 is had scoring of for each lobe. Therefore the right middle lobe of approximately 10% of total lung is actually estimated as 20% by CT severity scoring. As CT severity scoring was not exact for an area, we chose a standard method. However, in consideration of the need of the on-site physician who used CT severity scoring, we wrote score jointly. It is described in lines 171-175. CT severity scoring [11] was calculated per each of the 5 lobes considering the extent of involvement, as follows: 0, no involvement; 1, < 5% involvement; 2, 5-25% involvement; 3, 26-50% involvement; 4, 51-75% involvement; and 5, > 75% involvement. The CT severity score was the sum of each individual lobar score (0 to 25). It is described in lines 226-227. The ROC curve for CT severity score demonstrated a sensitivity of 83.3%, specificity of 62.8%, and cut-off value of 9. It is described in lines 287-289. In the ROC curve for CT severity score, the sensitivity, specificity, and cut-off values were 70.6%, 75.0%, and 6 in the T2 period; 76.4%, 67.1%, and 9 in the T3 period; and 90.9%, 83.3%, and 10 in the T4 period. Minor concern 1: Since the 65 patients without CT scans and the 8 patients without pneumonia presented at chest CT scans were excluded, the title should be verified as “The aggravation of coronavirus disease-19 pneumonia in chest computed tomography scans”. ⇒We changed the title to “The aggravation of coronavirus disease-19 pneumonia in chest computed tomography scans” Minor concern 2: Figure 2 to Figure 5 should annotate the longitudinal axis meaning to indicate what kind of percentage. Figure 2A lacks horizontal bar to indicate mean values. ⇒ We added “Lung damage volume (%)” in Figure 2 to Figure 5 Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0276738.r002
2 May 2022 Decision Letter - Wen-Wei Sung, Editor PONE-D-21-37765R1Predicting the aggravation of coronavirus disease-19 pneumonia using chest computed tomography scansPLOS ONE Dear Dr. Seido Ooka, 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 May 31, 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, Wen-Wei Sung, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: 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. 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: Comments Minor Issues: Line 205 Table 1 The superscript characters of “a” and “b” represent “number” and “standard deviation” respectively in Table 1. However, there are already abbreviations of “n” and “SD” to represent “number” and “standard deviation” in the same table. The superscript characters of “a” and “b” are superfluous. Line 215 Table 2 The superscript characters of “a”, “b” and “c” represent “not significant” and “number” and “standard deviation” respectively in Table 2. However, there are already abbreviations of “n.s.”, “n” and “SD” in the table. The superscript characters of “a”, “b” and “c” are superfluous. Line 251 “middlefield” →“middle field” Line 268 “The time point when a significant difference would appear in findings in CT scans conducted after the day of onset was examined.” →“The time point (X) when a significant difference would appear in findings in CT scans conducted after the day of onset was examined. ” Line 269 “ In the area with damage combining GGO and consolidation,” →“In the area with damage(Y) combining GGO and consolidation,” ****** 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.0276738.r003
Revision 2
28 Sep 2022 Author Response Thank you very much for your reviewing. We totally agree to your suggestions and re-vised the text. Revised portions were colored red. We believe that this revision made the text better than before. Please, consider my article for publication in your journal. Reviewers' comments: Reviewer #1: Line 205 Table 1 The superscript characters of “a” and “b” represent “number” and “standard deviation” respectively in Table 1. However, there are already abbreviations of “n” and “SD” to represent “number” and “standard deviation” in the same table. The superscript charac-ters of “a” and “b” are superfluous. ⇒We thank the reviewer for the advice. I deleted the superscript characters of "a" and "b" Line 215 Table 2 The superscript characters of “a”, “b” and “c” represent “not significant” and “number” and “standard deviation” respectively in Table 2. However, there are already abbrevia-tions of “n.s.”, “n” and “SD” in the table. The superscript characters of “a”, “b” and “c” are superfluous. ⇒We thank the reviewer for the advice. I deleted the superscript characters of "a" and "b" Line 251 “middlefield” →“middle field” ⇒We thank the reviewer for the advice. I corrected it according to your advice. Line 268 “The time point when a significant difference would appear in findings in CT scans con-ducted after the day of onset was examined.” →“The time point (X) when a significant difference would appear in findings in CT scans conducted after the day of onset was examined. ” ⇒We thank the reviewer for the advice. I corrected it according to your advice. Line 269 “ In the area with damage combining GGO and consolidation,” →“In the area with dam-age(Y) combining GGO and consolidation,” ⇒We thank the reviewer for the advice. I corrected it according to your advice. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0276738.r004
13 Oct 2022 Decision Letter - Wen-Wei Sung, Editor Predicting the aggravation of coronavirus disease-19 pneumonia using chest computed tomography scans PONE-D-21-37765R2 Dear Dr. Seido Ooka, 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, Wen-Wei Sung, M.D., Ph.D. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276738.r005
Formally Accepted
26 Oct 2022 Acceptance Letter - Wen-Wei Sung, Editor PONE-D-21-37765R2 Predicting the aggravation of coronavirus disease-19 pneumonia using chest computed tomography scans Dear Dr. Ooka: 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. Wen-Wei Sung Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0276738.r006

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