Clinical features of and severity risk factors for COVID-19 in adults during the predominance of SARS-CoV-2 XBB variants in Okinawa, Japan

Shuhei Ideguchi; Kazuya Miyagi; Wakaki Kami; Daisuke Tasato; Futoshi Higa; Noriyuki Maeshiro; Shota Nagamine; Hideta Nakamura; Takeshi Kinjo; Masashi Nakamatsu; Shusaku Haranaga; Akihiro Tokushige; Shinichiro Ueda; Jiro Fujita; Kazuko Yamamoto

doi:10.1371/journal.pone.0309808

Peer Review History

Original SubmissionApril 26, 2024
20 May 2024 Decision Letter - Liling Chaw, Editor PONE-D-24-16162Clinical features of and severity risk factors for COVID-19 in adults during the epidemic wave induced by SARS-CoV-2 XBB variants in Okinawa, JapanPLOS ONE Dear Dr. Miyagi, 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 Jul 04 2024 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 financial disclosure: "S.I. and K.Y. are funded by a research grant of Advanced Medical Research Center, Faculty of Medicine, University of the Ryukyus, Japan. There is no grant number. URL: https://amrc.skr.u-ryukyu.ac.jp/aboutus/ The sponsor played no role in this study." Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. We will update your Data Availability statement on your behalf to reflect the information you provide. Additional Editor Comments: Dear authors, Please address the reviewer's comments, particularly on the definition of XBB variant and justifying the exclusion criteria used. [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: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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 ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: It is an interesting manuscript. The authors described the characteristics of patients, symptoms and signs, as well as the risk factors of COVID-19 patients in Okinawa. Although the titles mention about SARS-CoV-2 XBB variants, the paper lack of information about the methods for the XBB variants identification in the patients enrolled in this study. Learning that XBB variant correspond to 80% of the genomic surveillance does not reflect directly to the proportion among the patients enrolled in this study. I advise not to include XBB variants in the title, since it will be misleading to the readers. Moreover, there are several suggestions to improve this manuscript: 1. Lines 64: This phrase cannot clearly understandable “….XBB/XBB1.5 had more prior infections than…. “ 2. Fig 1. Should be explained in the result, but not in the introduction. The methods to collect the data need to be describe clearly in the methods. Otherwise, cite from the original publication. 3. Line 97: There is some disagreement that antigen testing can be use as confirmatory diagnosis for COVID-19. Authors need to address this in discussion with solid references. 4. Lines 99-100: Please describe the diagnosis criteria for bacterial pneumoniae. Is it supported with culture from blood or respiratory specimen? Or other methods such as NAAT? 5. Line 46: How authors defined hospital acquired infection for COVID-19? Does the author want to explain that 38% of the subjects contracted with COVID-19 while they were stayed in the hospital because of suffering from other diseases? Or, it means that 38% of the patients have other HAIs (not the COVID-19) 6. Table 1. Why only male is presented? 7. This study only recruited elderly (64 – 91) patients. Though it may reflect the actual hospitalization cases in Okinawa, the author should address these issues. Authors should refer to other countries reports which may have different segment of patients ages. This is important to give comprehensive insight into the characteristics, symptoms and sign, as well as risk factors for the XBB variant. Reviewer #2: The study examined clinical features of COVID-19 caused by the XBB variant of SARS-CoV-2 and explored risk factors for severe disease among hospitalized patients. The study was done in 4 tertiary care hospitals in Japan. Patients with complications related to bacterial infections were excluded. Exclusion criteria appear to be complications that one would expect to occur in severe disease, so it is not clear why those who had these outcomes were excluded. In a cohort study, exclusions are made based on factors knowable before day 1 for each patient, not on factors that occur after day 1. Here it is not explicitly stated, but one would assume day 1 for each patient to be the date of diagnosis of COVID-19. Many of the items listed as exclusion criteria would not have been knowable on that day. The authors may want to reconsider their exclusion criteria. The authors should add how the diagnosis of COVID-19 was made. For the purpose of this study, grouping into "mild" and "severe" disease appears to be based on whether or not patients required supplemental oxygen or ICU admission. This could be stated simply. It may be unnecessarily complicated to describe the MHLW guidelines when stating how severity was defined. Discussion, line 201-202: It would be more correct to state that the study found an association between prior booster vaccination and lower severity of XBB-variant COVID-19 among hospitalized patients with COVID-19. This study design does not allow one to claim that the study revealed that bivalent omicron booster vaccination reduced the severity of COVID-19. ****** 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: Yes: Nabin K. Shrestha ******** [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.0309808.r001
Revision 1
2 Aug 2024 Author Response Thank you for reviewing our paper and for this suggestion. We performed a whole- genome analysis of stored nasopharyngeal specimens from patients admitted to our hospital and have added the distribution of sub-lineages to the manuscript. We have also changed the title. We have revised our manuscript to the best of our ability according to your suggestions. Please find our responses to your comments below. [C1] Lines 64: This phrase cannot clearly understandable “….XBB/XBB1.5 had more prior infections than…. “ (R1) Thank you for pointing this out. We have corrected the sentence (lines 68-71). [C2] Fig 1. Should be explained in the result, but not in the introduction. The methods to collect the data need to be describe clearly in the methods. Otherwise, cite from the original publication. (R2) Thank you for pointing this out. We have removed Fig 1 and have added the information as a reference because it is not part of the results of this study but was rather added to the Introduction as a description to help readers gain a better understand of the background of this study (line 82). [C3] Line 97: There is some disagreement that antigen testing can be use as confirmatory diagnosis for COVID-19. Authors need to address this in discussion with solid references. (R3) Thank you for pointing this out. To address this, we have stated as part of the limitations in the Discussion section that antigen testing is used at many facilities in Japan for the diagnosis of COVID-19 and is known to be as specific as PCR for omicron variants (lines 294-297). [C4] Lines 99-100: Please describe the diagnosis criteria for bacterial pneumoniae. Is it supported with culture from blood or respiratory specimen? Or other methods such as NAAT? (R4) As you have indicated, the diagnosis of bacterial pneumonia is supported by the results of sputum culture. The diagnostic criteria of bacterial pneumonia have been described in lines 101-103. [C5] Line 46: How authors defined hospital acquired infection for COVID-19? Does the author want to explain that 38% of the subjects contracted with COVID-19 while they were stayed in the hospital because of suffering from other diseases? Or, it means that 38% of the patients have other HAIs (not the COVID-19) (R5) Thank you for pointing this out. We defined hospital-acquired infection as new-onset COVID-19 during hospitalization for other diseases. We have described the criteria for hospital-acquired COVID-19 in lines 128-129. [C6] Table 1. Why only male is presented? (R6) Thank you for pointing this out. We added the data for female patients in Table 1. [C7] This study only recruited elderly (64 – 91) patients. Though it may reflect the actual hospitalization cases in Okinawa, the author should address these issues. Authors should refer to other countries reports which may have different segment of patients ages. This is important to give comprehensive insight into the characteristics, symptoms and sign, as well as risk factors for the XBB variant. (R7) As you have indicated, most of the eligible patients in this study were older adults. We have added information regarding the differences in age distribution from that in other countries and need for further research on the effects on young adults to the Discussion (lines 232-237). Reviewer #2: The study examined clinical features of COVID-19 caused by the XBB variant of SARS-CoV-2 and explored risk factors for severe disease among hospitalized patients. Thank you for reviewing our paper. We have revised our manuscript to the best of our ability according to your suggestions. Please find our responses below. [C1] The study was done in 4 tertiary care hospitals in Japan. Patients with complications related to bacterial infections were excluded. Exclusion criteria appear to be complications that one would expect to occur in severe disease, so it is not clear why those who had these outcomes were excluded. In a cohort study, exclusions are made based on factors knowable before day 1 for each patient, not on factors that occur after day 1. Here it is not explicitly stated, but one would assume day 1 for each patient to be the date of diagnosis of COVID-19. Many of the items listed as exclusion criteria would not have been knowable on that day. The authors may want to reconsider their exclusion criteria. (R1) Thank you for pointing this out. However, COVID-19 is often associated with bacterial co-infection or secondary bacterial infections, which are difficult to clearly identify. We considered that if symptoms and severity at diagnosis were obviously related to bacterial infection, it would greatly affect the evaluation of risk factors for severe COVID-19, which was the purpose of this study; therefore, we consulted with a statistics specialist before starting the study and added cases of clear bacterial infection to the exclusion criteria. We have added this intent to the limitations (lines 310-312). [C2] The authors should add how the diagnosis of COVID-19 was made. (R2) Thank you for pointing this out. Accordingly, we have added a clear description of the diagnostic criteria for COVID-19 to the revised manuscript (lines 96-100). [C3] For the purpose of this study, grouping into "mild" and "severe" disease appears to be based on whether or not patients required supplemental oxygen or ICU admission. This could be stated simply. It may be unnecessarily complicated to describe the MHLW guidelines when stating how severity was defined. (R3) Thank you for your kind suggestion. We have corrected the Methods in the abstract and main body accordingly (lines 40-41, lines 131-133). [C4] Discussion, line 201-202: It would be more correct to state that the study found an association between prior booster vaccination and lower severity of XBB-variant COVID-19 among hospitalized patients with COVID-19. This study design does not allow one to claim that the study revealed that bivalent omicron booster vaccination reduced the severity of COVID-19. (R4) Thank you for your kind suggestion. We have corrected the sentence in the abstract and main body accordingly (lines 49-50, lines 220-221). Attachments Attachment Submitted filename: Response_to_Reviewers.docx https://doi.org/10.1371/journal.pone.0309808.r002
20 Aug 2024 Decision Letter - Liling Chaw, Editor Clinical features of and severity risk factors for COVID-19 in adults during the predominance of SARS-CoV-2 XBB variants in Okinawa, Japan PONE-D-24-16162R1 Dear Dr. Miyagi, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Liling Chaw Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Nabin K. Shrestha ******** https://doi.org/10.1371/journal.pone.0309808.r003
Formally Accepted
22 Oct 2024 Acceptance Letter - Liling Chaw, Editor PONE-D-24-16162R1 PLOS ONE Dear Dr. Miyagi, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Liling Chaw Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0309808.r004

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