Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients

Hitoshi Kawasuji; Yusuke Takegoshi; Makito Kaneda; Akitoshi Ueno; Yuki Miyajima; Koyomi Kawago; Yasutaka Fukui; Yoshihiro Yoshida; Miyuki Kimura; Hiroshi Yamada; Ippei Sakamaki; Hideki Tani; Yoshitomo Morinaga; Yoshihiro Yamamoto

doi:10.1371/journal.pone.0243597

Peer Review History

Original SubmissionJune 30, 2020
10 Aug 2020 Decision Letter - Xi Pan, Editor PONE-D-20-20259 Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients PLOS 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. Specifically, please address the following areas. 1) Introduction: Define secondary transmission and clarify its importance to the topic (COVID-19). Clarify your research question and hypothesis. Clarify nasopharyngeal viral load and be consistent with the term through the manuscript. 2) Method: Clarify the case-control matching process (details are needed such as how the cases were matched with controls) and a graph of matching is needed. 3)Discussion: Discuss the implementation of findings of the study in Epidemiology and Public Health. Please submit your revised manuscript by Sep 24 2020 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'. 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Kind regards, Xi Pan Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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. Please include additional information regarding the telephone interview guide used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed the telephone questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. 3. Please include the date(s) on which you accessed the databases or records to obtain the data used in your study. [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 ******** 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? 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 ****** 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 ****** 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: The article is well written and the information provided is of relevance in the present scenario of the pandemic. The study design is also suitable and the statistical analysis performed is also accurate. However, it is advised that the potential confounding factors are clearly mentioned in the methods section. The introduction can be further strengthened by using the following references and also be utilized in the discussion component: Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance. 2020 Mar 12;25(10):2000180. Kim GU, Kim MJ, Ra SH, Lee J, Bae S, Jung J, Kim SH. Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19. Clinical Microbiology and Infection. 2020 May 1. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M. Presumed asymptomatic carrier transmission of COVID-19. Jama. 2020 Apr 14;323(14):1406-7. ****** 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". 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.0243597.r001
Revision 1
9 Oct 2020 Author Response Editor (Comments for the Author): Specific Comments: 1) Introduction: Define secondary transmission and clarify its importance to the topic (COVID-19). Clarify your research question and hypothesis. Clarify nasopharyngeal viral load and be consistent with the term through the manuscript. Response: We added the following sentence as suggested in the introduction section: “The unknown epidemiologic characteristics and transmission dynamics of a novel pathogen, such as SARS-CoV-2, complicate the development and evaluation of effective control policies. In a few recent contact-tracing studies, secondary transmissions were investigated because it gives invaluable clues about transmission dynamics that are more typical [1,2]. Secondary transmission was defined as the transmission of SARS-CoV-2 from an infected person (source patient) to a secondary patient as ascertained by exposure and symptom onset dates, with no evidence that the secondary patient had been exposed to anyone else with COVID-19. A few preliminary contact-tracing studies showed that the highest-risk exposure setting of COVID-19 transmission was the household [2]. Nevertheless, it is not known when and how long a patient with COVID-19 should be isolated or whether close contacts should be quarantined. Additional information is needed about the transmission risk.” (Lines 52-63 in the Manuscript, Lines 52-63 in the Revised Manuscript with Track Changes). “In addition, viral load can be associated with infectiousness, especially in the acute phase of COVID-19. However, little information is available on the relationship between SARS-CoV-2 nasopharyngeal viral load in nasopharyngeal swab specimens (nasopharyngeal viral load), which are usually obtained for serial viral load monitoring, and secondary transmission. We hypothesized that high nasopharyngeal viral loads contribute to secondary transmission of COVID-19 and viral loads may be higher among cases who transmit to others compared to cases who do not transmit to others. In this study, we reviewed patients with COVID-19, including family clusters, and conducted follow-up interviews to investigate the relationship between viral load and secondary infection.” (Lines 77-85 in the Manuscript, Lines 77-85 in the Revised Manuscript with Track Changes). 2) Method: Clarify the case-control matching process (details are needed such as how the cases were matched with controls) and a graph of matching is needed. Response: Although all immunocompetent patients who were admitted to and/or from whom viral loads were measured at Toyama University Hospital from April 13 to May 7, 2020 were included in the present study, it was difficult to use matched case-control design due to the small number of patients. Nevertheless, there was no significantly difference in patients’ demographics and clinical presentation between the index and non-index symptomatic patients. We added the following sentence: “Also, we could not perform case-control matching due to the small number of patients.” (Lines 213-214 in the Manuscript, Lines 213-214 in the Revised Manuscript with Track Changes). 3) Discussion: Discuss the implementation of findings of the study in Epidemiology and Public Health. Response: We added the following sentence as suggested: “During the COVID-19 pandemic, better understanding of the relationship between viral load and secondary transmission is important for the development and evaluation of effective control policies. Although it is not known when and how long a patient with COVID-19 should be isolated or whether close contacts should be quarantined, our results suggested that viral load may help the decision to when to discharge isolation, how wide the range of close-contact tracing is needed in individual patients.” (Lines 221-226 in the Manuscript, Lines 221-226 in the Revised Manuscript with Track Changes). Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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. Please include additional information regarding the telephone interview guide used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed the telephone interview questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. Response: We added telephone interview questionnaire in both English and the original language as Supporting Information (S1 Appendix and S2 Appendix). We added the following sentence: “For each patient, the following data were retrieved from medical charts and structured telephone interview sheets (S1 Appendix and S2 Appendix): demographics, clinical presentation, date of symptom onset, exposure history in the 14 days before symptom onset, date of initial sample collection, need for supplemental oxygen (moderate) and/or mechanical ventilation (severe), and dates of the first negative RT-qPCR test result and hospital discharge.” (Lines 103-107 in the Manuscript, Lines 103-107 in the Revised Manuscript with Track Changes). “Supporting Information S1 Appendix. The telephone interview questionnaire in English. S2 Appendix. The telephone interview questionnaire in the original language.” (Lines 234-236 in the Manuscript, Lines 234-236 in the Revised Manuscript with Track Changes). 3. Please include the date(s) on which you accessed the databases or records to obtain the data used in your study. Response: We added the following sentence: “Epidemiological and clinical data were obtained from immunocompetent laboratory-confirmed patients with COVID-19 who were admitted to and/or from whom viral loads were measured at Toyama University Hospital from April 13 to May 7, 2020.” (Lines 88-90 in the Manuscript, Lines 88-90 in the Revised Manuscript with Track Changes). “We conducted the structured telephone interviews and accessed the medical records from May 18-22, 2020 to obtain the data used in the present study.” (Lines 110-111 in the Manuscript, Lines 110-111 in the Revised Manuscript with Track Changes). Reviewer #1 (Comments for the Author): The article is well written and the information provided is of relevance in the present scenario of the pandemic. The study design is also suitable and the statistical analysis performed is also accurate. However, it is advised that the potential confounding factors are clearly mentioned in the methods section. Response: We agree with the reviewer’s comment. We added the following sentence: “The potential confounding factors which may have modified the observed viral load, such as received treatment including combinations of antivirals and antibiotics, have not been systematically investigated.” (Lines 108-110 in the Manuscript, Lines 108-110 in the Revised Manuscript with Track Changes). The introduction can be further strengthened by using the following references and also be utilized in the discussion component: Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance. 2020 Mar 12;25(10):2000180. Kim GU, Kim MJ, Ra SH, Lee J, Bae S, Jung J, Kim SH. Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19. Clinical Microbiology and Infection. 2020 May 1. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M. Presumed asymptomatic carrier transmission of COVID-19. Jama. 2020 Apr 14;323(14):1406-7. Response: We agree with the reviewer’s comment. We added the following sentences in the introduction and discussion sections: “In addition, some case reports and modeling studies suggest asymptomatic carriage of SARS-CoV-2 plays a role in transmission [3]. Studies have shown that 17.9-19.2% of SARS-CoV-2 infections are asymptomatic [4,5], which poses tremendous infection control challenges.” (Lines 64-66 in the Manuscript, Lines 64-66 in the Revised Manuscript with Track Changes). “However, a recent study reported that persons with asymptomatic infections appeared to be less effective in transmitting the virus [1]. Although viral load levels at the initial sample collection may not have been directly comparable between symptomatic and asymptomatic patients because the data collection period may differ, our result may partially explain the difference of secondary attack rate of COVID-19 between in symptomatic patients and asymptomatic patients. However, this finding should not discourage isolation and surveillance efforts.” (Lines 195-201 in the Manuscript, Lines 195-201 in the Revised Manuscript with Track Changes). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0243597.r002
25 Nov 2020 Decision Letter - Xi Pan, Editor Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients PONE-D-20-20259R1 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, Xi Pan Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for addressing all the comments that were previously highlighted in the detailed review. The manuscript is now suitable for publication. ****** 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.0243597.r003
Formally Accepted
1 Dec 2020 Acceptance Letter - Xi Pan, Editor PONE-D-20-20259R1 Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients 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. Xi Pan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243597.r004

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