Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK

Amanda T. Goodwin; Jonathan S. Thompson; Ian P. Hall

doi:10.1371/journal.pone.0281915

Peer Review History

Original SubmissionJuly 18, 2022
8 Nov 2022 Decision Letter - Seung-Hwa Lee, Editor PONE-D-22-19820Evaluation of outpatient treatment for non-hospitalised patients with COVID-19 in the UKPLOS ONE Dear Dr. Amanda T Goodwin, 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 2022-10-27. 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, Seung-Hwa Lee 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. You indicated that ethical approval was not necessary for your study. We understand that the framework for ethical oversight requirements for studies of this type may differ depending on the setting and we would appreciate some further clarification regarding your research. Could you please provide confirmation from your institutional review board or research ethics committee (e.g., in the form of a letter or email correspondence) that ethics review was not necessary for this study? Please include a copy of the correspondence as an "Other" file. 3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. 4. Thank you for stating the following in the Funding Section of your manuscript: “ATG holds an NIHR-funded Academic Clinical Lecturer post. IPH holds an NIHR Senior Investigator Award.” We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “ATG holds an NIHR-funded Academic Clinical Lecturer post. IPH holds an NIHR Senior Investigator Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. Thank you for stating the following in the Competing Interests section: “ATG and JST - None to declare IPH has a funded research collaboration with Boehringer Ingelheim (unrelated to the topic of this paper)” Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. 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. [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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 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: The current issue of the benefits from antivirals and nMAbs against SARS CoV-2 is extensively treated in this manuscripts, no final conclusions can be drawn due to the many limitations and caveats of the study correctly considered by the authors. What is striking is that, despite the large amount of patients potentially eligible, only for 1 third of them an assessment for treatment was done. This very low rate of suitable patients for assessment uncovers criticisms on referral pathway. This point has been underlined by the authors but some points need to be clarified: as for M&M it could be useful to clarify in the last paragraph of "Study design"if the process is computerized, if being within a high risk group is an information currently available for all the patients or physicians have to retrive this info case-by-case and which is the timing for registration/transfer of info to CMDU and so on. Finally, due to the poor external validity of these results I suggeste to modify the title in this way: "Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: a mono-institutional experience in UK" Reviewer #2: This is a retrospective review of UK experience of treating high risk immunosuppressed individuals with sotrovimab or molnupiravir for COVID-19. The experience is from December 2021 to Feb 2022 and so looks at the impact of Omicron BA1. At this time the majority were dual or better vaccinated. The criteria are based on UK guidelines for these agents and are already quite restrictive to people with high order immunosuppression. This is important data, as most governments have embraced the use of these agents in their vaccinated populations despite no evidence of efficacy or cost effectiveness. Both mortality and hospitalisation were rare and the analysis is probably under powered to detect a difference. Impact is also lessened by the change in variants and the fact that Sotrovimab is likely no longer effect with current variants, in addition Paxlovid with probably better efficacy would be a more valuable intervention to assess, but this is out of the control of the authors and the data still has value. Major points: 1. The 2 most important points, the first could be highlighted more is that resolving symptoms is an exclusion criteria. 266 were excluded with resolving symptoms, given the subjective nature of this, 2 deaths in the resolving symptoms group, and 15 admissions at d28 for COVID suggests this should not be an exclusion criteria for treatment. This could be made clearer. 2. The fact that those from more deprived backgrounds are also less likely to receive treatment is important but well highlighted. Can the authors give any further insight why? 3. Admission at d28 was 3% in untreated vs 1.2% in treated with an OR 0.4 (95%CI 0.12 to 1.36). Can the authors calculate/estimate the sample size they would need to see an effect with this event rate? 4. Table 2 in vaccination status, would be helpful to add categories for more than x2 and more than x3 vaccinations with percentages. ****** 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: Peter AB Wark ******** [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.0281915.r001
Revision 1
15 Dec 2022 Author Response Many thanks for your feedback on our manuscript. Please find attached a revised manuscript addressing each of the reviewer and editor comments, and details of how we have responded to these comments below. Journal Requirements: 1) We have reformatted our manuscript to meet PLOS ONE’s style requirements 2) We have uploaded correspondence from the research governance team in the Research and Innovation department of Nottingham University Hospitals confirming that ethical review was not required for this work. 3) The “funding information” section on the submission portal has been updated with award numbers. Please could the funding statement be recorded as below: “ATG holds an NIHR-funded Academic Clinical Lecturer post. IPH holds an NIHR Senior Investigator Award (award number NF-SI-0617-10096). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Please note, the ACL post held by ATG is not associated with an award number, therefore this is not stated. 4) The “funding information” section of the manuscript has been removed 5) The “competing interests” section has been updated to confirm that our declarations of interest do not alter our adherence to PLOS ONE policies on sharing data and materials. This statement should now read as below: “Competing interests: ATG and JST - None to declare. IPH has a funded research collaboration with Boehringer Ingelheim (unrelated to the topic of this paper). This does not alter our adherence to PLOS ONE policies on sharing data and materials.” 6) We have reviewed the reference list, which is complete and correct. Reference 1 has been edited slightly to ensure that the reported number of COVID-19 related deaths is up to date (edited from 6.2 to 6.6 million deaths worldwide in the opening paragraph of the introduction). The URLs in references 8, 10, and 15 (original numbers) have been updated and we confirm that these led to the correct information on 1st December 2022. References 11-13 (original numbers) have been updated with the full citations (i.e. page numbers); this information was unavailable at the time of the original submission. We have also added an additional reference to address Reviewer 2’s comment on the deprivation data. Reviewer comments Reviewer 1 1) Reviewer comment: “ This very low rate of suitable patients for assessment uncovers criticisms on referral pathway. This point has been underlined by the authors but some points need to be clarified: as for M&M it could be useful to clarify in the last paragraph of "Study design" if the process is computerized, if being within a high risk group is an information currently available for all the patients or physicians have to retrive this info case-by-case and which is the timing for registration/transfer of info to CMDU and so on” Response: We agree that our study reveals inefficiencies in the referral pathway to CMDU. We have added more detail about the CMDU referral pathways to the “study design” section of the revised manuscript. Additions have also been made to the first paragraph of the discussion to expand upon possible reasons for the inefficiencies that we observed. 2) Reviewer comment: “Finally, due to the poor external validity of these results I suggest to modify the title in this way: "Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: a mono-institutional experience in UK"” Response: We agree with this comment, and have edited our title to “Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK”. We have opted to call this a “regional” study rather than mono-institutional, as our CMDU covers a large region of mid- and south Nottinghamshire in the UK, which encompasses areas covered by several different NHS hospital trusts. Reviewer 2 1) Reviewer comment: “Resolving symptoms is an exclusion criteria. 266 were excluded with resolving symptoms, given the subjective nature of this, 2 deaths in the resolving symptoms group, and 15 admissions at d28 for COVID suggests this should not be an exclusion criteria for treatment. This could be made clearer” Response: Thank you for this comment. We have added a section to the discussion (3rd paragraph of discussion) to address this. We have referred to the 7 covid-related hospital attendances rather than the 15 hospital admissions within 28 days, as some of these admissions were deemed to be unrelated to Covid-19. 2) Reviewer comment: “The fact that those from more deprived backgrounds are also less likely to receive treatment is important but well highlighted. Can the authors give any further insight why?” Response: Unfortunately, the reasons that patients gave for declining treatment were not frequently recorded, and thus we could not analyse this in more detail. We suspect that patients from more deprived backgrounds are less likely to be able to attend for a sotrovimab infusion (for example time off work or childcare), are more reluctant to travel for treatment, or they may be more likely to minimise their symptoms and decline treatment. Furthermore, patients from more deprived backgrounds may be less trusting of and therefore less willing to accept these relatively new treatments. The reasons behind inequitable access to treatment are an important area of further research, and the Nuffield Trust has reported that patients from areas of greater deprivation are more likely to receive poorer quality care across a range of healthcare services (Scobie S, Morris J. Quality and inequality: digging deeper. Nuffield Trust and the Health Foundation. 2020. https://www.nuffieldtrust.org.uk/public/files/2020-01/quality_inequality.) We have edited paragraph 6 of the discussion to emphasise this further, and added the reference to the study by Scobie et al. 3) Reviewer comment: “Admission at d28 was 3% in untreated vs 1.2% in treated with an OR 0.4 (95%CI 0.12 to 1.36). Can the authors calculate/estimate the sample size they would need to see an effect with this event rate?” Response: Many thanks for this suggestion. On our power calculations, we estimate that, assuming equal matching in the groups and power set at 80%, the required number of subjects to detect a significant difference in outcome based on the event rates we observed would be 1990. We have added this to the manuscript discussion. 4) “Table 2 in vaccination status, would be helpful to add categories for more than x2 and more than x3 vaccinations with percentages” We have edited Table 2 to include the percentages of patients who had received 1, 2, 3, or 4 doses of a Covid-19 vaccination, and separate section for those that received two doses or less / 3 doses or more of a Covid-19 vaccination. Many thanks for your continued consideration of our manuscript for publication. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0281915.r002
5 Jan 2023 Decision Letter - Seung-Hwa Lee, Editor PONE-D-22-19820R1Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UKPLOS ONE Dear Dr. Amanda T Goodwin 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 Feb 10 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, Seung-Hwa Lee 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. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Here is response from Reviewer 1 The current issue of the benefits from antivirals and nMAbs against SARS CoV-2 is extensively treated in this manuscripts, no final conclusions can be drawn due to the many limitations and caveats of the study correctly considered by the authors. What is striking is that, despite the large amount of patients potentially eligible, only for 1 third of them an assessment for treatment was done. This very low rate of suitable patients for assessment uncovers criticisms on referral pathway. This point has been underlined by the authors but some points need to be clarified: as for M&M it could be useful to clarify in the last paragraph of "Study design"if the process is computerized, if being within a high risk group is an information currently available for all the patients or physicians have to retrive this info case-by-case and which is the timing for registration/transfer of info to CMDU and so on. Finally, due to the poor external validity of these results I suggeste to modify the title in this way: "Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: a mono-institutional experience in UK" and Review 2 This is a retrospective review of UK experience of treating high risk immunosuppressed individuals with sotrovimab or molnupiravir for COVID-19. The experience is from December 2021 to Feb 2022 and so looks at the impact of Omicron BA1. At this time the majority were dual or better vaccinated. The criteria are based on UK guidelines for these agents and are already quite restrictive to people with high order immunosuppression. This is important data, as most governments have embraced the use of these agents in their vaccinated populations despite no evidence of efficacy or cost effectiveness. Both mortality and hospitalisation were rare and the analysis is probably under powered to detect a difference. Impact is also lessened by the change in variants and the fact that Sotrovimab is likely no longer effect with current variants, in addition Paxlovid with probably better efficacy would be a more valuable intervention to assess, but this is out of the control of the authors and the data still has value. Major points: 1. The 2 most important points, the first could be highlighted more is that resolving symptoms is an exclusion criteria. 266 were excluded with resolving symptoms, given the subjective nature of this, 2 deaths in the resolving symptoms group, and 15 admissions at d28 for COVID suggests this should not be an exclusion criteria for treatment. This could be made clearer. 2. The fact that those from more deprived backgrounds are also less likely to receive treatment is important but well highlighted. Can the authors give any further insight why? 3. Admission at d28 was 3% in untreated vs 1.2% in treated with an OR 0.4 (95%CI 0.12 to 1.36). Can the authors calculate/estimate the sample size they would need to see an effect with this event rate? 4. Table 2 in vaccination status, would be helpful to add categories for more than x2 and more than x3 vaccinations with percentages. [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.0281915.r003
Revision 2
10 Jan 2023 Author Response Dear Dr Lee and the editorial board of PLOS-ONE, Many thanks for your feedback on our manuscript. Please find attached a revised manuscript addressing each of the reviewer and editor comments, and details of how we have responded to these comments below. Journal Requirements: 1) We have reformatted our manuscript to meet PLOS ONE’s style requirements 2) We have uploaded correspondence from the research governance team in the Research and Innovation department of Nottingham University Hospitals confirming that ethical review was not required for this work. 3) The “funding information” section on the submission portal has been updated with award numbers. Please could the funding statement be recorded as below: “ATG holds an NIHR-funded Academic Clinical Lecturer post (CL-2020-12-003). IPH holds an NIHR Senior Investigator Award (award number NF-SI-0617-10096). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” 4) The “funding information” section of the manuscript has been removed 5) The “competing interests” section has been updated to confirm that our declarations of interest do not alter our adherence to PLOS ONE policies on sharing data and materials. This statement should now read as below: “Competing interests: ATG and JST - None to declare. IPH has a funded research collaboration with Boehringer Ingelheim (unrelated to the topic of this paper). This does not alter our adherence to PLOS ONE policies on sharing data and materials.” 6) We have reviewed the reference list, which is complete and correct, and does not contain any retracted papers. Reference 1 has been edited slightly to ensure that the reported number of COVID-19 related deaths is up to date (edited from 6.2 to 6.6 million deaths worldwide in the opening paragraph of the introduction). The URLs in references 8, 10, and 15 (original numbers) have been updated and we confirm that these led to the correct information on 1st December 2022. References 11-13 (original numbers) have been updated with the full citations (i.e. page numbers); this information was unavailable at the time of the original submission. We have also added an additional reference to address Reviewer 2’s comment on the deprivation data. Reviewer comments Reviewer 1 1) Reviewer comment: “ This very low rate of suitable patients for assessment uncovers criticisms on referral pathway. This point has been underlined by the authors but some points need to be clarified: as for M&M it could be useful to clarify in the last paragraph of "Study design" if the process is computerized, if being within a high risk group is an information currently available for all the patients or physicians have to retrive this info case-by-case and which is the timing for registration/transfer of info to CMDU and so on” Response: We agree that our study reveals inefficiencies in the referral pathway to CMDU. We have added more detail about the CMDU referral pathways to the “study design” section of the revised manuscript. Additions have also been made to the first paragraph of the discussion to expand upon possible reasons for the inefficiencies that we observed. 2) Reviewer comment: “Finally, due to the poor external validity of these results I suggest to modify the title in this way: "Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: a mono-institutional experience in UK"” Response: We agree with this comment, and have edited our title to “Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK”. We have opted to call this a “regional” study rather than mono-institutional, as our CMDU covers a large region of mid- and south Nottinghamshire in the UK, which encompasses areas covered by several different NHS hospital trusts. Reviewer 2 1) Reviewer comment: “Resolving symptoms is an exclusion criteria. 266 were excluded with resolving symptoms, given the subjective nature of this, 2 deaths in the resolving symptoms group, and 15 admissions at d28 for COVID suggests this should not be an exclusion criteria for treatment. This could be made clearer” Response: Thank you for this comment. We have added a section to the discussion (3rd paragraph of discussion) to address this. We have referred to the 7 covid-related hospital attendances rather than the 15 hospital admissions within 28 days, as some of these admissions were deemed to be unrelated to Covid-19. 2) Reviewer comment: “The fact that those from more deprived backgrounds are also less likely to receive treatment is important but well highlighted. Can the authors give any further insight why?” Response: Unfortunately, the reasons that patients gave for declining treatment were not frequently recorded, and thus we could not analyse this in more detail. We suspect that patients from more deprived backgrounds are less likely to be able to attend for a sotrovimab infusion (for example time off work or childcare), are more reluctant to travel for treatment, or they may be more likely to minimise their symptoms and decline treatment. Furthermore, patients from more deprived backgrounds may be less trusting of and therefore less willing to accept these relatively new treatments. The reasons behind inequitable access to treatment are an important area of further research, and the Nuffield Trust has reported that patients from areas of greater deprivation are more likely to receive poorer quality care across a range of healthcare services (Scobie S, Morris J. Quality and inequality: digging deeper. Nuffield Trust and the Health Foundation. 2020. https://www.nuffieldtrust.org.uk/public/files/2020-01/quality_inequality.) We have edited paragraph 6 of the discussion to emphasise this further, and added the reference to the study by Scobie et al. 3) Reviewer comment: “Admission at d28 was 3% in untreated vs 1.2% in treated with an OR 0.4 (95%CI 0.12 to 1.36). Can the authors calculate/estimate the sample size they would need to see an effect with this event rate?” Response: Many thanks for this suggestion. On our power calculations, we estimate that, assuming equal matching in the groups and power set at 80%, the required number of subjects to detect a significant difference in outcome based on the event rates we observed would be 1990. We have added this to the manuscript discussion. 4) “Table 2 in vaccination status, would be helpful to add categories for more than x2 and more than x3 vaccinations with percentages” We have edited Table 2 to include the percentages of patients who had received 1, 2, 3, or 4 doses of a Covid-19 vaccination, and separate section for those that received two doses or less / 3 doses or more of a Covid-19 vaccination. Many thanks for your continued consideration of our manuscript for publication. Dr Amanda Goodwin Dr Jonathan Thompson Professor Ian Hall Attachments Attachment Submitted filename: Response to reviewers Jan 23.docx https://doi.org/10.1371/journal.pone.0281915.r004
5 Feb 2023 Decision Letter - Seung-Hwa Lee, Editor Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK PONE-D-22-19820R2 Dear Dr. Amanda T Goodwin, 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, Seung-Hwa Lee Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0281915.r005
Formally Accepted
14 Feb 2023 Acceptance Letter - Seung-Hwa Lee, Editor PONE-D-22-19820R2 Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK Dear Dr. Goodwin: 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. Seung-Hwa Lee Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281915.r006

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