Comparison of long COVID, recovered COVID, and non-COVID Post-Acute Infection Syndromes over three years

Caleb R. Carr; Nicole L. Gentile; Jeanne Bertolli; Warren Szewczyk; Jin-Mann S. Lin; Elizabeth R. Unger; Quan M. Vu; Nona Sotoodehnia; Annette L. Fitzpatrick

doi:10.1371/journal.pone.0323104

Peer Review History

Original SubmissionNovember 18, 2024
18 Nov 2024 Author Response https://doi.org/10.1371/journal.pone.0323104.r001
20 Dec 2024 Decision Letter - Dong Keon Yon, Editor PONE-D-24-52642Comparison of Long COVID, Recovered COVID, and Non-COVID Post-Acute Infection Syndromes over three yearsPLOS ONE Dear Dr. Fitzpatrick, 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 03 2025 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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Additional guidance on preparing raw data for publication can be found in our Data Policy (https://journals.plos.org/plosone/s/data-availability#loc-human-research-participant-data-and-other-sensitive-data) and in the following article: http://www.bmj.com/content/340/bmj.c181.long. Please remove or anonymize all personal information (<specific identifying information in file to be removed>), ensure that the data shared are in accordance with participant consent, and re-upload a fully anonymized data set. Please note that spreadsheet columns with personal information must be removed and not hidden as all hidden columns will appear in the published file. Additional Editor Comments: Please address the excellent comments from the reviewers. [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: No 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 article is well-written, easy to read, and interesting. - For Non-COVID PAIS patients, it would be interesting to know if there is another associated infectious diagnosis (etiological or clinical) to better understand what other microorganisms might cause this post-viral syndrome. Considering there are only 106 patients, I am not sure if it would be feasible to determine whether there is a record of any infectious condition within the six months prior to the Non-COVID PAIS diagnosis. - In Table 1, it might be helpful to record only "Yes" responses to simplify the table. For non-U.S. readers, discussing race and ethnicity separately can feel unusual; perhaps these could be categorized under a single category. - I do not fully understand the extracted codes for symptoms and clinical history. When are the codes extracted, and from where? My understanding is that these codes pertain to a distinct episode of COVID/recovered/non-COVID and are not pulled from free text within the COVID/recovered/Non-COVID episode. It might be helpful to explain this in the methods section with a table: one column for the codes related to the patient’s medical history prior to the COVID/recovered/Non-COVID episode, another for the symptoms/abnormalities (e.g., pneumonia, abnormal radiological findings) recorded during the illness, and a final column for symptom codes that emerge afterward. When presenting the results, this structure should be followed. Mixing everything together makes the presentation less clear. - Figures 3 and 4 are very interesting, but the data are mixed, making them harder to interpret. Categorizing them by personal history, clinical presentation, and complications could improve clarity. For example, it is unclear whether stroke or thromboembolism occurred after the episode or if they are pre-existing conditions. I assume they are complications, but the graph does not make this clear. Reviewer #2: This study presents an interesting approach by comparing Long COVID with other post-acute infection syndromes (PAIS) to identify potential shared disease mechanisms. The findings, particularly the similarities between Long COVID and PAIS, are relevant and valuable for clinicians and researchers. However, I have several concerns about this study before publication. 1. The methods in the abstract should briefly describe the analytical techniques used in the study, such as multivariate regression or other statistical approaches used to derive results. 2. The methods in the abstract should specifically specify the total number of individuals included in the Washington University School of Medicine Electronic Health Records (EHR) database. 3. The abstract results should present the final sample size for each group (long COVID, recovered COVID, non-COVID PAIS) to clearly indicate the scale of the analysis; this information should not be left in the Methods section. 4. The definition of long-term COVID used in this study should be clarified. Because acute sequelae usually occur over a longer period of time, including data within 30 days of SARS-CoV-2 index testing seems too short to define long-term COVID. 5. The study does not mention how reinfection cases were handled. In order to accurately interpret the findings, it is important to describe whether individuals who have been infected multiple times with SARS-CoV-2 were included, excluded, or analyzed separately. 6. You should provide details on how the individual follow-up end date was determined. You should also report the mean and median of the follow-up periods for each group to clarify the temporal range of the study. 7. The definition of PAIS and its rationale should be specified accurately. The inclusion criteria of PAIS diagnostic codes should be justified to ensure the validity of the comparisons conducted in the study. 8. The definition and rationale for the analyzed results should be further explained. For example, how have heart rhythm abnormalities, cognitive and emotional symptoms, and sleep disorders been identified? The source or diagnostic criteria for these results should be clearly explained. ****** 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.0323104.r002
Revision 1
12 Feb 2025 Author Response RESPONSE TO EDITORS AND REVIEWERS’ COMMENTS: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have checked for style and formatting requirements and believe that we have followed all of them . 2. Please note that funding information should not appear in any 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. There is no funding information in the manuscript. 3. Thank you for stating the following financial disclosure: “Funding for this project was received through a contract from the Centers for Disease Control and Prevention (CDC), contract number 75D30121C10207.” Role of funders is as follows: The funder’s role was consultation on the analysis and interpretation of data, providing input on the decision to publish, and participation in the preparation of the manuscript. 4. 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. Our data have ethical restrictions for sharing as the source is from electronic health records of patients in a healthcare system. Although medical record numbers have been removed, other data including dates and locations of care are included. It may be possible to identify individuals from one or a combination of data fields. Our IRB approval through the University of Washington does not allow our sharing of these records. Should someone wish to use our data, we can accommodate requests by addressing their individual needs. Data requests may be made to: Dr. Kari Stephens Vice Chair for Research Department of Family Medicine University of Washington, Seattle WA 98195 kstephen@uw.edu 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 NA 5. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. In Methods we include our IRB approval number for a waiver of consent. 6. We note that there is identifying data in the Supporting Information file <S1_File.pdf>. Due to the inclusion of these potentially identifying data, we have removed this file from your file inventory. We are not sure why you believed our S1 supplementary file has identifying information in it as the tables only reflect groupings of ICD-10 codes used in the manuscript. We have uploaded it again and hope that you will include it for the reviewers as its omission created some confusion with one of the reviewers. Additional Editor Comments: Please address the excellent comments from the reviewers. Reviewer #1: - The article is well-written, easy to read, and interesting. We appreciate your general overview. 1) For Non-COVID PAIS patients, it would be interesting to know if there is another associated infectious diagnosis (etiological or clinical) to better understand what other microorganisms might .cause this post-viral syndrome. Considering there are only 106 patients, I am not sure if it would be feasible to determine whether there is a record of any infectious condition within the six months prior to the Non-COVID PAIS diagnosis. This is a great question and for a very few individuals, an infectious organism (e.g., influenza, infectious gastroenteritis, or tuberculosis) could be identified as a probable cause. However, for most of the patients in our study, ICD-10 codes were not included to identify microorganisms. As a result, we could not make any inferences about other organisms that cause post-infectious syndromes, and this is stated as a limitation in the discussion. 2) In Table 1, it might be helpful to record only "Yes" responses to simplify the table. For non-U.S. readers, discussing race and ethnicity separately can feel unusual; perhaps these could be categorized under a single category. We have revised Table 1 and grouped race and ethnicity together as suggested. We agree it is easier to understand. 3) I do not fully understand the extracted codes for symptoms and clinical history. When are the codes extracted, and from where? My understanding is that these codes pertain to a distinct episode of COVID/recovered/non-COVID and are not pulled from free text within the COVID/recovered/Non-COVID episode. It might be helpful to explain this in the methods section with a table: one column for the codes related to the patient’s medical history prior to the COVID/recovered/Non-COVID episode, another for the symptoms/abnormalities (e.g., pneumonia, abnormal radiological findings) recorded during the illness, and a final column for symptom codes that emerge afterward. When presenting the results, this structure should be followed. Mixing everything together makes the presentation less clear. We completely agree with this comment. In the submitted manuscript we had structured the study – and have presented results – to show the different time periods in which the ICD-codes were included in the patient record. For each individual, the codes are grouped relative to the index PCR test: prior to the test, within 30 days, and greater than 30 days. These three timeframes correspond to Figures 3, 4, and 5. We have modified text in Methods to try to make this more clear. 4) Figures 3 and 4 are very interesting, but the data are mixed, making them harder to interpret. Categorizing them by personal history, clinical presentation, and complications could improve clarity. For example, it is unclear whether stroke or thromboembolism occurred after the episode or if they are pre-existing conditions. I assume they are complications, but the graph does not make this clear. As mentioned above, Figures 3, 4, and 5 correspond to the three timeframes relative to the index PCR test: prior to the test, within 30 days, and greater than 30 days. The two different graphs in each figure represent the comparisons between the Long COVID group and the two other groups. We have tried to clarify this distinction in Methods and the Figure legends. Reviewer #2: This study presents an interesting approach by comparing Long COVID with other post-acute infection syndromes (PAIS) to identify potential shared disease mechanisms. The findings, particularly the similarities between Long COVID and PAIS, are relevant and valuable for clinicians and researchers. However, I have several concerns about this study before publication. Thank you. 1) The methods in the abstract should briefly describe the analytical techniques used in the study, such as multivariate regression or other statistical approaches used to derive results. This is a great point and we now have adjusted the abstract to describe the use of multivariate regression to analyze the different groups in the three different timeframes. 2) The methods in the abstract should specifically specify the total number of individuals included in the Washington University School of Medicine Electronic Health Records (EHR) database. We have adjusted the abstract to mention the total number (n=139,472) of individuals in the University of Washington Medicine electronic health record (EHR) database extracted for the study. 3) The abstract results should present the final sample size for each group (long COVID, recovered COVID, non-COVID PAIS) to clearly indicate the scale of the analysis; this information should not be left in the Methods section. The sample size for each group was already included in the abstract but we have tried to make it more obvious by restructuring the sentence. 4) The definition of long-term COVID used in this study should be clarified. Because acute sequelae usually occur over a longer period of time, including data within 30 days of SARS-CoV-2 index testing seems too short to define long-term COVID. We defined a probable Long COVID group from the SARS-CoV-2 PCR positive base population by selecting individuals with an ICD-10-CM diagnostic code of U09.9 (post COVID-19 condition, unspecified), B94.8 (sequelae of other specified infectious and parasitic diseases), and/or G93.3 (postviral fatigue syndrome) at least 30 days after their positive index SARS-CoV-2 PCR test. We used 30 days from the index PCR test date as the cut point to define the post-acute infection period because previous literature indicated many symptoms associated with post-COVID-19 conditions persist or begin four weeks after the initial SARS-CoV-2 infection and early Long COVID definitions used during the time of data collection utilized a four week post-infection cutoff. We acknowledge that the current definition of Long COVID has been revised to 3 months or longer post-infection (National Academy of Sciences, Engineering and Medicine 2024), however, physicians providing codes at the time these data were collected not have considered this definition. 5) The study does not mention how reinfection cases were handled. In order to accurately interpret the findings, it is important to describe whether individuals who have been infected multiple times with SARS-CoV-2 were included, excluded, or analyzed separately. The outcome in this study is defined as the first incidence of a positive SARS-COV-2 PCR test. For those with more than one positive test, the first positive was defined as the index infection. This is noted in Methods. 6) You should provide details on how the individual follow-up end date was determined. You should also report the mean and median of the follow-up periods for each group to clarify the temporal range of the study. The end date for this study was the last date a patient record was accessed (January 31, 2022) and is based on when data were downloaded from the EHR. A new row to Table 1 has been added that shows the median and interquartile range in days for the follow-up time for each group. An image of the new row is pasted below. 7) The definition of PAIS and its rationale should be specified accurately. The inclusion criteria of PAIS diagnostic codes should be justified to ensure the validity of the comparisons conducted in the study. We defined PAIS based on ICD-10 codes found in patient records. Our definitions, included in the text, are as follows: Long COVID group definition from text: A probable Long COVID group was extracted from the SARS-CoV-2 PCR positive base population by selecting individuals with an ICD-10-CM diagnostic code of U09.9 (post COVID-19 condition, unspecified), B94.8 (sequelae of other specified infectious and parasitic diseases), and/or G93.3 (postviral fatigue syndrome) at least 30 days after their positive index SARS-CoV-2 PCR test. Because the U09.9 code was not introduced until October 1st, 2021, patients who received a U07.1 (COVID-19) code through September 30, 2021, at a healthcare encounter both prior to and 30 days after their positive index PCR test were included in this Long COVID group (n=580) (Fig 1). These ICD-10-CM codes were selected based on the recommendations of clinicians working in a Long COVID clinic at the University of Washington. Non-COVID PAIS group definition from text: A third group was identified from the SARS-CoV-2-PCR negative group who had no indication of COVID-19 but had a post infectious syndrome ICD-10-CM code (B94.8, sequelae of other specified infectious and parasitic diseases; G93.3: postviral fatigue syndrome) (n=106, Fig 1). No indication of COVID-19 was defined by having only negative PCR tests on record and no COVID-19-associated ICD-10-CM codes (U07.1: COVID-19; Z86.16: personal history of COVID-19; J12.82: pneumonia due to coronavirus disease 2019; U09.9: post COVID-19 condition, unspecified; B97.21: SARS-associated coronavirus as the cause of diseases classified elsewhere; B97.29: other coronavirus as the cause of diseases classified elsewhere; B34.2: coronavirus infection, unspecified). 8) The definition and rationale for the analyzed results should be further explained. For example, how have heart rhythm abnormalities, cognitive and emotional symptoms, and sleep disorders been identified? The source or diagnostic criteria for these results should be clearly explained. We have included a supplement to the manuscript that provides all ICD-10 codes used in our definitions. We hope this will provide sufficient details on categories used in the paper. Attachments Attachment Submitted filename: Response to Reviewers_Carr_PONE-D-24-52642.docx https://doi.org/10.1371/journal.pone.0323104.r003
20 Mar 2025 Decision Letter - Dong Keon Yon, Editor PONE-D-24-52642R1Comparison of Long COVID, Recovered COVID, and Non-COVID Post-Acute Infection Syndromes over three yearsPLOS ONE Dear Dr. Fitzpatrick, 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 04 2025 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, Dong Keon Yon, MD, FACAAI, FAAAAI 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. Additional Editor Comments: This is an excellent paper. Finally, please see my comments. #1. Long COVID -> long COVID #2. Recovered COVID patients -> "r"ecovered patients with COVID-19 - Please use the patient-first language. #3. Non-COVID -> "n"on-COVID #4. Charlson Comorbidity Index -> Charlson comorbidity index #5. In data section, the authors describe " smoking exposure (current, former, none", but in Table 1, yes or no. #6. Likewise, many of the organ systems affected by the symptoms and diagnoses identified in the period >30 days following the index SARS-CoV-2 test, such as cardiovascular [#1], neurologic [#2], and musculoskeletal [#3], have been well documented to be associated with Long COVID [3, 32, 33] Please add the top-tier paper reference. [1-3] [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thanks to the authors for their work and for addressing all my concerns. I believe the article should be accepted. ****** 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.0323104.r004
Revision 2
31 Mar 2025 Author Response 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. The reference list has been checked for completion and correctness. The only change was the addition of three references in relation to point #6 below. Additional Editor Comments: This is an excellent paper. Finally, please see my comments. #1. Long COVID -> long COVID This change has been implemented throughout the text and figures. #2. Recovered COVID patients -> "r"ecovered patients with COVID-19 - Please use the patient-first language. This change has been implemented throughout the text and figures. #3. Non-COVID -> "n"on-COVID This change has been implemented throughout the text and figures. #4. Charlson Comorbidity Index -> Charlson comorbidity index This change has been implemented throughout the text and figures. #5. In data section, the authors describe " smoking exposure (current, former, none", but in Table 1, yes or no. Current and former smokers were grouped as yes for smoking exposure, while “none” smokers were marked as no. The text in the data section has been modified to clearly state this classification #6. Likewise, many of the organ systems affected by the symptoms and diagnoses identified in the period >30 days following the index SARS-CoV-2 test, such as cardiovascular [#1], neurologic [#2], and musculoskeletal [#3], have been well documented to be associated with Long COVID [3, 32, 33] Please add the top-tier paper reference. [1-3] The text and references have been modified to include references specifically for cardiovascular, neurologic, and musculoskeletal related issues, which are referenced in the manner specified above. Attachments Attachment Submitted filename: Response to Reviewers_PLOS_One_Final.docx https://doi.org/10.1371/journal.pone.0323104.r005
2 Apr 2025 Decision Letter - Dong Keon Yon, Editor Comparison of Long COVID, Recovered COVID, and Non-COVID Post-Acute Infection Syndromes over three years PONE-D-24-52642R2 Dear Dr. Fitzpatrick, 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, Dong Keon Yon, MD, FACAAI, FAAAAI Academic Editor PLOS ONE Additional Editor Comments (optional): This is an excellent paper. Reviewers' comments: https://doi.org/10.1371/journal.pone.0323104.r006
Formally Accepted
Acceptance Letter - Dong Keon Yon, Editor PONE-D-24-52642R2 PLOS ONE Dear Dr. Fitzpatrick, 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 You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days 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. Dong Keon Yon Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0323104.r007

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