Care for post-COVID-19 condition in Germany from the perspectives of patients, informal caregivers and general practitioners: Study protocol for a mixed methods study

Melanie Brinkmann; Maike Stolz; Annika Herr; Christoph Herrmann-Lingen; Imke Koch; Christiane Müller; Frank Müller; Uta Sekanina; Jona Theodor Stahmeyer; Martina de Zwaan; Christian Krauth; Nils Schneider

doi:10.1371/journal.pone.0316335

Peer Review History

Original SubmissionMay 3, 2024
30 Jul 2024 Decision Letter - Vanessa Carels, Editor PONE-D-24-12578Care for post-COVID-19 condition in Germany from the perspectives of patients, informal caregivers and general practitioners: Study protocol for a mixed methods studyPLOS ONE Dear Dr. Stolz, 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 note that we have only been able to secure a single reviewer to assess your manuscript. We are issuing a decision on your manuscript at this point to prevent further delays in the evaluation of your manuscript. Please be aware that the editor who handles your revised manuscript might find it necessary to invite additional reviewers to assess this work once the revised manuscript is submitted. 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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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Partly ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Partly ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: No ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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: No ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Two general comments; How FS fit in with the PCS needs to be better described. All surveys and interview schedules should be provided as appendices. Abstract: The comment about “fatigue syndrome is one of the most common symptoms of PCC” appears a bit ‘random’ in the abstract since the following sentence is about PCC more broadly. I would recommended either adding more context – e.g., tell the reader you’re paying particular attention to fatigue syndrome. Or remove it from the abstract. Methods: the tense of this section needs to be changed to future since it’s a protocol. E..g, Informal caregivers perspective will be collected rather than informal caregivers perspective is collected” What is AOK? It is unlcear what these two surveys are. It appears as though you are describing two cohorts of participants rather than actual surveys. This should be clarified. What does the GP online survey evaluate/collect? There is no information on what is collected in the survey data therefore it’s unclear if descriptive analysis is appropriate. Who are the “experts” involved in the workshops. Introduction: Line 73: It is very important that “fatigue syndrome (FS)” be carefully defined. The authors should include what syndrome they are describing here. For review see: Sandler CX, Wyller VBB, Moss-Morris R, Buchwald D, Crawley E, Hautvast J, Katz BZ, Knoop H, Little P, Taylor R, Wensaas KA, Lloyd AR. Long COVID and Post-infective Fatigue Syndrome: A Review. Open Forum Infect Dis. 2021 Sep 9;8(10):ofab440. doi: 10.1093/ofid/ofab440. PMID: 34631916; PMCID: PMC8496765. What is meant by “claims data” (line 108). Is this private health insurance claim. Please note the reader may not be familiar with the German health care system and may require some background information to understand the context. It may be helpful to provide some context for Lower Saxony and how this area of Germany is different/similar to the rest of the country. Highlighting this may provide a stronger rationale for the benefits of this study. (note, I have made this comment in the discussion section too). Objectives: This is the first time the reader has understood PCC to be different to FS. The authors should clarify this. Wouldn’t there be people who have “both” Why is only the perspective of GPs included. What about other specialist e.g., ID physicians, respiratory physicians etc, nurses What is mean by complementary and alternative services? Do you mean complimentary services? How will you assess if there are regional differences if you don’t assess any other region? Informal caregivers should be defined. What’s the difference between formal and informal. And why wouldn’t you include formal? Line 138 – how can GPs “rate the health care of individuals? Are you referring to the quality of health care AVAILABLE to individuals? Methods: Line 150: Figure 1 is very difficult to read – this needs to be improved. Claims data needs to be defined. AOK needs to be defined Line 164 – change to “will be “ conducted Line 167 – how will the reliability of the PCC diagnosis be assessed. As the authors stated in the introduction – the PCC diagnosis requires careful medical and psychiatric investigation. Is there data available to demonstrate this has happened. Will all patient have confirmed COVID-19? What definition of PCC will be used? It would be helpful to reader to have this included in the text Regarding the second online survey – if they have not been diagnosed with PCC or there is only self-selection of COVID-19 – what is the benefit of including them? The biases related to this cohort should be described. One suggestion would be to give each of these survey’s a name (e.g., AOK survey for survey 1 and public survey for survey 2) to help the reader identify the difference in cohorts. Line 193: could the authors include the details of the in-house demographic questions collected. E.g. similar to table 1 so the reader has a full access to the survey. Alternatively the survey could be provided as an appendix. I want to congratulate the authors on selecting well-validated and relevant questionnaires. What are the potential bias by selecting those insured by AOK only? Line 199 – how long is it anticipated the survey will take. This information should be included in the methods. Line 203: what does psychosomatic counselling at Hannover Medical School (MHH) involve and why is it important for participants to be offered this? Line 206 – how is group 3 different to group 1? The authors should consider adding subheadings to the methods to help the reader understand the groups and methods used. The semi-structured interview scheduled should be made available as an appendix. Same for the care givers. What are the criteria for the GPs? Do they need to have an interest/speciality in PCS? How was the sample size of the GP focus groups determined? Data analysis: How will “formally affected” individuals be defined? Is this self-nominated? Is it based on level of function or work status? This detail should also be added to the methods. What is the sample size of the workshop? What will be the outcome? Discussion: The authors should include some detail on although this study is conducted in a specific area of Germany – how can it inform the wider literature. It may also be helpful to provide some context for Lower Saxony and how this area of Germany is different/similar to the rest of the country. Highlighting this may provide a stronger rationale for the benefits of this study. ****** 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.0316335.r001
Revision 1
10 Sep 2024 Author Response Dear editor, We would like to thank the reviewer for the useful comments. Please find below our answers to the comments of the reviewer and journal requirements. We have revised our manuscript accordingly. Kind regards, Maike Stolz, on behalf of all authors. 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 We have reviewed the requirements and made appropriate adjustments. 2. Thank you for stating the following in the Competing Interests section: “CH-L has received a lecture honorarium from Novartis and royalties from Hogrefe Publishers for the German version of the Hospital Anxiety and Depression Scale. His research is supported by grants from the German Ministry of Education and Research, the German Research Foundation and the European Commission. The other authors declare that they have no competing interests.” 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." We have added the corresponding sentence. 3. In the online submission form, you indicated that [The survey data used and analysed in this study can be obtained in anonymised form from the study team, upon reasonable request.]. All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval. We have adapted the statement accordingly. “No data is generated or analysed for the current publication. Relevant data will be made available via an online repository when the study is completed and published in peer reviewed journals. To maintain patient privacy, the transcripts from the qualitative data as well as claims data sets will be only made available upon reasonable request after approval from research ethics board.” 4. 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. We have checked the reference list but have not found any necessary adjustments except the newly added source based on the reviewer's comments. Reviewer comments Reviewer #1: Two general comments; How FS fit in with the PCS needs to be better described. All surveys and interview schedules should be provided as appendices. Thank you very much for your comprehensive review and helpful suggestions. Unfortunately, at this stage of the project, we cannot provide all interview guidelines and surveys, as some of them are still being developed in the course of the project (this mainly concerns the surveys of GPs). Due to the online format of the surveys with detailed filtering, it is also not possible to make the entire surveys available as a document. However, as suggested as an alternative, we have summarised all the contents of the questionnaires in detail in a table and made them available as S1-S3 appendices. Please find our further adaptations and responses below. Abstract: The comment about “fatigue syndrome is one of the most common symptoms of PCC” appears a bit ‘random’ in the abstract since the following sentence is about PCC more broadly. I would recommended either adding more context – e.g., tell the reader you’re paying particular attention to fatigue syndrome. Or remove it from the abstract. Thank you for your suggestion. We removed this part from the manuscript. Methods: the tense of this section needs to be changed to future since it’s a protocol. E..g, Informal caregivers perspective will be collected rather than informal caregivers perspective is collected” Thank you for your remark. We have changed it accordingly in the whole manuscript. What is AOK? The AOK Lower Saxony is a statutory health insurance fund in Lower Saxony. We removed this abbreviation from the abstract because it is not relevant here. It is unclear what these two surveys are. It appears as though you are describing two cohorts of participants rather than actual surveys. This should be clarified. Thank you for this recommendation. We have reworded the part of the summary to make it clearer. Line 43-48: “Patients’ perspective will be evaluated through an online survey of: (1) 21,000 adult individuals with a PCC diagnosis (ICD10 U09.9!) in their statutory health insurance claims data in 2022 (“AOK survey”) and (2) a self-selected sample of adult individuals with a proven SARS-CoV-2 infection in 2023 and persistent symptoms (“public survey”).” What does the GP online survey evaluate/collect? There is no information on what is collected in the survey data therefore it’s unclear if descriptive analysis is appropriate. Who are the “experts” involved in the workshops. We understand that it would be helpful at this point to have more information about the content of the surveys and the methods used. However, due to the limited number of characters available for the abstract, it is not possible to include all of this additional information. Introduction: Line 73: It is very important that “fatigue syndrome (FS)” be carefully defined. The authors should include what syndrome they are describing here. For review see: Sandler CX, Wyller VBB, Moss-Morris R, Buchwald D, Crawley E, Hautvast J, Katz BZ, Knoop H, Little P, Taylor R, Wensaas KA, Lloyd AR. Long COVID and Post-infective Fatigue Syndrome: A Review. Open Forum Infect Dis. 2021 Sep 9;8(10):ofab440. doi: 10.1093/ofid/ofab440. PMID: 34631916; PMCID: PMC8496765. Thank you for pointing this out. After reviewing the recommended source, we decided not to put a special emphasis on "fatigue syndrome", but to mention fatigue (measured on the Chalder Fatigue Scale) as one of the most common symptoms of PCC, as we have no way to specify and validate "post-COVID fatigue" with the collected data in the recommended way. We have changed the entire manuscript accordingly, especially in the "Objectives" section (line 134-152). What is meant by “claims data” (line 108). Is this private health insurance claim. Please note the reader may not be familiar with the German health care system and may require some background information to understand the context. We understand the concerns. However, this is the title under which the study was registered in the German Clinical Trials Registry, so we have not changed it in the manuscript. We have added the registration information for clarification of the context. Line 112-116: “The present protocol describes the study “Care for patients with post-COVID: Analysis of claims data and the perspectives of patients, informal caregivers and general practitioners (VePoKaP)” [German: Versorgung von Patientinnen mit Post-COVID: Analysen von Kassendaten und von Perspektiven der Patientinnen, Angehörigen und Hausärztinnen (VePoKaP)] registered at the German Clinical Trials Register (DRKS00032846).” We have also reworded the part on claims data in the abstract to make it clearer. Line 44-46: “(1) 21,000 adult individuals with a PCC diagnosis (ICD10 U09.9!) in their statutory health insurance claims data in 2022 (“AOK survey”)” It may be helpful to provide some context for Lower Saxony and how this area of Germany is different/similar to the rest of the country. Highlighting this may provide a stronger rationale for the benefits of this study. (note, I have made this comment in the discussion section too). We have added additional information mainly in the discussion. Line 406-412: “Lower Saxony in general comprises nearly 10 % of the German population and is made up of rural, urban and metropolitan regions. In terms of age structure and unemployment rate, Lower Saxony is very close to the national average. The proportion of foreigners, the proportion of the employed persons with academic qualifications and the net income per capita are slightly lower than the German average [52]. However, due to the rather small differences, the results of this study are expected to be transferable to the whole of Germany.” Objectives: This is the first time the reader has understood PCC to be different to FS. The authors should clarify this. Wouldn’t there be people who have “both” Thank you for your advice. We have changed the manuscript as described above. Why is only the perspective of GPs included. What about other specialist e.g., ID physicians, respiratory physicians etc, nurses You are right that the perspectives of other professionals would also be interesting. Due to limited resources, we had to decide which professional perspective we wanted to include. We opted for the perspective of GPs, as they are usually the first point of contact in the healthcare system, the first to diagnose PCC and play a key role in the management of PCC patients and their multiplicity of symptoms. What is mean by complementary and alternative services? Do you mean complimentary services? “Complementary and alternative medical procedures” is a common term for non-conventional treatment methods (for review see e.g.: 10.3389/fnut.2021.791899 ) like natural medicine or traditional Chinese medicine. How will you assess if there are regional differences if you don’t assess any other region? Lower Saxony comprises rural, urban and metropolitan regions which are to be compared with each other. We have added it accordingly. Line 130-132: 1) Which health care services are used by PCC patients? To what extent are complementary and alternative services used? Are there regional differences in Lower Saxony (comparison rural, urban and metropolitan regions)? Informal caregivers should be defined. What’s the difference between formal and informal. And why wouldn’t you include formal? Informal caregivers are non-professional persons (such as a family member, neighbour or friend) who provide care in a home setting for another person (for review see e.g.: https://doi.org/10.1111/inr.12194). We included this information in the introduction. Line 92-95: “The functional limitations associated with PCC impact patients’ social lives and fulfilment of everyday tasks [3, 4], thereby necessitating the support services of informal caregivers (non-professional persons (both kin and non-kin caregivers like neighbours and friends) who provide care in a home setting).” Formal carers, on the other hand, are healthcare professionals and are included here in the form of general practitioners. Line 138 – how can GPs “rate the health care of individuals? Are you referring to the quality of health care AVAILABLE to individuals? Thank you for this question. We have reworded the question to make our intention clearer. Line 144-146: “How do GPs rate the health care of individuals with PCC in terms of the diagnostic process, availability and quality of treatment options and improvement in health status?” Methods: Line 150: Figure 1 is very difficult to read – this needs to be improved. Claims data needs to be defined. AOK needs to be defined Thank you for your advice. We have uploaded our figure file to the PACE diagnostic tool to make sure that it meets PLOS ONE requirements and adapted the explanation to make it clearer. Line 158-165:” Fig 1. Study design: Perspectives and data collection methods. © Hanna A. A. Röwer via Canva.com. a individuals who have statutory health insurance with the AOK Lower Saxony; ≥ 18 years old; post-COVID-19 condition (ICD10 U09.9) in their outpatient billing data or certificates of incapacity for work (claims data) in 2022; place of residence: Lower Saxony; continuously insured with the AOK Lower Saxony since 2019; no individuals whose affairs are managed by a guardian; no employees of the AOK Lower Saxony. b Persons with SARS-CoV-2 infection (self-test sufficient) in 2023 and persistent symptoms in self-perception; ≥ 18 years old; place of residence: Lower Saxony.” Line 164 – change to “will be “ conducted Thank you for your remark. We have adjusted the tense throughout the methods section. Line 167 – how will the reliability of the PCC diagnosis be assessed. As the authors stated in the introduction – the PCC diagnosis requires careful medical and psychiatric investigation. Is there data available to demonstrate this has happened. Will all patient have confirmed COVID-19? What definition of PCC will be used? It would be helpful to reader to have this included in the text The validity of the PCC diagnosis is indeed a point that needs to be carefully discussed especially in subsequent publications of the results. In principle, we trust the medical diagnosis. The explanation of the diagnosis code ICD U09.9! states: "This code number is to be used when an otherwise classified disease related to a previous coronavirus disease-2019 (COVID-19) is to be reported. This code number is not to be used if COVID-19 is still present.", so we assume that all those affected had a SARS-CoV-2 infection. However, the online survey also asks again how long the symptoms have been present and whether a SARS-CoV-2 infection was present, so that we can validate the information from the claims data and only include patients in the analyses who were still affected 12 or more weeks after an infection according to the WHO definition of PCC used. At the same time, it is possible to see from the claims data which medical specialists were consulted due to the PCC diagnosis. We have included a section on this issue in the methods. Line 206-210: “The selection of patients for the AOK survey is based on a medical PCC diagnosis, which is generally considered trustworthy. However, it is also possible to validate this secondary data against the primary data from the AOK survey to ensure that only individuals who have had a previous SARS-CoV-2 infection and whose symptoms have persisted for three months according to the WHO definition are actually included in the analyses.“ Regarding the second online survey – if they have not been diagnosed with PCC or there is only self-selection of COVID-19 – what is the benefit of including them? The biases related to this cohort should be described. The self-selected sample was integrated in order to reach people who had not yet seen a GP or specialist or had not received a PCC diagnosis. This was done on the assumption that this group could differ from the AOK sample, e.g. with regard to the utilisation of alternative medical measures which are not included in the claims data. There are some additional questions asked to validate the self-report. We added this information in the methods section. Line 219-224: “This public survey group recruitment via self-selection will aim at reaching currently affe Attachments Attachment Submitted filename: Response to Reviewers.pdf* https://doi.org/10.1371/journal.pone.0316335.r002
4 Oct 2024 Decision Letter - Nuru Abdu, Editor PONE-D-24-12578R1Care for post-COVID-19 condition in Germany from the perspectives of patients, informal caregivers and general practitioners: Study protocol for a mixed methods studyPLOS ONE Dear Dr. Stolz, 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 Nov 18 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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, Mr. Nuru Abdu 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: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: No Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Thank you for considering my remarks. I feel that have been adequately addressed. i have no further comments. Reviewer #2: The study is interesting and the use of mixed method to reduce confounders and biases makes the protocol original. However, there are some issues that should be in addressed: 1. Define informal health care givers and the scope of the GPs to be included in the survey. 2. When referring PCC in the objectives section use the formal definition used in the introduction section of the protocol. Why FS, as it has different ICD and will confound the results. 3. Why are the second survey group selected as self-selection, as this will lead to bias. What other strategies did you use to reduce bias other than the DSQ-PEM. 4. The claims data should be clarified, as readers may not be familiar with the system 5. Provide the survey questionnaire contents to be used for GPs. 6. Provide justification how the survey conducted in Lower Saxony can be generalizable to Germany, or provide as limitation in the discussion section. 7. The expected duration of the survey is not included and should be provided. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: 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.0316335.r003
Revision 2
21 Oct 2024 Author Response Dear editor, We would like to thank reviewer 1 for the positive review and reviewer 2 for the useful comments. We feel that the comments of reviewer 2 refer to the manuscript originally submitted in March rather than the revised version submitted in September, as almost all of the comments have already been addressed in the revised version on the basis of very similar comments from reviewer 1. Nevertheless, we have taken the helpful suggestions of reviewer 2 into account and made an addition in lines 244-248. Please find below our answers to the comments of the reviewer 2. Kind regards, Maike Stolz, on behalf of all authors. Reviewer comments Reviewer #1: Thank you for considering my remarks. I feel that have been adequately addressed. i have no further comments. Thank you for the positive review. Reviewer #2: The study is interesting and the use of mixed method to reduce confounders and biases makes the protocol original. However, there are some issues that should be in addressed: Thank you very much for your comprehensive review and helpful suggestions. We feel that your comments refer to the manuscript originally submitted in March rather than a revised version submitted in September, as almost all of your comments have already been addressed in this version on the basis of very similar comments from a second reviewer. Please find the corresponding changes below. 1. Define informal health care givers and the scope of the GPs to be included in the survey. We included the definition of informal caregivers in the introduction. Line 92-95: “The functional limitations associated with PCC impact patients’ social lives and fulfilment of everyday tasks [3, 4], thereby necessitating the support services of informal caregivers (non-professional persons (both kin and non-kin caregivers like neighbours and friends) who provide care in a home setting).” We are not quite sure what is meant by ‘scope of the GPs included’. To be invited to the survey, the only requirement is that you are registered as a GP with a license from the statutory health insurance provider and are actively practicing. To participate in the preparatory focus groups, the GPs must also have treated patients with PCC. We have added this accordingly. Line 310-311: GPs who treat or have treated people with PCC and are interested in taking part will be invited to contact the research team by telephone or email. 2. When referring PCC in the objectives section use the formal definition used in the introduction section of the protocol. Why FS, as it has different ICD and will confound the results. Thank you for pointing this out. We will now not put a special emphasis on "fatigue syndrome", but mention fatigue (measured on the Chalder Fatigue Scale) as one of the most common symptoms of PCC. We have changed the entire manuscript accordingly, especially in the "Objectives" section (line 134-152). 3. Why are the second survey group selected as self-selection, as this will lead to bias. What other strategies did you use to reduce bias other than the DSQ-PEM. The self-selected sample was integrated in order to reach people who had not yet seen a GP or specialist or had not received a PCC diagnosis. This was done on the assumption that this group could differ from the AOK sample, e.g. with regard to the utilisation of alternative medical measures which are not included in the claims data. There are some additional questions asked to validate the self-report. We added this information in the methods section. Line 219-224: “This public survey group recruitment via self-selection will aim at reaching currently affected individuals who have not necessarily presented to outpatient or inpatient care, or have not been diagnosed with PCC by a GP or medical specialist. Despite the bias associated with self-reporting the presence of PCC symptoms, this potentially vulnerable group is considered separately. Individual additional questions are asked to validate the self-report.” 4. The claims data should be clarified, as readers may not be familiar with the system We have reworded the part on claims data in the abstract and added a sentence in the methods section to make it clearer. Line 44-46: “(1) 21,000 adult individuals with a PCC diagnosis (ICD10 U09.9!) in their statutory health insurance claims data in 2022 (“AOK survey”)” Line 242-248: “The claims data of the 27,275 adult individuals with a PCC diagnosis in 2022 who are insured by AOK Lower Saxony (AOK claims data group) will serve as a secondary data source. The routine data of the statutory health insurers contain, in addition to the insured persons' sociodemographic data, billing data from reimbursed healthcare services providing an overview of the services utilised by patients from the time of diagnosis, with respect to outpatient care, medication, therapeutics, inpatient care and rehabilitation, and periods of sick leave incurred.” 5. Provide the survey questionnaire contents to be used for GPs. Unfortunately, we cannot provide the content of the survey for the general practitioners at this stage of the project, as it is still being identified based on the results of the focus groups. 6. Provide justification how the survey conducted in Lower Saxony can be generalizable to Germany, or provide as limitation in the discussion section. Thank you for this advice. We have added additional information to the discussion. Line 408-414: “Lower Saxony in general comprises nearly 10 % of the German population and is made up of rural, urban and metropolitan regions. In terms of age structure and unemployment rate, Lower Saxony is very close to the national average. The proportion of foreigners, the proportion of the employed persons with academic qualifications and the net income per capita are slightly lower than the German average [52]. However, due to the rather small differences, the results of this study are expected to be transferable to the whole of Germany.” 7. The expected duration of the survey is not included and should be provided. We added this information in the methods section. Line 230 (patients): “Answering the survey is estimated to take about 30 minutes.” Line 288-289 (informal caregivers): “Answering the survey is estimated to take about 15 minutes.” Attachments Attachment Submitted filename: Response to Reviewers_2.pdf https://doi.org/10.1371/journal.pone.0316335.r004
10 Dec 2024 Decision Letter - Nuru Abdu, Editor Care for post-COVID-19 condition in Germany from the perspectives of patients, informal caregivers and general practitioners: Study protocol for a mixed methods study PONE-D-24-12578R2 Dear Dr. Stolz, 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. 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Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: the authors have already address the previous feedback i provided. I have reviewed the feedback provided by the other reviewer and feel they have also been addressed Reviewer #2: I have no further comments for the provided reviewed manuscript. All the comments have been addressed as suggested by the reviewers. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0316335.r005
Formally Accepted
17 Dec 2024 Acceptance Letter - Nuru Abdu, Editor PONE-D-24-12578R2 PLOS ONE Dear Dr. Stolz, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Mr. Nuru Abdu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0316335.r006

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