SARS-CoV-2 pneumonia follow-up and long COVID in primary care: A retrospective observational study in Madrid city

Sara Ares-Blanco; Marta Pérez Álvarez; Ileana Gefaell Larrondo; Cristina Muñoz; Vanesa Aguilar Ruiz; Marta Castelo Jurado; Marina Guisado-Clavero

doi:10.1371/journal.pone.0257604

Peer Review History

Original SubmissionMarch 22, 2021
9 Jun 2021 Decision Letter - Muhammad Adrish, Editor PONE-D-21-09441 SARS-CoV-2 pneumonia follow-up and long COVID in Primary care: a retrospective observational study in Madrid City PLOS ONE Dear Dr. Guisado-Clavero, 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 review comments made by reviewers and provide point by point response in your revised manuscript. Please submit your revised manuscript by July 8th 2021. 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. 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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 authors present a thorough discussion of the duration of COVID19 symptoms following acute infection. While this is a useful contribution, the terminology uses is imprecise and unclear, particularly given the varying and non-standardized definitions of "long-COVID". Additionally, as the pathophysiology of this process is not understood, a purely descriptive report in which the average duration of different clinical symptoms are reported, without the addition of syndromic terminology. Reviewer #2: First I would like to thank the authors on their efforts in writing this manuscript about describing COVID-19 pneumonia and identify the cut offs to define long covid in primary care patients. Please see my comments. Intro- Overall good introduction to the topic and literature review. The research aimed to determine patient and disease characteristics associated with SARS- CoV-2 pneumonia since the pneumonia diagnosis until recovery in a study population aged 18 to 91 years during the follow-up in primary care. The secondary outcome was to describe patients who still had symptoms 4 weeks after the diagnosis of SARS-CoV-2 pneumonia. I would recommend the authors to revise the aim to be clearer. From the abstract, results and findings, it seems its more on describing characteristics as well as identifying/evaluating the cut-offs for long COVID in primary care? Please clarify and revise the statement in intro to be more consistent and clearer as a purpose/aim for the study. Methods: Line 102= “patient with lung affection by infiltration…” – do you mean infection? Please clarify. It was a little bit difficult to follow methods although it was very well detailed and described. However, from a flow perspective it was a little bit difficult. In the selection of study subjects, authors mentioned that about 1023 patients were seen in the PHCC clinic, and the sample was limited to 10th of march to 7th of April 2020. Later in line 103- it says that data was collected 6 months after the diagnosis. Just to clarity, was the sample of 155 (that was included in the study, were seen during that one month period 3/10 to 4/7 2020? Please clarify as it is not clear. Results- I am not sure if data of the excluded patients should be included since the study has a pre-defined inclusion criteria in which only 155 patients qualified. Thus, data in supplementary file might not be needed from an exclusion criteria perspective. I would recommend the authors to move the long COVID definition and describe all of its aspects from definition and cut off points in the methodology section (excluding the reporting data). Then data and results can be presented in the results section. The purpose of the results section to report the data without interpretation nor definitions. Figure 1 – the figure is nice as it captures the study time line. However, modification is strongly recommended. For example, baseline time for blood test is not identified. In addition, the presented time line is not clear. Does it describe 0 from diagnosis (march and April) and then all the way to 12 weeks? If so, I would recommend adding a horizontal line that shows mean with IQR on top of the hospital LOS median that way its more clear. Looking at the two symptoms figure, please describe the values (i.e. Fever, is that %? Of so, please add the total and % in the figure legend or inside the figure it self. Table 3- regarding phone calls follow up , does that reflect number of patients who had /received phone calls? Or number of times the physician/nurse called? Please clarify. ****** 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: Yes:** John Cafardi 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.0257604.r001
Revision 1
1 Jul 2021 Author Response ANSWERS TO THE REVIEWRS: Reviewer 1: The authors present a thorough discussion of the duration of COVID19 symptoms following acute infection. While this is a useful contribution, the terminology uses is imprecise and unclear, particularly given the varying and non-standardized definitions of "long-COVID". Additionally, as the pathophysiology of this process is not understood, a purely descriptive report in which the average duration of different clinical symptoms are reported, without the addition of syndromic terminology. ANSWER: We are grateful for the commentary and we agree as there is not a unique definition of long COVID. We decided to change the terminology to ≤4 weeks and >4 weeks to avoid confusion. Changes are located throughout the all manuscript (abstract in lines 48-52, results section in lines 170-175; discussion section in lines 190-197 and line 215, 241, 256-257). Reviewer 2: First I would like to thank the authors on their efforts in writing this manuscript about describing COVID-19 pneumonia and identify the cut offs to define long covid in primary care patients. - Intro: Overall good introduction to the topic and literature review. The research aimed to determine patient and disease characteristics associated with SARS- CoV-2 pneumonia since the pneumonia diagnosis until recovery in a study population aged 18 to 91 years during the follow-up in primary care. The secondary outcome was to describe patients who still had symptoms 4 weeks after the diagnosis of SARS-CoV-2 pneumonia. I would recommend the authors to revise the aim to be clearer. From the abstract, results and findings, it seems its more on describing characteristics as well as identifying/evaluating the cut-offs for long COVID in primary care? Please clarify and revise the statement in intro to be more consistent and clearer as a purpose/aim for the study. ANSWER: We agree about your commentary. We have cleared up the aims to give a clearer objective. We have added (introduction section line 87-91): “The research aimed to determine patient and disease characteristics associated with SARS-CoV-2 pneumonia since the pneumonia diagnosis until recovery in a study population aged 18 to 91 years during the follow-up in primary care especially focusing on patients who still had symptoms 4 weeks after SARS-CoV-2 pneumonia diagnosis. The secondary outcome was to describe the different cut-off points of long COVID definition in week 4 and in week 12. “ - Methods: Line 102= “patient with lung affection by infiltration…” – do you mean infection? Please clarify. It was a little bit difficult to follow methods although it was very well detailed and described. However, from a flow perspective it was a little bit difficult. In the selection of study subjects, authors mentioned that about 1023 patients were seen in the PHCC clinic, and the sample was limited to 10th of march to 7th of April 2020. Later in line 103- it says that data was collected 6 months after the diagnosis. Just to clarity, was the sample of 155 (that was included in the study, were seen during that one month period 3/10 to 4/7 2020? Please clarify as it is not clear. ANSWER: Thank you for your observations. For a better comprehension, we have proceed to modify the following points - Line 104 (previous line 102) has been changed to “Patients with lung affection by SARS-CoV-2 infection” to clarify the concept. - We have added a flow chart (Figure 1) to simplify the flow of patients in this study. In the manuscript, methods section line 93-96, has been added the following explanation “The PHCC provided care to 21814 population, from whom 1,023 patients were diagnose from COVID-19 (confirmed by RCP or symptoms compatible with COVID-19), from the 10th of March to the 7th of April of 2020. Pneumonia was present in 251 and 155 were diagnosed and followed-up by Federica Montseny PHCC during 6 months (Figure 1).” We have also added it in the eligibility criteria (methods section, line 107): “Eligibility criteria were considered in patients ≥ 18 years, followed-up by the primary care practice during the next 6 months after SARS-CoV-2 pneumonia diagnosis, with a suspicious of SARS-CoV-2 pneumonia and a radiologist report which confirmed the SARS-CoV-2 pneumonia”. - Results: I am not sure if data of the excluded patients should be included since the study has a pre-defined inclusion criteria in which only 155 patients qualified. Thus, data in supplementary file might not be needed from an exclusion criteria perspective. ANSWER: We have removed Supplementary file 1 as the reviewer suggested, we wanted to show the maximum transparency, which was the reason for including it. If the editor thinks the material should be included, we are pleased to include it again. All Supplementary files order has been reorganized thought the manuscript according to the exposed change. I would recommend the authors to move the long COVID definition and describe all of its aspects from definition and cut off points in the methodology section (excluding the reporting data). Then data and results can be presented in the results section. The purpose of the results section to report the data without interpretation nor definitions. ANSWER: We agree with the commentary and we are grateful for the opinion shared. We have described the methodology and results as “patients who had symptoms ≤ 4 weeks” or patients “who persisted symptoms >4 weeks” to avoid misinterpretation of the data (abstract in lines 48-52, results section in lines 170-175; discussion section in lines 190-197 and line 215, 241, 256-257). - Figure 1: The figure is nice as it captures the study time line. However, modification is strongly recommended. For example, baseline time for blood test is not identified. In addition, the presented time line is not clear. Does it describe 0 from diagnosis (March and April) and then all the way to 12 weeks? If so, I would recommend adding a horizontal line that shows mean with IQR on top of the hospital LOS median that way its more clear. Looking at the two symptoms figure, please describe the values (i.e. Fever, is that %? Of so, please add the total and % in the figure legend or inside the figure it self. ANSWER: Thank you for your recommendations. A new version of this figure has been uploaded for a better understanding of this primary-care follow-up sample considering your observations. After previous changes, this figure has been labelled as Figure 2. - Table 3: regarding phone calls follow up, does that reflect number of patients who had /received phone calls? Or number of times the physician/nurse called? Please clarify. ANSWER: The phone calls reflect the number of times the physician or nurse made to follow-up the patient. We have changed in Table 2 the title to: “Number of phone calls by GP or nurse during the follow-up”. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0257604.r002
6 Sep 2021 Decision Letter - Muhammad Adrish, Editor SARS-CoV-2 pneumonia follow-up and long COVID in Primary care: a retrospective observational study in Madrid City PONE-D-21-09441R1 Dear Dr. Guisado-Clavero, 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, Muhammad Adrish, MD, MBA, FCCP, FCCM Academic Editor PLOS ONE Additional Editor Comments (optional): All comments have been addressed Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No 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. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: The authors have address the reviewers comments. The modified manuscript with the new figure as well as adding the logistic regression is good to have for clarity of the manuscript. ****** 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.0257604.r003
Formally Accepted
14 Sep 2021 Acceptance Letter - Muhammad Adrish, Editor PONE-D-21-09441R1 SARS-CoV-2 pneumonia follow-up and long COVID in Primary care: a retrospective observational study in Madrid City Dear Dr. Guisado-Clavero: 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. Muhammad Adrish Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257604.r004

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