Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study

Christopher Burton; Helen Dawes; Simon Goodwill; Michael Thelwell; Caroline Dalton

doi:10.1371/journal.pone.0280343

Peer Review History

Original SubmissionJune 14, 2022
18 Aug 2022 Decision Letter - Ioannis G. Fatouros, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-22-17123 Symptom variation, correlations, and relationship to physical activity in Long Covid: intensive longitudinal study PLOS ONE Dear Dr. Burton, 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 Oct 02 2022 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. 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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: Partly ******** 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript was enjoyable to read. I would like to address some points that might be confusing. 1. The title should be more representative of the results. For instance, symptom assessment was based on perceived evaluation by the participants subjectively. Additionally, due to the lack of correlations, perhaps the term of interoception, as a potential explanation of the results, should be added in the title. 2. A figure depicting study design would be nice. 3. I see that fatigue was the main symptom. However, I haven’t understood how the rest of the symptoms were measured and expressed independently of fatigue. Fatigue is a broad and vague symptom with multifactorial origins. It may affect the interoception of the rest of the symptoms examined. How was fatigue distinguished from other post-COVID-19 symptoms, independently? In other words, how the possibility of a confounding intercorrelation was addressed/excluded? Is it possibly implied that fatigue amplifies the expression of the rest of the symptoms? Towards the same direction goes the lack of activity. Exercise is thought to intervene with the information processing and the output of the interoceptive system. 4. 57 citation should be excluded as it has not been peer-reviewed – despite the clear indication provided. 5. Please, proofread as some typographic mistakes were found. Reviewer #2: This is an excellent study with high clinical significance. My comments are listed below: Major concerns: Even though in the current study’s title is stated the word “long covid” the study design has included only 27 participants described having a positive PCR test. It is stated clearly that the analysis of variance showed no significant difference in baseline measures between those testing positive for Covid-19, negative or not tested, however, it is misleading to discuss about Long Covid Symptoms when only the 33% of the participants were verified covid patients. The authors need to address this issue by either changing the title of the manuscript or removing all non-tested participants (or running a separate analysis including only those with positive test). Minor: I was wondering if the authors have considered the lack of commitment to comply with the researchers’ instructions in collecting the data as one of the symptoms of Long covid? Please elaborate further in the manuscript the fact that the adherence rate was moderate. Minor: What about the rate of vaccination among the participants? Any relation to the severity of the symptoms? Please response. ****** 6. 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Revision 1
11 Nov 2022 Author Response Thank you for the constructive and thoughtful comments of your reviewers. We are pleased that the found the manuscript to be of high quality, clinical importance and enjoyable to read. They both raise important points and we have responded to them in sequence. Reviewer #1: The manuscript was enjoyable to read. I would like to address some points that might be confusing. 1. The title should be more representative of the results. For instance, symptom assessment was based on perceived evaluation by the participants subjectively. Additionally, due to the lack of correlations, perhaps the term of interoception, as a potential explanation of the results, should be added in the title. Thanks for encouraging us to think again about this. We have changed it to “Within and between-day variation and associations of symptoms in Long Covid: intensive longitudinal study.” We have chosen this in order to emphasise the time-scales on which this data was collected and analysed (which is what differentiates it from other studies). From this, we think that it follows that the symptoms are a subjective experience. We have not included interoception in the title because (a) we didn’t formally test it, and (b) our patient advisors felt it was imposing an answer prematurely. 2. A figure depicting study design would be nice. We have added this 3. I see that fatigue was the main symptom. However, I haven’t understood how the rest of the symptoms were measured and expressed independently of fatigue. Fatigue is a broad and vague symptom with multifactorial origins. It may affect the interoception of the rest of the symptoms examined. How was fatigue distinguished from other post-COVID-19 symptoms, independently? In other words, how the possibility of a confounding intercorrelation was addressed/excluded? The point about fatigue and its intersection with other symptoms is well made, indeed this is one of the issues that this work exposes. However, in most accounts of lived experience in this condition, fatigue is described as a distinct thing and we are cautious about challenging this subjective experience so bluntly. On the other hand, as the reviewer points out, the data show that fatigue is strongly correlated with other symptoms. We should have said more in the original manuscript about the development and pilot study. We checked with people with lived experience, during initial app development and after our pilot study to ensure that the app made sense and that they felt able to distinguish the different symptoms. There were no reported problems. We have added a sentence to this effect in the Methods / Study Design section. We could also have been clearer about addressing this issue by reporting both adjusted and unadjusted (partial) correlations. We have edited the Overview of Analysis subsection to describe this. Is it possibly implied that fatigue amplifies the expression of the rest of the symptoms? That is one possible explanation. Equally if fatigue is the “feeling that occurs when voluntary action should stop or not be started” then it is highly likely that other symptoms will trigger a state of fatigue. At this stage we know so little about fatigue that we prefer to keep an open mind. Towards the same direction goes the lack of activity. Exercise is thought to intervene with the information processing and the output of the interoceptive system. We are not saying that it doesn’t. But in this research, we were focused on short-term associations not on longer term changes. If we take an altered interoception approach to interpreting this condition, then short term increases in activity will create more noise in the interoceptive system without changing the predictive priors the brain uses. Any change in priors probably takes time or perhaps specific disruption (which is perhaps where anecdotal things like cold water swimming might come in). 4. 57 citation should be excluded as it has not been peer-reviewed – despite the clear indication provided. We have found increasing citation in journals of material on public preprint servers. Before deleting this, we would prefer to check with the editorial team. 5. Please, proofread as some typographic mistakes were found. We have done this and apologise for missing these in the original submission. Reviewer #2: This is an excellent study with high clinical significance. My comments are listed below: Major concerns: Even though in the current study’s title is stated the word “long covid” the study design has included only 27 participants described having a positive PCR test. It is stated clearly that the analysis of variance showed no significant difference in baseline measures between those testing positive for Covid-19, negative or not tested, however, it is misleading to discuss about Long Covid Symptoms when only the 33% of the participants were verified covid patients. The authors need to address this issue by either changing the title of the manuscript or removing all non-tested participants (or running a separate analysis including only those with positive test). Thanks for this comment which reflects on important issues both of defining the illness and of the issue of whose illness this actually is. We agree that more information could have been included and we have added additional data about the comparison between groups in our baseline measures, visual analogue scales and accelerometery. We have made additions to methods and results and added an additional figure. However, we found little difference between the PCR groups in any of the data we collected / analysed (the exception, as always, being loss of taste / smell). However, we disagree with the reviewer that it is “misleading” to include people without a positive PCR and in this we are strongly supported by our patient collaborators. Firstly one third of cases had their acute illness in the early stages of the pandemic when PCR testing was not available for community cases. Second, we know from a large French study that while approximately half of people with the post covid condition did not have a positive PCR, at least half of these had positive antibodies (before vaccination). On balance, we believe that it is not appropriate in the current state of knowledge to exclude people on the basis of a limited availability / once-off PCR test and certainly our patient collaborators hold very strongly to this view. Minor: I was wondering if the authors have considered the lack of commitment to comply with the researchers’ instructions in collecting the data as one of the symptoms of Long covid? Please elaborate further in the manuscript the fact that the adherence rate was moderate. We had considered something like this. In the results we note that “There was no association between number of completed entries and mean self-reported fatigue (spearman’s rho -0.05)”. We have now added a sentence to the discussion indicating that completion rates (78% of possible entries) were comparable to those expected in a definitive text on the intensive longitudinal method (80%). Minor: What about the rate of vaccination among the participants? Any relation to the severity of the symptoms? Please response. We have added a sentence to the Participant Characteristics section that because the large majority had become unwell before immunisation was available, we did not collect that data. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0280343.r002
27 Dec 2022 Decision Letter - Ioannis G. Fatouros, Editor Within and between-day variation and associations of symptoms in Long Covid: intensive longitudinal study. PONE-D-22-17123R1 Dear Dr. Burton, 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, Ioannis G. Fatouros Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors, Unfortunately both reviewers have not responded to my second call. As such, I moved ahead and I reviewed your manuscript my self. It appears that you have addressed all of the reviewers' comments successfuly and you have improved your manuscript considerably. However, I agree with the comment raised by Reviewer 2 on deleting citation 57. As such, I find your manuscript suitable for publication but you need to eliminate reference 57. Sincerely, Ioannis G. Fatouros Reviewers' comments: https://doi.org/10.1371/journal.pone.0280343.r003
Formally Accepted
6 Jan 2023 Acceptance Letter - Ioannis G. Fatouros, Editor PONE-D-22-17123R1 Within and between-day variation and associations of symptoms in Long Covid: intensive longitudinal study. Dear Dr. Burton: 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. Ioannis G. Fatouros Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0280343.r004

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