Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection

Laurie G. Jacobs; Elli Gourna Paleoudis; Dineen Lesky-Di Bari; Themba Nyirenda; Tamara Friedman; Anjali Gupta; Lily Rasouli; Marygrace Zetkulic; Bindu Balani; Chinwe Ogedegbe; Harinder Bawa; Lauren Berrol; Nabiha Qureshi; Judy L. Aschner

doi:10.1371/journal.pone.0243882

Peer Review History

Original SubmissionAugust 12, 2020
28 Sep 2020 Decision Letter - Giordano Madeddu, 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-20-25200 Persistence of Symptoms and Quality of Life at 35 Days After Hospitalization for COVID-19 Infection PLOS ONE Dear Dr. Jacobs, 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 12 2020 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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Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. 3. Thank you for stating the following in the Competing Interests section: "The authors disclose the following financial relationships present during the 36 months prior to publication, which did not present any conflicts of interest: Laurie G. Jacobs -no conflicts of interest, no financial relationships Elli Gourna Paleoudis -no conflicts of interest, no financial relationships Dineen Lesky-DiBari - no conflicts of interest, no financial relationships Anjali Gupta -no conflicts of interest, no financial relationships Lily Rasoulli - no conflicts of interest, no financial relationships Themba Nyrirenda - no conflicts of interest, no financial relationships Tamara Friedman - no conflicts of interest, no financial relationships Marygrace Zetkulic -no conflicts of interest, no financial relationships Bindu Balani - Financial relationships: Gilead- PI, Remdisivir clinical trial, 2020, personal fees; Merck advisory committee; Abbvie speaker, personal fees Chinwe Ogedegbe -no conflicts of interest, no financial relationships Harinder Bawa -no conflicts of interest, no financial relationships Nabiha Qureshi -no conflicts of interest, no financial relationships Lauren Berrol -no conflicts of interest, no financial relationships Judy Aschner -Gilead Science, stock owner" 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). 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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 by Laurie G. Jacobs et al. describes the characterization of the prevalence and persistence of symptoms of COVID-19 following hospital discharge and their impact in several parameters, such as quality of life, mental, physical and psychosocial function. The topic has been already studied in the literature, and the quantity missing data make this work unattractive. In particular, it seems to be important to underline the lacking of data related to previous patients’ conditions in order to understand the real impact of SARS-CoV-2 infection on investigated parameters. Although previous co-morbidities are present in the baseline description, no data are shown regarding the quality of life and the social, psychological and physical conditions of enrolled patients. Moreover, the description of the prevalence and persistence should be improved, clarifying aspects within the text and placing into the tables the number of patients with persistence of each symptom during follow-up. The percentage values should be reported in the denominator. In the manuscript it is unclear. On line 219, the affirmation “…95.4% of all participants […] were classified as having a mild severity of illness requiring no oxygen…” seems not to be in agreement with the previous sentence: “The majority of participants […] required oxygen support…” (line 218). The OR value and relative CI on line 49 of the abstract and in table 4 (third row) seem to be inaccurate (OR 0.092, CI 0.026-0.033). Reviewer #2: Jacobs et al present an interesting manuscript about medium-term consequences/persistence of COVID-19 symptoms. This is the first time that a paper explore follow-up experiences with COVID-19, even though only by phone or email interview, and an important point of view over this new disease. Authors show through sound results and an excellent statistical analysis that COVID-19 symptoms may persist long after the viral RNA is not detectable anymore. Moreover, they also show that older patients, and in particular female ones, have significant higher odds of experiencing persistent symptoms. The manuscript is well organized and clearly written. ****** 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. 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Revision 1
4 Nov 2020 Author Response Responses to Reviewer’s comments: Reviewer #1: The article by Laurie G. Jacobs et al. describes the characterization of the prevalence and persistence of symptoms of COVID-19 following hospital discharge and their impact in several parameters, such as quality of life, mental, physical and psychosocial function. The topic has been already studied in the literature, and the quantity missing data make this work unattractive. In particular, it seems to be important to underline the lacking of data related to previous patients’ conditions in order to understand the real impact of SARS-CoV-2 infection on investigated parameters. Although previous co-morbidities are present in the baseline description, no data are shown regarding the quality of life and the social, psychological and physical conditions of enrolled patients. Moreover, the description of the prevalence and persistence should be improved, clarifying aspects within the text and placing into the tables the number of patients with persistence of each symptom during follow-up. The percentage values should be reported in the denominator. In the manuscript it is unclear. On line 219, the affirmation “…95.4% of all participants […] were classified as having a mild severity of illness requiring no oxygen…” seems not to be in agreement with the previous sentence: “The majority of participants […] required oxygen support…” (line 218). The OR value and relative CI on line 49 of the abstract and in table 4 (third row) seem to be inaccurate (OR 0.092, CI 0.026-0.033). Author’s Response: There is a literature regarding quality of life, mental, physical and psychosocial function but only one prior to this submission, as referenced in the manuscript (refence #11), which assesses of quality of life, mental, physical and psychosocial function with regard to patients surviving COVID-19. The one published prior to the submission of this manuscript, from Italy, cited, represents a more limited assessment using one question, not a standardized tool, and did not have prior assessments of quality of life. The lack of baseline quality of life assessments prior to the patients’ contracting COVID-19 and prior to admission to hospital is not optimal, however, it was not possible to identify community patients who would be admitted, and upon admission, these data could not be collected due to the patient’s severity of illness. We did, however, include one “baseline” question about patients’ evaluation of their pre-COVID-19 status regarding general health. We have primarily focused on the post-hospital course, partially to avoid recollection bias since we did not have the option of talking to these patients prior to or at admission. A study design that anticipated admission would have been ideal but not feasible during the pandemic surge period of the study unfortunately. To respond to reviewer #1, we have added text in the results section shown below on new lines 250-255, a new Table 4, also below, which presents the associations between the patients’ response to the question regarding their pre-COVID-19 general health and the general health and quality of life at the time of the survey, 35 days later. Patients were asked about these parameters referencing their COVID-19 illness, using the PROMIS instruments to provide a standard tool and response. In addition, comments were added to the discussion section Lines 250-255: Comparing patients’ baseline general health (pre-COVID-19 illness) to post-COVID-19 general health (at time of survey) indicated that patients who reported excellent/very good or good health post-COVID-19 were more likely to have reported an excellent/very good or good pre-COVID health status (Table 4). Similarly, reporting an excellent/very good quality of life, physical health and mental health post-COVID-19 was more frequent among those reporting excellent/very good pre-COVID health. Table 4. Associations Between Pre-COVID-19 General Health and Post-COVID-19 (35 Days) General Health and Quality Of Life Outcome Effect (reference. category: Poor, Fair) Odds Ratio 95% CI P-Value General Health Very Good, excellent pre-COVID-19 Good 5.248 (1.093,25.20) 0.0384 General Health Good pre-COVID-19 Good 4.017 (1.130,14.28) 0.0317 General Health Very Good, excellent pre-COVID-19 Very good, excellent 8.847 (2.178,35.93) 0.0023 General Health Good pre-COVID-19 Very good, excellent 2.442 (0.792,7.533) 0.1203 Quality of Life Very Good, excellent pre-COVID-19 Good 2.916 (0.618,13.75) 0.1762 Quality of Life Good pre-COVID-19 Good 1.296 (0.383,4.390) 0.6767 Quality of Life Very Good, excellent pre-COVID-19 Very good, excellent 5.478 (1.301,23.07) 0.0204 Quality of Life Good pre-COVID-19 Very good, excellent 1.285 (0.421,3.920) 0.6594 Physical Health Very Good, excellent pre-COVID-19 Good 6.500 (1.199,35.23) 0.0300 Physical Health Good pre-COVID-19 Good 5.500 (1.451,20.85) 0.0122 Physical Health Very Good, excellent pre-COVID-19 Very good, excellent 13.20 (2.747,63.44) 0.0013 Physical Health Good pre-COVID-19 Very good, excellent 4.320 (1.249,14.95) 0.0209 Social Relationship pre-COVID-19 Good 1.587 (0.487,5.173) 0.4439 Social Relationship pre-COVID-19 Very good, excellent 2.121 (0.717,6.279) 0.1744 We have edited the former Table 2 (now 3) as suggested to insert the number of patients with persistence of each symptom. In addition, the denominators are added to data in lines 227-234. Line 219 regarding oxygen use and the WHO classification has been clarified in the text as: “The majority of participants (89.6% overall; 87.4% of males, 92.7% of females) required oxygen support during hospitalization (Table 2). The WHO severity criteria[14], identified that 95.4% of all participants, 91.9% of males, and 81.1% of females, were classified as having a mild severity of illness, which includes those requiring no oxygen, or oxygen by nasal prongs or nonrebreather mask.” As well, an additional table, now Table 2, below, has been added to further clarify this point. Table 2. Oxygen Requirements During Hospitalization for COVID-19 All Participants Male Sexa Female Sexa WHO Severity15 Oxygen Delivery Requirement Count (% of 183) Count (% of 111) Count (% of 69) None 19 (10·4) 14 (12·6) 5 (7·2) Mild Nasal prongs 118 (72·4) 73 (65·8) 43 (62·3) Mild Nonrebreather mask 23 (12·6) 15 (13·5) 8 (11·6) Mild High-Flow 15 (9·2)) 6 (5·4) 8 (11·6) Severe Intubation and mechanical ventilation 8 (4·94) 3 (2·7) 5 (7·2) Severe The OR and Relative CI on line 49 of the abstract and now in Table 5 have been corrected as “odds rating general health (41.5%, OR 0.093 [95% CI: 0.026, 0.329], p=0.0002), Tables 2, 3, 4 have been relabeled as Tables 3, 5, and 6 as a two new Tables, Table 2 and Table 4 have been added. With regard to the issue of the impact of co-morbid conditions present on admission, and their impact on the quality of life and the social, psychological and physical conditions of enrolled patients, we have added the following text on lines 273-285, Table 6, and additional text on lines 384 – 389 in the Discussion Section below: The most prevalent comorbidities - hypertension, obesity, diabetes and cardiovascular disease - did not appear to have an effect on post-COVID-19 quality of life responses (captured at the time of the survey and during the prior seven days). Similarly, these co-morbidities did not effect post-COVID-19 mental health, social relationships and general health responses. Prior comorbidities, however, did affect post-COVID-19 physical health responses. Patients with hypertension and diabetes, in particular, were less likely to report good or very good/excellent physical health. Those with hypertension and good physical health responses trended to be less likely (OR 0.428, [95% CI: 0.199,0.921], p-value= 0.0300), and physical health responses in diabetics of good (OR 0.330, [95% CI: 0.145,0.747], p-value= 0.0079) and very good/excellent (OR 0.308, [95% CI: 0.138,0.686], p-value= 0.0040 ). In addition, responses of excellent, very good and good physical health were more likely to be reported among those who reported having no known comorbidities at admission (OR= 2.822, p-value: 0.05 and OR= 3.600, p-value 0.01 for excellent/very good health and good health respectively). Table 6. Associations between quality of life outcomes and persistent symptoms of COVID-19 patients at day 35 Quality of life outcome variable Outcome comparison category Odds ratio (95% CI) P-value General health (ref. cat.: poor, fair)a good 0.530 (0.136, 2.057) 0.3587 very good, excellent 0.093 (0.026, 0.329) 0.0002 Quality of life (ref. cat.: poor, fair) good 0.536 (0.159, 1.809) 0.3149 very good, excellent 0.116 (0.038, 0.364) 0.0002 Physical health (ref. cat.: poor, fair) good 0.384 (0.098, 1.504) 0.1694 very good, excellent 0.055 (0.016, 0.193) <0.0001 Mental health (ref. cat.: poor, fair) good 0.286 (0.061, 1.342) 0.1125 0.093 (0.021, 0.418) 0.0019 Social relationships (ref. cat.: poor, fair) very good, excellent 0.245 (0.123, 0.486) Social active role (ref. cat.: poor, fair) good 0.196 (0.060, 0.637) very good, excellent 0.095 (0.031, 0.291) Daily physical activity (ref. cat.: a little not at all) moderately 0.584 (0.058, 5.925) mostly, completely 0.059 (0.008, 0.451) Emotional (ref. cat: always, often) sometimes 0.876 (0.252, 3.051) rarely, never 0.301 (0.096, 0.947) Fatigue (ref. cat.: severe, very severe) moderately 0.786 (0.085, 7.276) none, mild 0.104 (0.013, 0.819) Table 6 Legend aAbbreviations ref. cat. reference category, CI Confidence interval Lines 384-389 Overall, no significant associations were found between pre-existing conditions (comorbidities at admission) and post-COVID evaluations of health and quality of life as captured through mental health and social relationships. This could suggest that any reports of poor health and quality of life post-COVID could be attributed to patients’ COVID illness that might have not been completely resolved given the number of persistent symptoms 35 days post-discharge. https://doi.org/10.1371/journal.pone.0243882.r002
1 Dec 2020 Decision Letter - Giordano Madeddu, Editor Persistence of Symptoms and Quality of Life at 35 Days After Hospitalization for COVID-19 Infection PONE-D-20-25200R1 Dear Dr. Jacobs, 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, Giordano Madeddu Academic Editor PLOS ONE Additional Editor Comments (optional): 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: (No Response) 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: Yes 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: 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. 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: I read the revised version of the manuscript. The Authors added several information and clarifications in the work, making it more attractive. Reviewer #2: The authors revised the manuscript according to the previous observations made by the reviewers. The article was improved and it is now acceptable for publication. ****** 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.0243882.r003
Formally Accepted
3 Dec 2020 Acceptance Letter - Giordano Madeddu, Editor PONE-D-20-25200R1 Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection Dear Dr. Jacobs: 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. Giordano Madeddu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243882.r004

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