Predictors of life-threatening complications in relatively lower-risk patients hospitalized with COVID-19

Christopher J. Gonzalez; Cameron J. Hogan; Mangala Rajan; Martin T. Wells; Monika M. Safford; Laura C. Pinheiro; Arnab K. Ghosh; Justin J. Choi; Clare A. Burchenal; Pooja D. Shah; Martin F. Shapiro

doi:10.1371/journal.pone.0263995

Peer Review History

Original SubmissionJuly 13, 2021
8 Oct 2021 Decision Letter - Marlene Camacho-Rivera, Editor PONE-D-21-22788Predictors of Life-Threatening Complications in Relatively Lower-Risk Patients Hospitalized with COVID-19PLOS ONE Dear Dr. Gonzalez, 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 within 60 days of receipt of this email. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ****** 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: 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 ****** 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: 1. General comments The authors conducted retrospective cohort studies to assess the rate and predict life-threatening complications among relatively lower-risk adults hospitalized with COVID-19. Though this study is limited, I agree that this cohort, which focused on the low-risk population, is beneficial. However, I have some concerns that should be addressed. 2. Specific comments ① As shown below, I think you need to exclude from the study all those that have been proven to be a risk in at least one meta-analysis. ・Pregnancy and recent pregnancy ・Smoking, current and former https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html ② The CDC webpage indicates that obesity as a risk for severe COVID-19 illness is a BMI ≧ 30 kg/m2. Therefore, in your manuscript, you should describe why you did not adopt this result and defined BMI ≧ 35 kg/m2 as obesity. ③ COVID-19 illness is a disease in which a high probability of intubation even without complication. However, the intubation rate is low compared to life-threatening complications in this study, and it is questionable whether all these complications were really life-threatening complications. What kind of arrhythmia is included? Were there any false positives or contamination in the blood cultures? How did you confirm venous thrombus embolism? You should show details of how these illnesses were diagnosed in this study. ④ The mortality rate of COVID-19 in this population is higher than the general mortality rate (PMID: 33007452). Therefore, you should explain more details about this cohort, such as indications for hospitalization. ⑤ According to this study, living in areas with limited English proficiency was associated with life-threatening complications. This may be a localized problem, and many readers are unfamiliar with New York City, so they may not share this issue. In order to provide beneficial information, please describe the characteristics of the limited English proficiency in New York City. ****** 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 [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.0263995.r001
Revision 1
30 Nov 2021 Author Response Dear Editor, Thank you for reviewing our manuscript and for your thoughtful feedback. We have addressed the limitations noted within the review, further clarifying our rationale for the inclusion and exclusion criteria used within the study, and have elaborated on context of the study findings. Please find a response to each point raised in the review. 1. As shown below, I think you need to exclude from the study all those that have been proven to be a risk in at least one meta-analysis. (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html) a. Pregnancy and recent pregnancy b. Smoking, current and former RESPONSE: With regard to the exclusion criteria for our sample, classification as “relatively lower-risk” was based on the absence of preexisting comorbid conditions, defined using the Charlson Comorbidity Index (CCI), which itself predicts 10-year survival using age and the presence or absence of 16 health conditions, rather than on the CDC list of underlying medical conditions associated with higher risk for severe COVID-19, which has continued to evolve over the course of the pandemic. Smoking and pregnancy are not conditions in the Charlson Index. As a result, relatively-lower risk adults with a history of smoking (n=33) or pregnancy (n=15) were included in our main analytic sample (n=963). The number of pregnant individuals in our sample has been added to Table 1. In Supplementary Appendix 2 (now S2 Table) of our original manuscript, we reported an additional analysis that expanded our exclusion criteria based on existing literature regarding risk factors for COVID-19 severity and mortality. That analysis excluded patients with hypertension and any severity of obesity (BMI >30mg/k2). Based on reviewer comments, the revised manuscript now also excludes patients with a history of smoking or with pregnancy from the relatively low-risk sample in this additional analysis (S2 Table). We have clarified this change in the statistical methods section of the revised manuscript (Page 6). 2. The CDC webpage indicates that obesity as a risk for severe COVID-19 illness is a BMI ≧ 30 kg/m2. Therefore, in your manuscript, you should describe why you did not adopt this result and defined BMI ≧ 35 kg/m2 as obesity. RESPONSE: While prior meta-analyses cited by the CDC have concluded that obesity is associated with the development of critical condition in COVID-19 patients, these studies have noted that the BMI ranges at which the association are observed have varied considerably between individual studies, and have predominantly been observed in ranges over 35 kg/m2. (PMID 32686331) Notably, none of the four individual studies included in that meta-analysis showed a statistically significant association between obesity and severe COVID-19 when using a BMI range of 30-35 kg/m2 to define obesity. Furthermore, this meta-analysis assessed the relation of obesity to critical condition, rather than the risk of mortality. In the revised manuscript, we have clarified the reasoning for using this selection criteria, stating “we considered patients with severe obesity ([BMI] ≥35 kg/m2) to have a preexisting comorbid condition because individual studies have consistently shown that severe obesity is independently associated with COVID-19 severity and mortality. Patients with BMI ≥30 but <35 kg/m2, referred to as low-risk obesity, were included in our cohort because independent associations with COVID-19 morbidity and mortality have not been consistently established in this group.” (Page 4) 3. COVID-19 illness is a disease in which a high probability of intubation even without complication. However, the intubation rate is low compared to life-threatening complications in this study, and it is questionable whether all these complications were really life-threatening complications. You should show details of how these illnesses were diagnosed in this study. a. What kind of arrhythmia is included? b. Were there any false positives or contamination in the blood cultures? c. How did you confirm venous thrombus embolism? RESPONSE: In regards to outcomes observed in our sample, specifically the rate of life-threatening complications, our primary outcome was a composite score of life-threatening complications that included intubation and death. Consistent with reviewer comments about the high probability of intubation without other complication in COVID-19, intubation and death were in fact the most common complications observed in our sample and contributed to a large proportion of all life-threatening complications observed. In regards to details about how illnesses were diagnosed in this study, outcome data were collected by manual abstraction from the electronic medical records, as noted in our methods. We have provided further details about how these outcomes were abstracted, including the following statement: "Abstraction of life-threatening complications was adjudicated based on physician documentation and/or diagnostic results within the electronic medical records. Major arrhythmias included physician documentation of atrial fibrillation, supraventricular tachycardias, ventricular fibrillation and/or ventricular tachycardia. Positive blood cultures were directly abstracted from microbiology reports. Confirmation of VTE was based on imaging such as a CT-PE or ultrasound." (Page 5) Moreover, we cited an additional limitation in the limitations section of our manuscript: “Due to inherent limitations in the chart abstraction process, including a lack of complete clinical context, clinical interpretations of blood culture results were not conducted, and potential contaminants may have been included in the analysis. Notably, the prevalence of this complication was low in our sample (3.2% and 3.8% in those <55 and ≥55 years respectively).” (Page 14) 4. The mortality rate of COVID-19 in this population is higher than the general mortality rate (PMID: 33007452). Therefore, you should explain more details about this cohort, such as indications for hospitalization. RESPONSE: The mortality rate of COVID19 has certainly varied across populations, as is reflected in this interesting reference. However, the mortality rate observed in our paper is the mortality rate in a relatively lower-risk patient population hospitalized with COVID-19. It does not represent the fatality rate, which would include the number of deaths among all those in the entire population that may be potentially infected. The mortality rate in our study approaches those seen among other patients hospitalized with COVID-19 during similar time periods.(PMID 32320003) The mortality rate in our sample was lower than other hospitalized cohorts given the relative health of this cohort (they are by definition relatively lower-risk). Regarding the indication for hospitalization in our study, we have added a statement to our manuscript stating that the decision to hospitalize patients was based on the clinical judgement of the admitting physician at the time of presentation and unaffected by this retrospective study.(Page 4) 5. According to this study, living in areas with limited English proficiency was associated with life-threatening complications. This may be a localized problem, and many readers are unfamiliar with New York City, so they may not share this issue. In order to provide beneficial information, please describe the characteristics of the limited English proficiency in New York City. RESPONSE: We have expanded on the linguistic demographics of New York City within our discussion (Page 14), describing the characteristics of limited English proficiency in New York City. 1. Reviewer Comment: We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data RESPONSE: The data is not a core part of the research being presented and the phrase has been removed. Thank you for your consideration of our manuscript. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0263995.r002
2 Feb 2022 Decision Letter - Marlene Camacho-Rivera, Editor Predictors of life-threatening complications in relatively lower-risk patients hospitalized with COVID-19 PONE-D-21-22788R1 Dear Dr. Gonzalez, 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, Marlene Camacho-Rivera, ScD, MPH 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: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) ****** 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 https://doi.org/10.1371/journal.pone.0263995.r003
Formally Accepted
7 Feb 2022 Acceptance Letter - Marlene Camacho-Rivera, Editor PONE-D-21-22788R1 Predictors of life-threatening complications in relatively lower-risk patients hospitalized with COVID-19 Dear Dr. Gonzalez: 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. Marlene Camacho-Rivera Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0263995.r004

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