Smoking is associated with increased risk of cardiovascular events, disease severity, and mortality among patients hospitalized for SARS-CoV-2 infections

Ram Poudel; Lori B. Daniels; Andrew P. DeFilippis; Naomi M. Hamburg; Yosef Khan; Rachel J. Keith; Revanthy Sampath Kumar; Andrew C. Strokes; Rose Marie Robertson; Aruni Bhatnagar

doi:10.1371/journal.pone.0270763

Peer Review History

Original SubmissionJanuary 3, 2022
25 Jan 2022 Decision Letter - Gaetano Santulli, Editor PONE-D-22-00192Smoking is Associated with Increased Risk of Cardiovascular Events, Disease Severity, and Mortality Among Patients Hospitalized for SARS-CoV-2 InfectionsPLOS ONE Dear Dr. Bhatnagar, 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 Mar 11 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. 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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This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ The strengths and limitations of the study should be deeply addressed, taking into account sources of potential bias or imprecision: Discuss both direction and magnitude of any potential bias. The fundamental role of endothelial dysfunction in the systemic manifestations of COVID-19 should be better discussed: -J Clin Med. 2020;9(5):1417; doi: 10.3390/jcm9051417 -Expert Opin Ther Targets. 2020 Jun 27:1-8. doi: 10.1080/14728222.2020.1783243 -Cells. 2020 Jul 9;9(7):E1652. doi: 10.3390/cells9071652 -Eur Heart J. 2021 May 23;7(3):e2-e3. doi: 10.1093/ehjcvp/pvaa145. -Atherosclerosis. 2021;322:39-50. doi: 10.1016/j.atherosclerosis.2021.02.009. -EClinicalMedicine. 2021 Sep 9:101125. doi: 10.1016/j.eclinm.2021.101125. -Oxid Med Cell Longev. 2021 Aug 21;2021:8671713 -Theranostics. 2021;11(16):8076-8091. -Crit Care. 2021 Aug 25;25(1):306. -Front Physiol. 2020 Aug 4;11:989. doi:10.3389/fphys.2020.00989 (chronological appraisal of the publications on COVID-19 and endothelial dysfunction). [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 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: Yes Reviewer #2: No ****** 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 paper aimed to investigate the association of smoking and Covid-19 in hospitalized patients. The idea is interesting and the study has been presented in a scientific manner. I have just few concerns: - I see that data come from previously published AHA registries. Howevere, did you obtain the ethical approval from your committe? If no, please clarify the reason. - Please improve the discussion and the reference section discussing and citing the following PMID: 34655476 35027590 33540664 32464099 33246296 32341101 Reviewer #2: The data and analysis in this paper are fine, but there are several issues that need to be resolved before the paper can be accepted. 1. The association between smoking and COVID-19 disease severity among people diagnosed with COVID is not "limited" or "unclear." There have been several meta-analyses published on this question (beginning with Patanavanich R, Glantz SA. Smoking Is Associated With COVID-19 Progression: A Meta-analysis. Nicotine Tob Res. 2020 Aug 24;22(9):1653-1656. doi: 10.1093/ntr/ntaa082. PMID: 32399563; PMCID: PMC7239135) which show a positive association using a variety of approaches. Thus, the authors overstate to marginal value of their paper. The actual contribution is to confirm this association in a well-characterized group of patients in the US (which is more than enough to warrant publication in PLOS One). This language throughout the paper needs to be toned down accordingly. 2. This situation is different from the question of how smoking affects risk of COVID infection which has been more equivocal, as illustrated in Ref 14 of the manuscript. Because the present manuscript deals only with hospitalized patients, it does not provide any information about the relationship between smoking can COVID risk. This distinction needs to be made clear throughout the paper. Beyond making this distinction and commenting on the lack of consensus on the effect of smoking on risk of COVID infection, discussion of this question should be dropped from the paper, including the Discussion section (pages 7 and * because the data and analysis in this paper does not contribute anything to the discussion of smoking and risk of COVID infection. 3. The authors lump e-cigarette use (vaping) in with smoking in their analysis. They need to justify this approach explicitly, both in terms of biology and by doing a sensitivity analysis showing that doing so does not affect the results. The fact that smoking and vaping are combined needs to be indicated in the abstract. Indeed, if smoking and vaping have similar increases in risk, that would be an important result on its own. 4. The finding that the risks associated with smoking are higher in younger patients is consistent with a recent meta-analysis that reached this conclusion based on data pooled across studies (Patanavanich R, Glantz SA. Smoking is associated with worse outcomes of COVID-19 particularly among younger adults: a systematic review and meta-analysis. BMC Public Health. 2021 Aug 16;21(1):1554. doi: 10.1186/s12889-021-11579-x. PMID: 34399729; PMCID: PMC8366155). The fact that the authors found this result in a single dataset is an important contribution of this paper. 5. The authors state that the data are available but do not say where it is deposited so that people can access it. ******** 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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. 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Revision 1
11 Jun 2022 Author Response Response to Reviewers’ Comments Reviewer # 1: 1. “I see the data come from previously published AHA registries. However, did you obtain ethical approval from your committee?” Get-With-The-Guidelines® (GWTG) is a continuous quality improvement program registry, overseen by the American Heart Association (AHA) and an Oversight Committee of clinician leaders in quality improvement, that retrospectively collects patient-level adherence data within 3,000 U.S. hospitals. To participate, hospital sites directly and retrospectively abstract or upload quality of care and outcomes data from hospitalized patients’ electronic health records into the registry. Demographic data, clinical data, and test results obtained as part of routine care for CVD patients, as well as pertinent treatments and in-hospital outcomes, are captured. Patient identities (e.g. name, social security number, medical record number, etc.) are not collected. Sites are responsible for assigning a unique study identifier to each submitted record, which is not shared outside the site so the patient cannot be re-identified. The data are collected for quality improvement purposes, and therefore patients are neither recruited nor consented. All research completed using analyses of the AHA GWTG program has been determined to be exempt from IRB oversight by Advarra (see attached). This has been added to the revised text (see page 3). 2. “Please improve the discussion and the reference section discussing and citing the following PMID” Thank you for pointing us to the relevant literature. To the extent possible, we have cited these references both in the introduction and the discussion. Reviewer # 2: 1. “The association between smoking and COVID-19 disease severity among people diagnosed with COVID is not "limited" or "unclear." There have been several meta-analyses published…... This language throughout the paper needs to be toned down accordingly.” The discussion has been “toned down” as suggested. The “limited” and “unclear” qualifications have been removed, although we do note that not all studies have led to consistent results. 2. “This situation is different from the question of how smoking affects risk of COVID infection which has been more equivocal, as illustrated in Ref 14 of the manuscript. Because the present manuscript deals only with hospitalized patients, it does not provide any information about the relationship between smoking can COVID risk. This distinction needs to be made clear throughout the paper. Beyond making this distinction and commenting on the lack of consensus on the effect of smoking on risk of COVID infection, discussion of this question should be dropped from the paper, including the Discussion section (pages 7 and * because the data and analysis in this paper does not contribute anything to the discussion of smoking and risk of COVID infection.” We have removed the discussion of the relationship between smoking and the risk of COVID-19 infection. 3. “The authors lump e-cigarette use (vaping) in with smoking in their analysis. They need to justify this approach explicitly, both in terms of biology and by doing a sensitivity analysis showing that doing so does not affect the results. The fact that smoking and vaping are combined needs to be indicated in the abstract. Indeed, if smoking and vaping have similar increases in risk, that would be an important result on its own.” The number of individuals in our registry who used e-cigarettes is very small – 41 patients reported e-cig only versus 2198 who reported smoking only without e-cigarettes. In our sensitivity analysis, removal of e-cigarette users from the dataset did not significantly affect the odds ratio of in-hospital death or mechanical ventilator use. This has been stated in the revised manuscript. 4. “The finding that the risks associated with smoking are higher in younger patients is consistent with a recent meta-analysis that reached this conclusion based on data pooled across studies … The fact that the authors found this result in a single dataset is an important contribution of this paper.” Thank you for pointing this out. We have cited the paper in our revised manuscript. 5. “The authors state that the data are available but do not say where it is deposited so that people can access it.” The American Heart Association has a strict policy regarding the use and integrity of its Get-With-The-Guidelines® data and is unable to provide public access to the COVID-19 dataset, in full or in part without other agreements in place. However, researchers are able to go to www.precision.heart.org , navigate to data, documentation, and COVID-19 to see data documentation, dictionary and coding information and explore the variables, descriptions, source, type, missingness and distribution of the data. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0270763.r002
17 Jun 2022 Decision Letter - Gaetano Santulli, Editor Smoking is Associated with Increased Risk of Cardiovascular Events, Disease Severity, and Mortality Among Patients Hospitalized for SARS-CoV-2 Infections PONE-D-22-00192R1 Dear Dr. Bhatnagar, 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, Gaetano Santulli, MD Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0270763.r003
Formally Accepted
7 Jul 2022 Acceptance Letter - Gaetano Santulli, Editor PONE-D-22-00192R1 Smoking is Associated with Increased Risk of Cardiovascular Events, Disease Severity, and Mortality Among Patients Hospitalized for SARS-CoV-2 Infections Dear Dr. Bhatnagar: 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 Professor Gaetano Santulli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0270763.r004

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