Initial mean arterial blood pressure (MABP) measurement is a risk factor for mortality in hypertensive COVID-19 positive hospitalized patients

Tenzin Yangchen; Farrukh M. Koraishy; Chang Xu; Wei Hou; Rajeev Rohatgi

doi:10.1371/journal.pone.0283331

Peer Review History

Original SubmissionApril 7, 2022
8 Jun 2022 Decision Letter - Yuyan Wang, Editor PONE-D-22-10325Normal mean arterial blood pressure (MABP) is a risk factor for mortality in hypertensive COVID-19 positive hospitalized patientsPLOS ONE Dear Dr. Rohatgi, 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. The authors had conducted a retrospective study to investigate the associations between MABPs and mortality in COVID-19 positive(+) patients. However, the research question is not well addressed in the manuscript. Please prepare appropriate revisions and replies to reviewers’ comments. Please submit your revised manuscript by Jul 23 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Yuyan Wang, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Additional Editor Comments: 1. Please design your analysis appropriately. Though the research question was clearly proposed in the manuscript, current results couldn’t answer the research question. Specially, if the research interest is the association between MABPs and COVID mortality, then only the COVID patients are needed. If the research interest is the association between MABPs and COVID infection, then both COVID positive and negative patients are needed. 2. Please check the distribution of the biomarkers before using mean/SD describing them. It’s obvious for some biomarkers the SDs are very large (even much larger than means). If distributions of the biomarkers are skewed, median/IQR should be used for description and nonparametric should be applied for comparison. 3. Please clarify if there are any variable selection procedure for MV analysis. [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: I Don't Know 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: 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: Interesting but hard to read. First, add the meaning of abbreviation and number in Second, in the discussion, it gives a long-winded explanation, meaning that many are on the results itself but not the interpretation and discussion on the results. And is there any evidence to support your conclusion, such as why low normal initial BP correlated with mortality and why in COVID 19 positive and why in patients with a history of HTN? Reviewer #2: Dear authors, Thank you for this submission. My comments are given below: Please add a reference or a reason for the cut-off values of MABP tertiles. Please add some detail regarding how control group was created to the methods section. It is only given at discussion but it would be more explanatory if given at methods section as well. Please add footnotes to the tables at supplement section to make clear meaning of asterisks. Table 2 at amin text and Table 2 at supplement are nearly same. It is like a repetition and hard to find where the difference is. Table 2 S might be revised the form that it only contains different data from Table 2 at main text. Please add footnote for asterisks at Table 2. It would be well if you may add systolic, diastolic blood pressure values and mean arterial blood pressure values as well to the tables 3 and 4 instead of only giving categorizations for them. Performing multivariate analysis is appreciated but models are created with variables significant at univariate adjustment. This made every multivariate model different from each other and avoid one to generalize results. The comment got form one figure is not valid for the other one although all were based on blood pressure. This made me confused a little bit. It is too much detail for the paper. There would be more comparison between Covid and control cases. I would like to see if there is any difference between two groups within the same MABP tertiles. This would be speculated in some ways: highlight importance of Covid if the Covid cases’ mortality were higher or importance of blood pressure if they were similar. ****** 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: Yes: Mustafa Sevinc ******** [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.0283331.r001
Revision 1
13 Jan 2023 Author Response Response to Critique Thank you for reviewing our manuscript and providing us an informative critique. We acknowledge the limitations noted by the reviewers and editor and hope to satisfy the critique. There has been some delay in responding to the critique because our original statistician, Ms. Yangchen, was out of the country, and after returning, started her PhD program. Dr. Wei Hou, a statistician at the Stony Brook University School of Medicine, agreed to assist in the follow up analysis. Reviewer#1 Interesting but hard to read. Thank you and will work to make the manuscript more readable. add the meaning of abbreviation and number in Please see supplementary tables. This includes all the abbreviations. in the discussion, it gives a long-winded explanation, meaning that many are on the results itself but not the interpretation and discussion on the results. And is there any evidence to support your conclusion, such as why low normal initial BP correlated with mortality and (a) why in COVID 19 positive and (b) why in patients with a history of HTN In the discussion I shortened the summary of the results to emphasize the clinically pertinent aspects and to speculate/hypothesize on mechanism of this finding. The study is not designed to answer why a low-normal blood pressure at initial evaluation of admitted COVID-19 (+) patients with long standing hypertension have a higher mortality. However, several clinical and basic science studies permit us to speculate why this finding may be true. Several clinical studies illustrate an association between the diagnosis of hypertension and mortality in COVID-19 (+) patients. The renin-angiotensin system, and specifically, ACE2 receptor, the receptor for COVID-19, is increased in bronchial biopsy specimens of patients with chronic systemic hypertension (1, 2). Thus, with greater availability of ACE2 receptors in hypertensive subjects, COVID-19 binding, entry and replication would be enhanced. Rapid viral replication tends to create a sicker and septic clinical picture associated with lower blood pressure; however, ACE2 receptor is a negative regulator of the renin-angiotensin system and its activation tends to reduce blood pressure. Therefore, it has been proposed that COVID-19 binding and internalization of ACE2 receptor could lead to unopposed angiontensin-2 affects leading to higher blood pressure. We asked this question about blood pressure, in part, to evaluate whether presenting blood pressure would be high (unopposed ACE2 receptor activity) or low (a more classic septic picture, with high viral load), and whether this could correlate this mortality. Based on our results, a lower MABP at presentation is a risk factor for mortality in hypertensive COVID-19 (+) subjects and, implies a septic clinical picture. The mortality in hypertensive subjects may be greater because (a) ACE2 receptors are more abundant leading to greater viral replication and entry and (b) long-standing hypertension leads to microvascular disease which, in the presence of modest hypotension, contributes to poor tissue perfusion. Reviewer#2 1. Please add a reference or a reason for the cut-off values of MABP tertiles. In an earlier analysis of the data, hospitalized COVID-19 (+) patients were divided according to JNC VII guidelines. Specifically, subjects were divided into the following groups: SBP 90-140 (normotensive), SBP 141-160 (moderate hypertension) and SBP > 161 (severe hypertension). ANOVA analysis of death in these groups demonstrated statistical difference; however, when comparing death between the normotensive group, which had the lowest mortality, and moderate or severe hypertension, no significance was noted. When subjects were categorized into SBP categories, normotensive subjects were n=1112, moderate hypertensives were n=271 and severe hypertensives were n=150. We chose to divide blood pressure into tertiles of mean arterial blood pressure (MABP). Dividing into tertiles of MABP equalizes the number of subjects in each group and enhances the strengths of the conclusions. This technique has been utilized by other investigators, including the SPRINT investigators(3). 2. Please add some detail regarding how control group was created to the methods section. It is only given at discussion but it would be more explanatory if given at methods section as well. All subjects (COVID-19 (-) and COVID-19 (+)) were also divided into tertiles of mean arterial blood pressure (MABP): T1 (65-85 mm Hg), T2 (86-97 mm Hg) and T3 (>98 mm Hg). For COVID-19 (+), the MABP category with the lowest mortality was identified as the control group and other two groups compared to it. The T2 MABP group had the lowest mortality amongst the three groups and was selected as the control group. It happened that in the COVID-19 (-) group that the highest mortality was in the T2 MABP group, and this was assigned as the control group. 3. Please add footnotes to the tables at supplement section to make clear meaning of asterisks. I included the footnotes in the supplementary tables. Thank you for pointing this out. 4. Table 2 at a min text and Table 2 at supplement are nearly same. It is like a repetition and hard to find where the difference is. Table 2S might be revised the form that it only contains different data from Table 2 at main text. Thank you for this comment. I have revised the tables so that they do not repeat the same data. 5. Please add footnote for asterisks at Table 2. The footnote to define the asterisks has been added to the end of each table (1-4). 6. It would be well if you may add systolic, diastolic blood pressure values and mean arterial blood pressure values as well to the tables 3 and 4 instead of only giving categorizations for them. Thank you for the comment. I have added MABP values to each of the BP categories in Table 3 and 4. 7. Performing multivariate analysis is appreciated but models are created with variables significant at univariate adjustment. This made every multivariate model different from each other and avoid one to generalize results. The comment got form one figure is not valid for the other one although all were based on blood pressure. This made me confused a little bit. It is too much detail for the paper. Based on the Editor’s comments, the tables and MV analysis were revised. Because biomarkers are not normally distributed, all the variables were reviewed and those variables that are not normally distributed were revised to median/IQR. Statistical analyses were then performed. Based on these changes, the univariate analysis of mortality no longer was statistically significant between T3 MABP and T2 MABP (See Table 2). Therefore, MV analysis (Figure 1) only included associated risk factors evaluating T1 MABP and T2 MABP. 8. There would be more comparison between Covid and control cases. I would like to see if there is any difference between two groups within the same MABP tertiles. This would be speculated in some ways: highlight importance of Covid if the Covid cases’ mortality were higher or importance of blood pressure if they were similar. The mortality at each level of MABP tertile was significantly greater in the COVID-19(+) subjects than the COVID-19 (-) (p<0.0001). Though we agree that it would be interesting to compare the characteristics of the MABP tertiles between COVID-19 (+) and COVID-19 (-) patients, we feel this would require a new focus. The goal of this manuscript was to identify where the initial, presenting blood pressure predicted mortality in the COVID-19 (+). We included COVID-19 (-) data to emphasize (a) the difference in mortality between COVID-19(+) and (-) patients during the same time frame and (b) illustrate MABP’s differential associations between COVID-19 (+) and (-) subjects. Additionally, the journal editor has requested that the focus remain limited to the hypothesis and not become overly broad. Editor 1. Please design your analysis appropriately. Though the research question was clearly proposed in the manuscript, current results couldn’t answer the research question. Specially, if the research interest is the association between MABPs and COVID mortality, then only the COVID patients are needed. If the research interest is the association between MABPs and COVID infection, then both COVID positive and negative patients are needed. Thank you and we acknowledge this concern. Few COVID-19 studies reported a comparator group of uninfected patients admitted to the hospital during the initial surge of SARs-CoV-2 infections. In addition, reviewer #2 specifically stated on comparison of between MABP in both COVID-19(+) and (-) patients would be of significant interest (see above). Because of this novelty, we elected to expand the hypothesis to include uninfected subjects admitted to SBUH during the COVID surge. The hypothesis has been modified to “ Due to SARS-CoV-2’s direct effects on the RAAS system, we hypothesized that an elevated BP at clinical presentation portended greater mortality, which differed from uninfected patients.” It expands the scope of investigation, but due the observation that tertiles of MABP in COVID-19 (-) subjects were not associated with differences in mortality, no further analysis was performed. 2. Please check the distribution of the biomarkers before using mean/SD describing them. It’s obvious for some biomarkers the SDs are very large (even much larger than means). If distributions of the biomarkers are skewed, median/IQR should be used for description and nonparametric should be applied for comparison. Thank you for this comment and the revised manuscript will follow your suggestion. 3. Please clarify if there are any variable selection procedure for MV analysis. In the original analysis the MV analysis was performed with variables that which statistically significant; however, after re-analysis of the data, death in T3 MABP did not differ from T2 MABP so figure 1B was removed. 1. Pinto BGG, Oliveira AER, Singh Y, Jimenez L, Goncalves ANA, Ogava RLT, et al. ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19. J Infect Dis. 2020;222(4):556-63. 2. Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy. 2020;75(11):2829-45. 3. Shapiro BP, Ambrosius WT, Blackshear JL, Cushman WC, Whelton PK, Oparil S, et al. Impact of Intensive Versus Standard Blood Pressure Management by Tertiles of Blood Pressure in SPRINT (Systolic Blood Pressure Intervention Trial). Hypertension. 2018;71(6):1064-74. Attachments Attachment Submitted filename: Response to Critique 221025.docx https://doi.org/10.1371/journal.pone.0283331.r002
7 Mar 2023 Decision Letter - Yuyan Wang, Editor Initial mean arterial blood pressure (MABP) is a risk factor for mortality in hypertensive COVID-19 positive hospitalized patients PONE-D-22-10325R1 Dear Dr. Rohatgi, 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, Yuyan Wang, Ph.D. 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: Dear authors, Thank you for revised version of the manuscript. It seems that you have answered all of my questions. I think it may be accepted 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 #2: Yes: Mustafa Sevinc ******** https://doi.org/10.1371/journal.pone.0283331.r003
Formally Accepted
21 Mar 2023 Acceptance Letter - Yuyan Wang, Editor PONE-D-22-10325R1 Initial mean arterial blood pressure (MABP) measurement is a risk factor for mortality in hypertensive COVID-19 positive hospitalized patients Dear Dr. Rohatgi: 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. Yuyan Wang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0283331.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .