C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19

Milad Sharifpour; Srikant Rangaraju; Michael Liu; Darwish Alabyad; Fadi B. Nahab; Christina M. Creel-Bulos; Craig S. Jabaley; on behalf of the Emory COVID-19 Quality & Clinical Research Collaborative

doi:10.1371/journal.pone.0242400

Peer Review History

Original SubmissionAugust 20, 2020
28 Sep 2020 Decision Letter - Stelios Loukides, Editor PONE-D-20-25813 C-Reactive Protein as a Prognostic Indicator in Hospitalized Patients with COVID-19 PLOS ONE Dear Dr. Sharifpour, 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. Some minor edits are needed. 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. 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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Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. 3. Please provide the names of the six cohorted COVID ICUs across three Emory Healthcare acute care hospitals in Atlanta, GA. 4. Thank you for stating the following financial disclosure: "No" At this time, please address the following queries: Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” If any authors received a salary from any of your funders, please state which authors and which funders. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. One of the noted authors is a group or consortium [Emory COVID-19 Quality and Clinical Research Collaborative]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 6. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. 7. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table. 8. 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. [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: 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 ****** 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: In this manuscript, the authors report a retrospective study investigating the temporal progression of C-reactive protein (CRP) and its association with all-cause hospital mortality. Comparison of patients that died with those that survived showed that hospitalization-wide median CRP levels were significantly higher in patients that died. CRP levels tended to increase linearly during the first week of hospitalization, peaking on day 5. However, patients that survived had lower peak CRP levels and earlier declines compared to patients that died. The authors suggest the utility of daily CRP values in the stratification and prognosis of patients with COVID-19 This is a thorough and interesting study investigating the potential utility of CRP values during hospitalization in assessing disease severity and prognosis in COVID-19 patients. The experimental design of the study is solid and the results and clearly presented. The manuscript is well-written and makes a positive contribution to the field. There are only a few minor revisions recommended. 1. In Table 1, please indicate the corresponding units for the variables (e.g., CRP, troponin, D-dimer, WBC). Please indicate the meaning of the acronyms for the clinical variables as well (e.g., DM, OSA, CAD, CRRT, CHF, CKD). 2. Table 2 shows two different models. Please indicate in the text what is the difference between them. 3. Please indicate in Materials and Methods what was the methodology used to measure CRP levels and whether it was the same for all six hospitals. 4. On lines 119-120, the word “one” is repeated. Did the authrors meant “only one”? ****** 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. Attachments Attachment Submitted filename: Review Comments regarding manuscript entitled.docx https://doi.org/10.1371/journal.pone.0242400.r001
Revision 1
30 Oct 2020 Author Response 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 Thank you! I have gone through the manuscript and to the best of my ability followed the PLOS ONE’s style requirements. 2. In your ethics statement in the Methods section and in the online submission form, please provide additional information about the data used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information. Thank you. The data were fully anonymized before we accessed them. Since this was a retrospective analysis, the IRB waived the requirement for informed consent. 3. Please provide the names of the six cohorted COVID ICUs across three Emory Healthcare acute care hospitals in Atlanta, GA. 1. 2 East ICU at Emory St. Joseph Hospital 2. Medical ICU at Emory University Hospital Midtown 3. Peachtree ICU at Emory University Hospital Midtown 4. 5G ICU at Emory University Hospital 5. 6G ICU at Emory University Hospital 6. 5E ICU at Emory University Hospital 4. Thank you for stating the following financial disclosure: "No" At this time, please address the following queries: a. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. a. This study was partly supported by internal funds (Department of Anesthesiology and Critical Care, Emory University Hospital) b. This study was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health b. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” a. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” c. If any authors received a salary from any of your funders, please state which authors and which funders. a. None of the authors received a salary from the funder. d. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.” a. Thank you very much. This is not applicable, and we have indicated our source of funding appropriately Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 5. One of the noted authors is a group or consortium [Emory COVID-19 Quality and Clinical Research Collaborative]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. Emory COVID-19 Quality and Clinical Research Collaborative Members (in alphabetical order): Max W. Adelman, Scott Arno, Sara C. Auld, Theresa Barnes, William Bender, James M. Blum, Gaurav Budhrani, Stephanie Busby, Laurence Busse, Mark Caridi-Scheible, David Carpenter, Nikulkumar Chaudhari, Craig M. Coopersmith, Gordon Dale, Lisa Daniels, Johnathan A. Edwards, Jane Fazio, Babar Fiza, Eliana Gonzalez, Ria Gripaldo, Charles Grodzin, Robert Groff, Alfonso C. Hernandez-Romieu, Max Hockstein, Dan Hunt, Craig S. Jabaley, Jesse T. Jacob, Colleen Kraft, Greg S. Martin, Samer Melham, Nirja Mehta, Chelsea Modlin, David J. Murphy, Jung Park, Deepa Patel, Cindy Powell, Amit Prabhaker, Jeeyon Rim, Ramzy Rimawi, Chad Robichaux, Nicholas Scanlon, Milad Sharifpour, Bashar Staitieh, Michael Sterling, Jonathan Suarez, Colin Swenson, Nancy Thakkar, Alexander Truong, Hima Veeramachaneni, Alvaro Velasquez, Aimee Vester, Michael Waldmann, Max Weinmann, Thanushi Wynn, and Joel Zivot. Dr. Sara Auld (sara.auld@emory.edu) is the lead author of the collaborative. 6. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical. Thank you. I have corrected this and both abstracts are now identical. 7. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 3 in your text; if accepted, production will need this reference to link the reader to the Table. Thank you. We have included a sentence in the results section (line 187) as follows, referencing Table 2. ‘These thresholds for CRP measures are shown in Table 2. Table 3 was changed to Table 2 in order to keep the correct order of Tables in the body of the text. 8. 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. 1. In Table 1, please indicate the corresponding units for the variables (e.g., CRP, troponin, D-dimer, WBC). Please indicate the meaning of the acronyms for the clinical variables as well (e.g., DM, OSA, CAD, CRRT, CHF, CKD). Thank you. These are reflected in the text/table now, as well as here. CRP: mg/L Troponin: ng/mL D-Dimer: ng/mL WBC: 10E3/mcL DM: Diabetes Mellitus CAD: Coronary Artery Disease OSA: Obstructive Sleep Apnea CRRT: Continuous Renal Replacement Therapy CHF: Congestive Heart Failure CKD: Chronic Kidney Disease 2. Table 2 shows two different models. Please indicate in the text what is the difference between them. We have changed table 2 to table 3 and included a foot note to Table 3 to clarify the differences between Models 1 and 2 as follows: Model 1: CRP slope and Maximum CRP levels during the first 7 days were used as continuous variables in the model. Model 2: CRP slope≥0 and Maximum CRP level ≥ 250 were used as thresholds in the model. 3. Please indicate in Materials and Methods what was the methodology used to measure CRP levels and whether it was the same for all six hospitals. All six hospitals use the same methodology to measure CRP. CRP reagent is used to measure CRP concentration by a turbidimetric method1,2 In the reaction, c-reactive protein combines with specific antibody to form insoluble antigen-antibody complexes. The Beckman Coulter SYNCHRON System(s) � (Beckman Coulter Life Sciences, Indianapolis, IN) automatically proportions the appropriate sample and reagent volumes into a cuvette. The ratio used is one part sample to 26 parts reagent. The system monitors the change in absorbance at 340 nanometers. This change in absorbance is proportional to the concentration of C-reactive protein in the sample and is used by the System to calculate and express C-reactive protein concentration based upon a single-point adjusted, pre-determined calibration curve 4. On lines 119-120, the word “one” is repeated. Did the authors mean “only one”? Thank you, I have corrected this and eliminated the redundant “one” and changed it to “only one” in line 119. References: 1. Boyden, A., Button, E., Germerog, D., "Precipitin Testing With Special Reference to the Measurement of Turbidity", J. Immunol., 57:211 (1947). 2. Hellsing, K., "The Effects of Different Polymers for Enhancement of the Antigen-Antibody Reaction as Measured with Nephelometry", Protides of the Biological Fluids, 23:579 (1973). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0242400.r002
3 Nov 2020 Decision Letter - Stelios Loukides, Editor C-Reactive Protein as a Prognostic Indicator in Hospitalized Patients with COVID-19 PONE-D-20-25813R1 Dear Dr. Sharifpour, 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, Stelios Loukides Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0242400.r003
Formally Accepted
10 Nov 2020 Acceptance Letter - Stelios Loukides, Editor PONE-D-20-25813R1 C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19 Dear Dr. Sharifpour: 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 Stelios Loukides Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0242400.r004

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