What about tocilizumab? A retrospective study from a NYC Hospital during the COVID-19 outbreak

Monica Mehta; Lawrence J. Purpura; Thomas H. McConville; Matthew J. Neidell; Michaela R. Anderson; Elana J. Bernstein; Donald E. Dietz; Justin Laracy; Shauna H. Gunaratne; Emily Happy Miller; Jennifer Cheng; Jason Zucker; Shivang S. Shah; Shaoli Chaudhuri; Christian A. Gordillo; Shreena R. Patel; Tai Wei Guo; Lara E. Karaaslan; Ran Reshef; Benjamin A. Miko; Joan M. Bathon; Marcus R. Pereira; Anne-Catrin Uhlemann; Michael T. Yin; Magdalena E. Sobieszczyk

doi:10.1371/journal.pone.0249349

Peer Review History

Original SubmissionNovember 25, 2020
16 Feb 2021 Decision Letter - Aleksandar R. Zivkovic, Editor PONE-D-20-37152 What about Tocilizumab? A Retrospective Study from a NYC Hospital during the COVID-19 Outbreak PLOS ONE Dear Dr. Mehta, 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 Apr 02 2021 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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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: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 5. Review Comments to the Author Reviewer #1: The article by Monica Metha and her collaborators entitled What about Tocilizumab? A retrospective study from NYC Hospital during the COVID-19 Outbreak is interesting. I suggest accepting it as proposed. Reviewer #2: This study adds to the literature on tocilizumab use in SARS-CoV2 infection. The conclusion of the study indicates that there is no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab. This is an important study for clinicians to be aware of. I do have a few comments for the authors: Some comments 1- How was information regarding receipt of tocilizumab prior to hospitalization obtained? Was it confirmed that patients were taking the tocilizumab? Could this be a limitation to the study? 2- What medication were given to COVID-19 patients along with tocilizumab? If the authors have collected data concerning each individual’s inpatient prescription chart beyond the details of their receipt. All participants received what standardized COVID-19 treatment protocol along with tocilizumab in regular medications? Reviewer #3: The manuscript is quite good written (I noticed a little mistake at line 262; will instead of with). There are however some points which deserve more attention. First of all the tocilizumab group seems composed of a number of patients with more comorbidities (1,031 vs 0,7 pro patient) than controls and these subjects were not matched with controls on the basis of the specific comorbidity ( diabetes with diabetes and so on). I naturally mean that the important thing at the end, among the two groups is that the single comorbidities are egually represented. There was also no mention of the other treatments undergone during hospital stay, and in my opinion it would be interesting to know which drugs have been administered in the two groups. It should be very good highlighted that in the tratment group, a low dose of Tocilizumab (400 mg once) was used. For what concerns the first point, I only would like to know authors opinion, in order to promote a positive exchange. Thankyou ****** 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:** Devendra Kumar Reviewer #3: 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.0249349.r001
Revision 1
4 Mar 2021 Author Response Comments are pasted here, but are better formatted in the letter attached. Reviewer 2 had two questions: 1. How was information regarding receipt of tocilizumab prior to hospitalization obtained? Was it confirmed that patients were taking tocilizumab? Could this be a limitation to the study? Response: Upon chart review, we did not identify any patients who received tocilizumab prior to admission in our electronic medical record. We also excluded patients with active malignancy; therefore, use of tocilizumab for cytokine release syndrome is highly unlikely. Moreover, that would be given in the inpatient setting. It is remotely possible that one of our study patients received tocilizumab as an outpatient at a different medical system. We can include a sentence in the discussion section making this point. Added, “Though no doses of tocilizumab prior to admission were documented in our electronic health record; there is a remote possibility that previous doses were given outside our hospital system for rheumatoid arthritis.” 2. What medication were given to COVID-19 patients along with tocilizumab? If the authors have collected data concerning each individual inpatient prescription chart beyond the details of their receipt. All participants received what standardized COVID-19 treatment protocol along with tocilizumab in regular medications? Response: Great question. See here with a table describing concurrent medications for our cohort. Because of uncertainty around implications of these medications, we did not include them in the final paper. At this point, the only medication with a clear mortality benefit is dexamethasone (or other corticosteroid), but patients receiving steroids were excluded from our study in order to understand the benefit of tocilizumab alone. We added a sentence describing remdesivir use between groups in our paper. Added, “Only 6.1% of patients in the tocilizumab group and 5.9% in the control group received remdesivir because it was only available by compassionate use during the study period.” Characteristics of Patients Receiving or Not Receiving Tocilizumab Tocilizumab N = 33 Control N = 74 Home medications ACE Inhibitors 11 (33.3) 18 (24.3) Corticosteroids 2 (6.1) 3 (4.1) Warfarin 4 (12.1) 6 (8.1) Statin 9 (27.3) 22 (29.7) COVID-19 medications Remdesivir 2 (6.1) 4 (5.9) Hydroxychloroquine 25 (75.5) 54 (73.0) Azithromycin 20 (60.6) 39 (52.7) Reviewer 3 had the following point: 1. The manuscript is quite good written (I noticed a little mistake at line 262; will instead of with).There are however some points which deserve more attention. First of all the tocilizumab group seems composed of a number of patients with more comorbidities (1,031 vs 0,7 pro patient) than controls and these subjects were not matched with controls on the basis of the specific comorbidity (diabetes with diabetes and so on). I naturally mean that the important thing at the end, among the two groups is that the single comorbidities are egually represented. There was also no mention of the other treatments undergone during hospital stay, and in my opinion it would be interesting to know which drugs have been administered in the two groups. It should be very good highlighted that in the tratment group, a low dose of Tocilizumab (400 mg once) was used. For what concerns the first point, I only would like to know authors opinion, in order to promote a positive exchange. Thankyou Response: Great points. 1. The typo of “will” was changed to “with” – thank you! 2. The statement that we didn’t match specific comorbidities (e.g. diabetes) with specific comorbidities is correct. However, we did two sets of matching to balance the level of illness between groups. First, we matched on a set of variables, including number of comorbidities: • age • sex • body mass index (BMI) • ethnicity • number of comorbidities (hypertension, diabetes, coronary artery disease, liver disease, and chronic kidney disease) • presence of pulmonary disease • initial laboratory levels of C-reactive protein (CRP) • lactate dehydrogenase • initial calculated PaO2:FiO2 • initial heart rate • level of care at admission And second, we performed multivariable ordinal logistic regression models to determine the relationship between tocilizumab use and day 14 and day 28 ordinal score, adjusted for the ordinal score prior to medication administration, the ordinal score on day of hospital admission, and whether the subject was in the intensive care unit (ICU) at the time of medication administration. Therefore, even though patients weren’t matched specifically for each comorbidity, they were matched for number of comorbidities, and numerous other disease severity markers (such as CRP and level of care at admission) and did a multivariable regression based on ordinal score. 3. The third point regarding concurrent medications is addressed above. 4. The last point regarding dose is a very good point and deserves more highlighting in the paper. We clarified the dose in several sections of the paper. Attachments Attachment Submitted filename: Response to Reviewers 2-18-21.docx https://doi.org/10.1371/journal.pone.0249349.r002
17 Mar 2021 Decision Letter - Aleksandar R. Zivkovic, Editor What about Tocilizumab? A Retrospective Study from a NYC Hospital during the COVID-19 Outbreak PONE-D-20-37152R1 Dear Dr. Mehta, 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, Aleksandar R. Zivkovic Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0249349.r003
Formally Accepted
30 Mar 2021 Acceptance Letter - Aleksandar R. Zivkovic, Editor PONE-D-20-37152R1 What about Tocilizumab? A Retrospective Study from a NYC Hospital during the COVID-19 Outbreak Dear Dr. Mehta: 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. Aleksandar R. Zivkovic Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0249349.r004

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