Use of glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19

Cristina Lavilla Olleros; Cristina Ausín García; Alejandro David Bendala Estrada; Ana Muñoz; Philip Erick Wikman Jogersen; Ana Fernández Cruz; Vicente Giner Galvañ; Juan Antonio Vargas; José Miguel Seguí Ripoll; Manuel Rubio-Rivas; Rodrigo Miranda Godoy; Luis Mérida Rodrigo; Eva Fonseca Aizpuru; Francisco Arnalich Fernández; Arturo Artero; Jose Loureiro Amigo; Gema María García García; Luis Corral Gudino; Jose Jiménez Torres; José-Manuel Casas-Rojo; Jesús Millán Núñez-Cortés; On behalf of the SEMI-COVID-19 Network

doi:10.1371/journal.pone.0261711

Peer Review History

Original SubmissionJuly 4, 2021
21 Jul 2021 Decision Letter - Aleksandar R. Zivkovic, Editor PONE-D-21-21800 Use of Glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19. PLOS ONE Dear Dr. Lavilla Olleros, 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 Sep 04 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 also indicate clearly a lead author for this group along with a contact email address. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer #1: The authors present their experience with high-dose corticosteroids (CS), referred to as megadoses, and compare these against low-dose CS. Intro, paragraph 2: consider rephrasing in order to be current with the literature. CS are the only intervention for severe COVID with consistent mortality impact across studies. I would avoid using the references 5-7 that raised controversies in CS use too early in the pandemic and based on theoretical assumptions from non-COVID diseases such as ARDS, SARS or MERS that have distinct etiology, epidemiology, phenotypes and outcomes. Instead, you can highlight even though CS have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large. Methods: Study conclusion: consider renaming this section Study endpoints to avoid confusion with the use of the word conclusion. The Literature search section does not add to the methods, consider removing. There are 2 definitions of megadoses, >150 mg of prednisone in 3-4 days and >150 mg of prednisone in 24h. Historically, high-dose CS in ARDS research has been defined as >200mg/Kg/day of methylprednisolone or its equivalent in other CS forms (prednisone, prednisolone, etc). If the authors choose to study >150mg of prednisone then I would recommend using the definition of >150mg in 24h and report the cumulative dose of steroids AND the daily dose in a "mg/Kg/day" format to keep up to the literature. Results: Overall the results are focused on all patients receiving CS vs those who didn't, and then in CS megadoses vs no megadoses. I believe it would be more useful to change to 3 groups in the tables: No CS, low-dose CS and CS megadoses. Table 2 is too long, try grouping comorbidities to clinically relevant terms that are well known risk factors for COVID, such as chronic lung disease, chronic cardiovascular disease, renal insufficiency, etc. Table 1 can be integrated at the end of table 2 as it does not add much as a stand-alone table. Revise spelling in the tables. For table 4 and 5 it would be more useful merged to have the mean/median of lab values instead of the proportion of abnormal labs in both groups as this can be misleading. Table 7 would be more useful if describing megadoses vs regular steroids. Consider adding APACHE, PaFiO2, or other proxies to clinical status upon admission. There are higher inflammatory markers in patient's receiving megadoses according to tables 4 and 5, this creates an uneven populations to compare the effect of megadoses. There are 2 ways to address this unbalance: inverse weight proportion analysis and propensity-score matching. Consider using one of these to strengthen results. Mortality metric used in too broad including follow-up of patients already discharged, with a median hospital stay of 12 days, using 30-day mortality would be preferred. Reviewer #2: From my point of view, it is of little interest to focus the study on the differences between patients who have received megadoses and those who have not. It is much more interesting to find out if the megadoses had negative consequences, in terms of complications, hospital stay or mortality. Most of the conclusions drawn by the authors are based on bivariate analyzes, which in an observational study like this one, have no more value than merely descriptive. As the authors note, there are a large number of important differences between patients treated with megadoses and those who are not, so the results in terms of complications or mortality are very difficult to interpret. The authors carry out a single multivariate analysis on mortality, in which they have only introduced a few, of the many factors that they have found asymmetrically distributed between groups, without providing an explanation of the selection process carried out. That is, there are enough confounding factors missed in the analysis, so the results most likely have residual confusion. In addition, some important confounding factors that can affect health outcomes in COVID-19 do not seem to have been available, such as saturation and the rest of vital signs, respiratory support, etc. Also, Multivariate analysis, which is essential in this type of observational studies, is limited to mortality results, and has not been done for other interesting results such as, for example, complications of the disease. Unfortunately, I do not believe that the results are valid for the outcomes of greatest interest, due to the lack of control for relevant confounders, so I cannot recommend the publication in its current state. However, the authors have a valuable database, and their idea of comparing the effect of high doses with other doses of steroids is interesting. I encourage them to choose a relevant outcome, such as mortality, and do a full multivariate analysis, which attempts to elucidate whether mega-doses are associated with higher mortality. They also have an exceedingly large sample, to match patients in whom megadoses were used, with controls with similar clinical characteristics, in which megadoses were not used. In short, they have many possibilities with this database, and I am sure they can make a much more robust analysis than the one presented here, to provide new knowledge about corticosteroids effect in this disease. ******** 6. 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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.0261711.r001
Revision 1
4 Dec 2021 Author Response Response to Reviewers: Reviewers' comments: Reviewer #1: The authors present their experience with high-dose corticosteroids (CS), referred to as megadoses, and compare these against low-dose CS. Intro, paragraph 2: consider rephrasing in order to be current with the literature. CS are the only intervention for severe COVID with consistent mortality impact across studies. I would avoid using the references 5-7 that raised controversies in CS use too early in the pandemic and based on theoretical assumptions from non-COVID diseases such as ARDS, SARS or MERS that have distinct etiology, epidemiology, phenotypes and outcomes. Instead, you can highlight even though CS have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large. → We agree with the aforementioned. We have changed it. “Corticosteroids (CS) have been widely adopted, there are still questions on dosing, timing and duration of CS that have not been systematically studied at large.” Methods: Study conclusion: consider renaming this section Study endpoints to avoid confusion with the use of the word conclusion. The Literature search section does not add to the methods, consider removing. → We agree with the aforementioned. We have changed it. There are 2 definitions of megadoses, >150 mg of prednisone in 3-4 days and >150 mg of prednisone in 24h. Historically, high-dose CS in ARDS research has been defined as >200mg/Kg/day of methylprednisolone or its equivalent in other CS forms (prednisone, prednisolone, etc). If the authors choose to study >150mg of prednisone then I would recommend using the definition of >150mg in 24h and report the cumulative dose of steroids AND the daily dose in a "mg/Kg/day" format to keep up to the literature. → We agree with the aforementioned. We have changed it. “The definition of >150mg in 24h”. About the cumulative dose of steroids AND the daily dose in a "mg/Kg/day", we cannot use this format, because we do not have data to calculate it. Results: Overall the results are focused on all patients receiving CS vs those who didn't, and then in CS megadoses vs no megadoses. I believe it would be more useful to change to 3 groups in the tables: No CS, low-dose CS and CS megadoses. → We agree with the aforementioned. We have changed it. Table 2 is too long, try grouping comorbidities to clinically relevant terms that are well known risk factors for COVID, such as chronic lung disease, chronic cardiovascular disease, renal insufficiency, etc. Table 1 can be integrated at the end of table 2 as it does not add much as a stand-alone table. Revise spelling in the tables. → We agree with the aforementioned. We have changed it. For table 4 and 5 it would be more useful merged to have the mean/median of lab values instead of the proportion of abnormal labs in both groups as this can be misleading. Table 7 would be more useful if describing megadoses vs regular steroids. Consider adding APACHE, PaFiO2, or other proxies to clinical status upon admission. → We agree with the aforementioned. We have changed it. There are higher inflammatory markers in patient's receiving megadoses according to tables 4 and 5, this creates an uneven populations to compare the effect of megadoses. There are 2 ways to address this unbalance: inverse weight proportion analysis and propensity-score matching. Consider using one of these to strengthen results. → Thank you for your input. We have tried to strengthen the results with multivariate analysis. Mortality metric used in too broad including follow-up of patients already discharged, with a median hospital stay of 12 days, using 30-day mortality would be preferred. → We agree with the aforementioned. We have changed it. Reviewer #2: From my point of view, it is of little interest to focus the study on the differences between patients who have received megadoses and those who have not. It is much more interesting to find out if the megadoses had negative consequences, in terms of complications, hospital stay or mortality. Most of the conclusions drawn by the authors are based on bivariate analyzes, which in an observational study like this one, have no more value than merely descriptive. As the authors note, there are a large number of important differences between patients treated with megadoses and those who are not, so the results in terms of complications or mortality are very difficult to interpret. The authors carry out a single multivariate analysis on mortality, in which they have only introduced a few, of the many factors that they have found asymmetrically distributed between groups, without providing an explanation of the selection process carried out. That is, there are enough confounding factors missed in the analysis, so the results most likely have residual confusion. In addition, some important confounding factors that can affect health outcomes in COVID-19 do not seem to have been available, such as saturation and the rest of vital signs, respiratory support, etc. Also, Multivariate analysis, which is essential in this type of observational studies, is limited to mortality results, and has not been done for other interesting results such as, for example, complications of the disease. Unfortunately, I do not believe that the results are valid for the outcomes of greatest interest, due to the lack of control for relevant confounders, so I cannot recommend the publication in its current state. However, the authors have a valuable database, and their idea of comparing the effect of high doses with other doses of steroids is interesting. I encourage them to choose a relevant outcome, such as mortality, and do a full multivariate analysis, which attempts to elucidate whether mega-doses are associated with higher mortality. They also have an exceedingly large sample, to match patients in whom megadoses were used, with controls with similar clinical characteristics, in which megadoses were not used. In short, they have many possibilities with this database, and I am sure they can make a much more robust analysis than the one presented here, to provide new knowledge about corticosteroids effect in this disease. → We agree with the suggested changes. We have performed the multivariate analysis in mortality and have also focused on the possible adverse effects of megadoses therapy. Thank you for all your comments. We hope to have addressed them in the hope of moving the work forward for early publication. Kind regards, Cristina Lavilla Attachments Attachment Submitted filename: renamed_42b84.docx https://doi.org/10.1371/journal.pone.0261711.r002
9 Dec 2021 Decision Letter - Aleksandar R. Zivkovic, Editor Use of Glucocorticoids megadoses in SARS-CoV-2 infection in a spanish registry: SEMI-COVID-19. PONE-D-21-21800R1 Dear Dr. Lavilla Olleros, 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.0261711.r003

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