Impact of early corticosteroids on 60-day mortality in critically ill patients with COVID-19: A multicenter cohort study of the OUTCOMEREA network

Claire Dupuis; Etienne de Montmollin; Niccolò Buetti; Dany Goldgran-Toledano; Jean Reignier; Carole Schwebel; Julien Domitile; Mathilde Neuville; Moreno Ursino; Shidasp Siami; Stéphane Ruckly; Corinne Alberti; Bruno Mourvillier; Sebastien Bailly; Virginie Laurent; Marc Gainnier; Bertrand Souweine; Jean-François Timsit; on behalf of the OutcomeReaTM research network

doi:10.1371/journal.pone.0255644

Peer Review History

Original SubmissionApril 18, 2021
8 Jun 2021 Decision Letter - Aleksandar R. Zivkovic, Editor PONE-D-21-11495 Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network PLOS ONE Dear Dr. Dupuis, 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 Jul 09 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 do not edit.] Comments to the Author Reviewer #1: This is a retrospective cohort study where the authors conclude that overall early(<48h) or non early CS (?>48h) steroid use has no statistically significant effect on 60 day mortality. In a subgroup analysis, patients who were >60 years of age may have favorable outcomes and those <60 years and with "low inflammation" seem to be at risk of harm. Low inflammation is defined as cut offs for CRP/Ddimer and Ferritin. Major concern Heterogeneity of treatment effect with steroids is well known. In a recently published observational analysis by Keller et al.. Hosp. Med 2020;8;489-493 in patients with CRP ≥20mg/dL, corticosteroid treatment was associated with a 75-80% reduction in the composite severe outcomes of mechanical ventilation and mortality (odds ratio [OR], 0.23; 95% CI, 0.08-0.70). Conversely, and as importantly, among those with CRP <10mg/dL, there was increase in severe outcomes (OR, 2.64; 95% CI, 1.39-5.03). Within the CRP category of 10-19.9mg/dL, corticosteroids were neither beneficial nor harmful (OR, 1.05; 95% CI, 0.46-2.39). Since the authors noted significant interaction between treatment and initial d dimer/ CRP level was recommend to do a post hoc adjusted analysis within each of the predefined subgroup variables Definition/Group assignment non early CS group is not defined. It appears it would include all patients who got steroids >48 after ICU admission but that does not seem to be the case since only 96/236 patients ended up getting steroids (Table 1). Also this is 40% and not 31.1% as mentioned in line 168. All 66 patients in the early CS group got steroids. Missing values Nearly 30% of CRP values are missing and nearly 43% of ferritin and d dimer are missing. With these large datasets missing multiple imputation might not be sufficient. Perhaps the missing values can be excluded for the analysis in which case the findings would be considered hypothesis generating. How were they dealt with in the model? Minor concerns Figure 1- the consort diagram numbers do not add up. I suspect some of the exclusion categories had shared patients Figure 3- numbers do not add up, adding age<60+age >60 =303; n was 302! Reviewer #2: Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network Summary This is a report of the associated mortality reduction of late-stage steroids in COVID-19 hospitalization. In general, the conclusions are supported by the data. Major Comments Table 1. Please list the COVID-19 specific treatment given before hospitalization. If this is uknown, please list as a limitation. Table 1. Please list the antiplatelet agents and antithrombotics used in the hospital. Discussion Please discuss and cite the data supporting hemagglutination and microthrombosis as a determinant of hypoxemia and “COVID-19” and how the antiplatelet and antithrombotic drugs used in the study could have influenced the results. Please insert a paragraph concerning the prehospital treatment received. If little or no prehospital therapy is received then this worked to worsened the outcomes observed. Please cite and mention this paper concerning significant reductions in events with prehospital therapy: Procter, MD, B. C., APRN, FNP-C, C. R. M., PA-C, MPAS, V. P., PA-C, MPAS, E. S., PA-C, MPAS, C. H., & McCullough, MD, MPH, P. A. (2021). Early Ambulatory Multidrug Therapy Reduces Hospitalization and Death in High-Risk Patients with SARS-CoV-2 (COVID-19). International Journal of Innovative Research in Medical Science, 6(03), 219 - 221. https://doi.org/10.23958/ijirms/vol06-i03/1100 Please indicate how the present results will be applicable now that more patients receive early treatment and avoid the hospital altogether, see and cite: McCullough PA, Alexander PE, Armstrong R, Arvinte C, Bain AF, Bartlett RP, Berkowitz RL, Berry AC, Borody TJ, Brewer JH, Brufsky AM, Clarke T, Derwand R, Eck A, Eck J, Eisner RA, Fareed GC, Farella A, Fonseca SNS, Geyer CE Jr, Gonnering RS, Graves KE, Gross KBV, Hazan S, Held KS, Hight HT, Immanuel S, Jacobs MM, Ladapo JA, Lee LH, Littell J, Lozano I, Mangat HS, Marble B, McKinnon JE, Merritt LD, Orient JM, Oskoui R, Pompan DC, Procter BC, Prodromos C, Rajter JC, Rajter JJ, Ram CVS, Rios SS, Risch HA, Robb MJA, Rutherford M, Scholz M, Singleton MM, Tumlin JA, Tyson BM, Urso RG, Victory K, Vliet EL, Wax CM, Wolkoff AG, Wooll V, Zelenko V. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/j.rcm.2020.04.264. PMID: 33387997. Reviewer #3: The article is very interesting. In my opinion, that the cut-off point of ferritin (1000) to define the inflammatory state is very high. It would be convenient a ROC curve with ferritin to identify patients who do not respond. [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/. 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Revision 1
16 Jul 2021 Author Response Reviewer #1: This is a retrospective cohort study where the authors conclude that overall early(<48h) or non early CS (?>48h) steroid use has no statistically significant effect on 60 day mortality. In a subgroup analysis, patients who were >60 years of age may have favorable outcomes and those <60 years and with "low inflammation" seem to be at risk of harm. Low inflammation is defined as cut offs for CRP/Ddimer and Ferritin. Major concern Heterogeneity of treatment effect with steroids is well known. In a recently published observational analysis by Keller et al.. Hosp. Med 2020;8;489-493 in patients with CRP ≥20mg/dL, corticosteroid treatment was associated with a 75-80% reduction in the composite severe outcomes of mechanical ventilation and mortality (odds ratio [OR], 0.23; 95% CI, 0.08-0.70). Conversely, and as importantly, among those with CRP <10mg/dL, there was increase in severe outcomes (OR, 2.64; 95% CI, 1.39-5.03). Within the CRP category of 10-19.9mg/dL, corticosteroids were neither beneficial nor harmful (OR, 1.05; 95% CI, 0.46-2.39). Since the authors noted significant interaction between treatment and initial d dimer/ CRP level was recommend to do a post hoc adjusted analysis within each of the predefined subgroup variables Thank you for this remark. We have now added subgroup analyses in the supplementary data depending on the levels of CRP, D-Dimers and Ferritin and studied the interaction between age and these covariates. Definition/Group assignment non early CS group is not defined. It appears it would include all patients who got steroids >48 after ICU admission but that does not seem to be the case since only 96/236 patients ended up getting steroids (Table 1). Also this is 40% and not 31.1% as mentioned in line 168. All 66 patients in the early CS group got steroids. Thank you for this remark. The Non-early-CS subgroup included all the patients who did not receive steroids during the first two days after ICU admission (N=237). Of these, only 94/237 (39.7%), equivalent to 31% (94/303) of the whole cohort, received steroids during their ICU stay but only on day 3 or thereafter. We have modified this result accordingly in the manuscript. Missing values Nearly 30% of CRP values are missing and nearly 43% of ferritin and d dimer are missing. With these large datasets missing multiple imputation might not be sufficient. Perhaps the missing values can be excluded for the analysis in which case the findings would be considered hypothesis generating. How were they dealt with in the model? Thank you for this truly relevant remark. We acknowledge this limitation. To minimize the effect of missing values we first tried to recover more data. We finally retrieved 47 (15.5%) missing CRP values, 89 (29%) missing D-Dimer values and 103 (34%) missing ferritin values. After multiple imputation, 202 (66.7%) of the patients are now considered as having inflammation according to our previous definition. To consolidate our results, sensitivity analyses were performed. First, we tested the impact of steroids in the subgroups defined only by CRP, D-Dimer and Ferritin levels, respectively. Finally, we performed complete case analyses for all those subgroups. The results are given in the supplementary data. Minor concerns Figure 1- the consort diagram numbers do not add up. I suspect some of the exclusion categories had shared patients. Thank you for this remark. We have modified the flow chart accordingly to avoid any confusion Figure 3- numbers do not add up, adding age<60+age >60 =303; n was 302! Thank you for this remark. We have corrected the mistake in the new version of the manuscript. Reviewer #2: Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network Summary This is a report of the associated mortality reduction of late-stage steroids in COVID-19 hospitalization. In general, the conclusions are supported by the data. Major Comments Table 1. Please list the COVID-19 specific treatment given before hospitalization. If this is unknown, please list as a limitation. Thank you for this remark. In table 1 we have now listed all the treatments received by the patients before admission to the ICU prospectively collected in our database. We also acknowledge in the limitations that some other treatments might have been missed. Table 1. Please list the antiplatelet agents and antithrombotics used in the hospital. Thank you for this remark. In Table 1, we have now reported the number of patients under preventive or curative anticoagulation on admission. Unfortunately, we did not record the antiplatelet agents. A sentence has been added in the limitations to underline this missing variable. We have also included these two variables (preventive and curative anticoagulation) in the propensity score. Discussion Please discuss and cite the data supporting hemagglutination and microthrombosis as a determinant of hypoxemia and “COVID-19” and how the antiplatelet and antithrombotic drugs used in the study could have influenced the results. Thank you for this advice. We had a paragraph supporting hemagglutination and microthrombosis as determinants of hypoxemia and COVID-19. We also now take into account these potential confounding factors in our analyses by adding anticoagulation and D-Dimer levels in our propensity score and by performing subgroup analyses according to D-Dimer levels. “Furthermore, hypoxemia in COVID-19 patients is also secondary to hypercoagulability (Piazza, JAMA, 2020; Huang, Lancet 2020) which is the cause of arterial or venous thrombotic events including microcirculation thrombosis (Ackermann, NEJM, 2020) and pulmonary embolism (Klok, Thromb Res , 2020). Elevated D-Dimer levels are associated with this increased risk of pulmonary embolism (Li, Br J Haematol, 2020). Anticoagulation strategies are consequently of paramount importance in COVID-19 patients (Susen, CC, 2020). The benefit of steroids might therefore be confounded by hypercoagulability and anticoagulation. In our cohort, anticoagulation strategies were quickly adapted to recommendations. To explore the impact of hypercoagulability, we report sub group analyses defined by D-Dimers levels.” Please insert a paragraph concerning the prehospital treatment received. If little or no prehospital therapy is received, then this worked to worsened the outcomes observed. Please cite and mention this paper concerning significant reductions in events with prehospital therapy: Procter, MD, B. C., APRN, FNP-C, C. R. M., PA-C, MPAS, V. P., PA-C, MPAS, E. S., PA-C, MPAS, C. H., & McCullough, MD, MPH, P. A. (2021). Early Ambulatory Multidrug Therapy Reduces Hospitalization and Death in High-Risk Patients with SARS-CoV-2 (COVID-19). International Journal of Innovative Research in Medical Science, 6(03), 219 - 221. https://doi.org/10.23958/ijirms/vol06-i03/1100 Please indicate how the present results will be applicable now that more patients receive early treatment and avoid the hospital altogether, see and cite: McCullough PA, Alexander PE, Armstrong R, Arvinte C, Bain AF, Bartlett RP, Berkowitz RL, Berry AC, Borody TJ, Brewer JH, Brufsky AM, Clarke T, Derwand R, Eck A, Eck J, Eisner RA, Fareed GC, Farella A, Fonseca SNS, Geyer CE Jr, Gonnering RS, Graves KE, Gross KBV, Hazan S, Held KS, Hight HT, Immanuel S, Jacobs MM, Ladapo JA, Lee LH, Littell J, Lozano I, Mangat HS, Marble B, McKinnon JE, Merritt LD, Orient JM, Oskoui R, Pompan DC, Procter BC, Prodromos C, Rajter JC, Rajter JJ, Ram CVS, Rios SS, Risch HA, Robb MJA, Rutherford M, Scholz M, Singleton MM, Tumlin JA, Tyson BM, Urso RG, Victory K, Vliet EL, Wax CM, Wolkoff AG, Wooll V, Zelenko V. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/j.rcm.2020.04.264. PMID: 33387997. Thank you for this advice. We had a sentence on previous treatments received by the patients and the recommended citations. “Finally, in our cohort, mostly achieved during the first wave of the pandemia in France, very few patients received before ICU admission anticoagulation, anti-viral or immunomodulatory treatments, which might have worsened the observed outcomes (Procter, Research in Medical Science, 2020). Our results might therefore be different now that more patients receive early treatment including steroids and anticoagulation and therefore prevent from admission hospitalization or admission in ICU (Alexander, Rev Cardiovasc Med. 2020)." Reviewer #3: The article is very interesting. In my opinion, that the cut-off point of ferritin (1000) to define the inflammatory state is very high. It would be convenient a ROC curve with ferritin to identify patients who do not respond. Thank you for the remark. We have now included the corresponding ROC curve and a cut-off value of 1816. We decided to keep the same cut-off as proposed by Rubio et al (Rubio-Rivas, International journal of infectious diseases, 2020). threshold specificity sensitivity accuracy Ferritin 0.57 [ 0.5 - 0.64 ] 1816 0.75 0.41 0.65 C REactive Protein 0.55 [ 0.47 - 0.62 ] 187 0.68 0.42 0.6 D-Dimers 0.54 [ 0.47 - 0.61 ] 1099.5 0.7 0.42 0.62 Attachments Attachment Submitted filename: Souweine 2021 COVID Corticoids Question reviewing.docx https://doi.org/10.1371/journal.pone.0255644.r002
21 Jul 2021 Decision Letter - Aleksandar R. Zivkovic, Editor Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network PONE-D-21-11495R1 Dear Dr. Dupuis, 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.0255644.r003
Formally Accepted
26 Jul 2021 Acceptance Letter - Aleksandar R. Zivkovic, Editor PONE-D-21-11495R1 Impact of Early Corticosteroids on 60-day Mortality in Critically Ill Patients with COVID-19: A Multicenter Cohort Study of the OUTCOMEREA Network Dear Dr. Dupuis: 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.0255644.r004

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