Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patients

Xanthe Brands; Fabrice Uhel; Lonneke A. van Vught; Maryse A. Wiewel; Arie J. Hoogendijk; René Lutter; Marcus J. Schultz; Brendon P. Scicluna; Tom van der Poll

doi:10.1371/journal.pone.0271637

Peer Review History

Original SubmissionOctober 26, 2021
28 Mar 2022 Decision Letter - Ehab Farag, Editor PONE-D-21-33755Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patientsPLOS ONE Dear Dr. Xanthe Brands , 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. I would appreciate if you pay a careful attention in your response to the reviewer's comments. Please submit your revised manuscript by May 07 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. 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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: This manuscript investigates immune biomarkers in plasma correlated with inflammatory pathways using patients admitted to ICU. The statistical analysis methods are fine for the presented data analysis. I have below questions and comments. The objective of this study was to determine the relationship between the degree of immune suppression and systemic inflammation in patients shortly after admission to the ICU. Was the TNF-a used to identify the degree of immune suppression? It is an observational study, but it is not clear how the sample size was decided. Please provide sample size considerations. Table 1 reported the distribution of the stratification TNF-a across infectious diseases. What’s the distribution of the stratification TNF-a across noninfectious diseases? How many noninfectious diseases also have signs of immune suppression? This study examined the correlations between TNF-a and other immune biomarkers by comparing immune biomarkers among quartile stratified group of TNF-a. Spearman’s r was also used for a couple of markers. For these correlations, would patient’s characteristics (e.g. age, sex, BMI, etc.) mediate the relationship between TNF-a and other immune biomarkers? ****** 6. 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Revision 1
14 Jun 2022 Author Response Reviewer This manuscript investigates immune biomarkers in plasma correlated with inflammatory pathways using patients admitted to ICU. The statistical analysis methods are fine for the presented data analysis. I have below questions and comments. Comment #1: The objective of this study was to determine the relationship between the degree of immune suppression and systemic inflammation in patients shortly after admission to the ICU. Was the TNF-a used to identify the degree of immune suppression? Response: We thank the reviewer for his/her insightful comments. Indeed, as specified in the results section (page 7, lines 143-146, 152-153): “Given that a reduced TNF-α production capacity by blood leukocytes has been widely recognized as a hallmark of immune suppression in critically ill patients, we stratified patients into four groups based on quartiles of LPS-induced TNF-α production. […] the stratification of patients based on TNF-α production capacity of blood leucocytes resulted in conditions of increasing degrees of immune suppression.” In other words, the identification of immune suppression was based on a reduced ability of blood leukocytes to produce TNF-α in response to LPS-stimulation. In order to further clarify this readout, we rephrased the objective of the study in the introduction: Introduction (Pages 3, 4): “To this end, we used the decreased capacity of whole blood leukocytes to produce TNF-α in response to LPS-stimulation as a readout for critically-ill patient immune suppression” Comment #2: It is an observational study, but it is not clear how the sample size was decided. Please provide sample size considerations. Response: We did not perform a formal sample size calculation prior to this study, since to the best of our knowledge previous studies testing the association between whole blood leukocyte stimulations to biomarkers of systemic inflammation have not been performed. Thus, our study provides preliminary estimates of variance, deviations etc.. for the design of future specific studies. This is now commented upon in the statistical paragraph as follows: Methods (page 6): “A formal sample size calculation was not done prior to the study (to the best of our knowledge previous studies associating whole blood leukocyte stimulations with biomarkers of systemic inflammation have not been performed)” Comment #3: Table 1 reported the distribution of the stratification TNF-a across infectious diseases. What’s the distribution of the stratification TNF-a across noninfectious diseases? How many noninfectious diseases also have signs of immune suppression? Response: Table one shows the distriubution of TNF-α production capacity in all patients admitted to the ICU, including patients admitted for an infectious(n=51) and for a non-infectious diagnosis (n=26). Of these, 40 (78.4%) patients with a sepsis admission diagnosis and 18 (69.2%) patients with a non-infectious admission diagnosis showed reduced TNF production capacity (≤896 pg/mL), consistent with immune suppression. In order to clarify this point, we added the following to the manuscript: Results (page 8): “Among patients admitted for a sepsis (n= 51) or for a non-infectious diagnosis (n= 26), 40 (78.4%) and 18 (69.2%) showed reduced TNF production capacity (≤896 pg/mL), respectively.” Comment #4: This study examined the correlations between TNF-a and other immune biomarkers by comparing immune biomarkers among quartile stratified group of TNF-a. Spearman’s r was also used for a couple of markers. For these correlations, would patient’s characteristics (e.g. age, sex, BMI, etc.) mediate the relationship between TNF-a and other immune biomarkers? Response: As shown in table 1, no association was found between TNF-α production capacity and patient age, sex or BMI. We therefore considered it unlikely that these clinical parameters mediate the association between TNF-α production capacity and other plasma biomarker concentrations. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0271637.r002
6 Jul 2022 Decision Letter - Ehab Farag, Editor Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patients PONE-D-21-33755R1 Dear Dr. Xanthe Brands , 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, Ehab Farag, MD FRCA FASA Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0271637.r003
Formally Accepted
15 Jul 2022 Acceptance Letter - Ehab Farag, Editor PONE-D-21-33755R1 Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patients Dear Dr. Brands: 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. Ehab Farag Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271637.r004

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