Sex differences in long-term survival after intensive care unit treatment for sepsis: A cohort study

Kelly Thompson; Naomi Hammond; Michael Bailey; Jai Darvall; Gary Low; Steven McGloughlin; Lucy Modra; David Pilcher

doi:10.1371/journal.pone.0281939

Peer Review History

Original SubmissionNovember 9, 2022
19 Dec 2022 Decision Letter - Chiara Lazzeri, Editor PONE-D-22-30745Sex differences in survival after intensive care unit treatment for sepsis: a cohort studyPLOS ONE Dear Dr. Thompson, 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 Feb 02 2023 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 see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 8. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: The aim of this study is to explore the impact of sex on survival for septic patients admitted in ICU The primary outcome is time to death for up to 3-years. The study included 50,956 patients from January 1, 2018 to December 31, 2020. The data were retrieved from ANZIC. Patient’s characteristics were different between men and women. Men were older (mean age 66·5 vs 63·6 years), more commonly received mechanical ventilation (27·4% vs 24·7%) and renal replacement therapy (8·2% vs 6·8%). The FU was up to 3 years and Cox proportional hazard models were used to estimate the effect of sex on time to death. Since patients’ characteristics were different according to sex, analysis were adjusted for age, diagnosis, acute illness severity, body mass index, chronic comorbidities, frailty, source of admission to ICU and to hospital, treatment limitation at ICU admission, socio-economic status, region of Australia, type of hospital (regional/rural, metropolitan, tertiary or private) and year of admission to ICU. Overall women had better survival for up to three-years after ICU admission. This result was confirmed by sensitivity analyses focusing on patients who survived the hospital admission. The effect of sex was more important among patients older than 75y than for patients younger than 54. Comments: This is a very nice study, addressing a question with some controversy. The large cohort of included patients validate the results although some other cofounding factors not considered in the adjustment might have contributed to the difference. It is also important to confirm that the better early prognosis was sustained over time up to 3 years after ICU admission. The manuscript is well written, easy to read, tables and figures are clear. Fig 3: what is the ref for CFS? OR is worse for CFS 5-6 than for CSF 7 an-8? Please comment The inclusion period was partly during the COVID-19 surge period. Did you analyse specifically the impact of sex in this population? See for exemple (Sex-specific treatment characteristics and 30-day mortality outcomes of critically ill COVID-19 patients over 70 years of age-results from the prospective COVIP study; Canadian Journal of Anaesthesia. 2022-08-09) Reviewer #2: This retrospective study of more than 50,000 sepsis ICU admissions in Australia showed that male sex was associated with an increased risk of ICU admission and that men had worse survival rates for up to 3-years, compared to women. As the authors themselves pointed out these findings are similar to those from a recent systematic review including 71,850 patients from 12 studies that reported a survival advantage for women at one year (Antequera A et al, 2021). The new information derived from this study, however, is that there is a survival advantage for women that persists for up to three years after sepsis. The present study also indicates that in all three age groups (<55 years, 55 to 74 years, ≥ 75 years), women had better survival than men from sepsis. As the authors also pointed out, a 2021 retrospective review of 12,321 ICU records in Boston reported similar overall findings of higher mortality due to sepsis in men compared to women overall, but no difference in short and longer-term survival for men and women aged over 50 years (Lin S et al, 2021). No explanation is provided for the differences in the results published by Lin et al compared to this study. The authors postulated that greater protection in women may be attributed to the immune enhancing effects of estrogen, and male disadvantage may be due to the immunosuppressive properties of male androgens, particularly testosterone. In this regard, testosterone is common intermediate between males and females and it gets converted enzymatically to 17β-estradiol by Aromatase or to 5α-dihydrotestosterone (DHT) by 5α-reductase. Thus, DHT rather than testosterone might be the active immunosuppressive steroid. Additionally, estrogen decrease with aging in women and clearly the majority of the women in this study were post-menopausal with low estrogen levels. It is therefore possible that post-menopausal women in this study were on HRT and thus they had better survival than men. However, hormonal status nor information about HRT was not provided in this study. In men, the levels of DHT also decrease with aging and thus aged men should do better than women – this, however, was not the case. So, the reason for the difference between men and women in survival remains unclear. Could it be due to a difference in the estrogen to DHT ratio? Unfortunately, this information was also not available in this study. Furthermore, appropriate explanation/justification for the difference in present from those of Lin S et al 2021 need to be provided. ****** 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: 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.0281939.r001
Revision 1
2 Feb 2023 Author Response 24 January 2023 Editor-in-Chief PLOS ONE Dear Editor-in-Chief RE: PONE-D-22-30745: Sex differences in survival after intensive care unit treatment for sepsis: a cohort study Thank you PLOS ONE Editors and Reviewers for your thoughtful review of our manuscript. Please find below our response to reviewer and academic editor feedback which we believe has considerably improved the quality of our manuscript. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Response: The files have been updated in accordance with PLOS ONE’s style requirements. 2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: -https://doi.org/10.1016/j.jinf.2022.04.035 -10.1001/jamaneurol.2018.0123 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. Response: As the corresponding author of the first of these papers, I have compared the manuscripts in Microsoft word and cannot see any significant overlapping text which would raise plagiarism concerns. My colleague David Pilcher, the senior author on this paper has done the same for the JAMA Neurology paper and has also found minimal overlapping text outside of the methods section. Please note, the description of the ANZICS APD in the methodology section is similar in all papers that are written using this bi-national registry. It is written in this way to comply with ANZICS requirements and is specifically to ensure consistency of description throughout all publications. 3. Thank you for stating the following financial disclosure: "KT received funding for the work from the National Health and Medical Research Council of Australia" Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. Response: Thank you for updating the online submission form on our behalf. The manuscript funding section at the end of the paper has been updated in tracked changes accordingly to confirm that: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Response: Thank you for updating this on our behalf. The data availability statement should be as follows: “Deidentified individual patient data are collected from each hospital ICU under Quality Assurance Legislation and standing agreements with each State and Territory health department of Australia and the Ministry of Health of New Zealand. Data are collected primarily for the purpose of benchmarking ICU activity and performance. Secondary access and use of the data is restricted other than under specific agreements with researchers. Applications for access to data can be made to anzics.core@anzics.com.au” 5. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Response: Please see the above response including the updated data availability statement. 6. Please upload a new copy of Figure 2 and 3 as the detail is not clear. Please follow the link for more information: Response: A new copy of Figure 2 has been uploaded. Please note, Figure 3 has now been separated into 2 figures, (Figs 3 and 4) to improve readability and clarity of text in the figure. 7. 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. Response: A new section with Supporting information file captions has been included at the end of the manuscript. Please confirm whether this is appropriate? After reading the supporting information instructions I was unsure as to whether the journal requires the figures and tables in the Supporting Information file to be uploaded to the manuscript. 8. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Response: No changes to the reference list were made. Comments to the Author Reviewer #1: Comments: Fig 3: what is the ref for CFS? OR is worse for CFS 5-6 than for CSF 7 an-8? Please comment Response: The reference group for the Clinical Frailty Score is ‘not frail’(the top HR reported). The most frail group (CFS >6) had the highest HR in both women and men. The HR at the bottom is for those with an unknown frailty score. Please let us know if further clarification is required? The inclusion period was partly during the COVID-19 surge period. Did you analyse specifically the impact of sex in this population? See for exemple (Sex-specific treatment characteristics and 30-day mortality outcomes of critically ill COVID-19 patients over 70 years of age-results from the prospective COVIP study; Canadian Journal of Anaesthesia. 2022-08-09) Response: Thank you for this comment. We included patients with COVID but did not examine COVID as a subgroup as this group represented a small component of the whole study population due to relatively few COVID admissions to ICU in Australia in 2020. On re-examining the data, there were 990 probable COVID positive patients included (which includes some probable COVID positive patients from right at the beginning of the pandemic who didn’t get definitive tests on admission but were likely positive). Of these 337 were female (9.8% mortality) and 613 male (16.3% mortality). There were 456 confirmed COVID positive pneumonitis patients. Of these 163 were female (11.0% mortality) and 293 were male (15.7% mortality). We have now made a comment on this in the main manuscript and have reported additional information related to SARS-CoV-2 survival for females and males in the Supporting Information (Figs S3 and S4). Reviewer #2: The authors postulated that greater protection in women may be attributed to the immune enhancing effects of estrogen, and male disadvantage may be due to the immunosuppressive properties of male androgens, particularly testosterone. In this regard, testosterone is common intermediate between males and females and it gets converted enzymatically to 17β-estradiol by Aromatase or to 5α-dihydrotestosterone (DHT) by 5α-reductase. Thus, DHT rather than testosterone might be the active immunosuppressive steroid. Additionally, estrogen decrease with aging in women and clearly the majority of the women in this study were post-menopausal with low estrogen levels. It is therefore possible that post-menopausal women in this study were on HRT and thus they had better survival than men. However, hormonal status nor information about HRT was not provided in this study. In men, the levels of DHT also decrease with aging and thus aged men should do better than women – this, however, was not the case. So, the reason for the difference between men and women in survival remains unclear. Could it be due to a difference in the estrogen to DHT ratio? Unfortunately, this information was also not available in this study. Furthermore, appropriate explanation/justification for the difference in present from those of Lin S et al 2021 need to be provided. Response: As the reviewer points out, we did not have any data related to women’s post-menopausal status (beyond age) or their use of Hormone Replacement Therapy. We agree that it is possible that 5α-dihydrotestosterone (DHT) may have had a role in male immunosuppression and have added this in the discussion section. In regards to the different findings in our study compared to the study conducted by Lin et al in Boston, one possibility could be the difference in follow-up time. We have added this in tracked changes to our discussion section. Thank you for your reconsideration of the manuscript for publication in PLOS ONE. Kind Regards Dr Kelly Thompson Conjoint Senior Lecturer, UNSW Research Fellow, The George Institute for Global Health Attachments Attachment Submitted filename: Response to reviewers_28Jan23.doc https://doi.org/10.1371/journal.pone.0281939.r002
5 Feb 2023 Decision Letter - Chiara Lazzeri, Editor Sex differences in long-term survival after intensive care unit treatment for sepsis: a cohort study PONE-D-22-30745R1 Dear Dr. Thompson, 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, Chiara Lazzeri Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0281939.r003
Formally Accepted
14 Feb 2023 Acceptance Letter - Chiara Lazzeri, Editor PONE-D-22-30745R1 Sex differences in long-term survival after intensive care unit treatment for sepsis: a cohort study Dear Dr. Thompson: 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. Chiara Lazzeri Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281939.r004

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