PONE-D-25-18837Neutropenic Sepsis and Septic Shock in ICU patients: a single-center experience over the Last Decade.PLOS ONE

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Reviewers' comments:

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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: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

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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 authors investigated a topic of interest and the results of this research appears of relevant importance to inform the clinicians. However, I would authors to address the following issues:

- specify what is intended with "source control" an what you mean with "early"

- report the time to appropriate antimicrobial therapy and whether fast microbiology was used; this point would provide a further potential explanation for mortality improvement despite patients were apparently more severe in recent years;

- perform a multivariable regression analysis that include mechanical ventilation

Reviewer #2: Thank you for the opportunity to review this manuscript.

The authors have completed a single-centre retrospective cohort study of 185 patients with neutropenic sepsis admitted to intensive care. The describe clinical characteristics and changes in outcome between 2012-2017 and 2018-2022.

Recent studies on this topic are often registry-based or rely on population and administrative datasets, so I think the patient-level detail gathered in this study is a worthwhile addition to the literature.

My main concern with the manuscript is that the authors report quite a wide range of findings from a relatively small sample size (e.g. profile of infections, changes over time, impact of aminoglycosides); some of these findings reported were secondary outcomes that the study was not explicitly designed for and I feel they are treated a bit superficially. Specifically, the question of aminoglycoside use in neutropenic sepsis is an important one, but this is a complex question and was not the main aim of the study. There is a substantial body of literature on this topic (which the authors acknowledge in the discussion section) including some well-designed retrospective studies and meta-analyses. In order to meaningfully extend the existing research, I think a more dedicated analysis would be needed. There would need to be a stronger attempt to control for confounding factors such as causative organism, receipt of appropriate antibiotic therapy, timing of antibiotic administration etc, and I think this would need review from a statistical reviewer. The authors are careful not to state a causative relationship, but I still don’t think the quality of evidence produced justifies the emphasis on aminoglycoside use that is given in the manuscript. In any case, the main aim of the study was not to investigate aminoglycoside use and I think overall the manuscript would be improved by clearer focus on the primary objectives and the primary outcome - i.e. describing clinical characteristics and outcomes, and their temporal trends over the last 10 years.

I also think the framing of sepsis-3 criteria needs reconsidering. This is given a lot of emphasis in the manuscript. However, the authors report Sepsis-3 criteria were applied to included patients only after patient identification using a registry based on ICD codes (line 91 onward). Therefore it isn’t really accurate to say that patients were identified with Sepsis-3 alone. ICD codes are known to lack sensitivity and some patients excluded from the registry may not have been assessed against sepsis-3 criteria at all. Also, because Sepsis-3 criteria are poorly validated in neutropenic patients, it doesn’t automatically follow that using Sepsis-3 over other patient identification strategies is necessarily a better approach, and this seems to be taken as a given in the manuscript. I think it’s a reasonable approach, just not necessarily a key strength of the study per se. Therefore, if the use of Sepsis-3 is to be a key focus in the manuscript, I think it needs more nuanced exploration. Some useful references on the topic include the below:

Nathan, N., J.-P. Sculier, L. Ameye, M. Paesmans, G. Bogdan-Dragos, and A.-P. Meert, Sepsis and Septic Shock Definitions in Patients With Cancer Admitted in ICU. Journal of Intensive Care Medicine, 2021. 36(3): p. 255-261.

Valentine, Jake C., Karin A. Thursky, and Leon J. Worth. "Sepsis in cancer: a question of definition." Australian and New Zealand journal of public health 44.3 (2020): 245.

Cheng, Q., Y. Tang, Q. Yang, E. Wang, J. Liu, and X. Li, The prognostic factors for patients with hematological malignancies admitted to the intensive care unit. Springerplus, 2016. 5(1): p. 1-12.

Duke, Graeme J., et al. "Performance of hospital administrative data for detection of sepsis in Australia: The sepsis coding and documentation (SECOND) study." Health Information Management Journal 53.2 (2024): 61-67.

Henig, Oryan, et al. "The performance of sepsis-3 criteria to predict mortality among patients with hematologic malignancy and post-transplant who have suspected infection." Open Forum Infectious Diseases. 2021: 8(11)

Otherwise I have a few specific comments

Abstract

In both the abstract and the discussion section the authors comment on lower mortality in the second period but this difference was not statistically significant - this should be more clearly reported

Introduction:

The introduction is a bit short. I’m not entirely clear about what the authors are trying to express and how the existing literature has informed the design of the study. I.e. what are the key gaps in the existing literature that led to development of this study? Is it that studies of cancer patients use inconsistent sepsis definitions or that dedicated studies of neutropenic sepsis are lacking?

Regarding sepsis definitions, in line 54 the authors state “Few studies of patients with cancer used the Sepsis-3 criteria, and none focused on patients with neutropenia [9–11].”

Reference 9 did perform an analysis stratified by neutropenic status and reference 24 uses Sepsis-3 criteria (together with clinical criteria) in neutropenic patients. Perhaps it would suffice to say that existing observational data are limited by inconsistent use of definitions and inclusion of heterogenous patient groups (e.g. clinically diagnosed sepsis or non-neutropenic cancer patients).

Methods

Please supply some more detail about data extraction. Lines 103-4 “table 1 and 2 were extracted from the electronic hospital and ICU databases." Who performed the data extraction? Was there a detailed chart review by a clinician or were data extracted automatically? What definitions were used e.g. to determine infection site? What definition was used to classify CVC-related infections defined (ECDC, CDC/NHSN, clinician-determined, ICD codes, other?)? How were BSI defined and did common skin commensals require additional criteria for inclusion?

Statistical analysis: “missing data were counted” Are these reported anywhere in the manuscript?

Line 130 “Survival curves plotted using the Kaplan-Meier method for the early and recent periods were compared by applying the log-rank test” Is this reported anywhere in the results? It needs to be more clearly labelled if so. If it was performed, was this only univariable analysis?

For the logistic regression model, what model validation was used? How was multicollinearity assessed and managed? What was the model AUROC? (This could just be reported with the model in the results)

For the multivariable model, given that mechanical ventilation and renal replacement therapy differed between the two time periods should this be included in the model? Mechanical ventilation is consistently associated with increased mortality and seems important. Should receipt of appropriate antibiotic therapy be included in the model for the same reason?

Some background information on your centre would be valuable. How large is the hospital, is it a dedicated cancer centre? Is quinolone prophylaxis used? What type of central lines are used in cancer patients? Were there any changes to routine care during the study period (especially considering the COVID pandemic impacting period 2 and not period 1).

Results

Suggest in general avoid fractions like “three 5ths” (Line 320, line 391) and just give a percentage throughout.

Table 3 – the authors report receipt of antifungal as a risk factor but it needs to be clear if this was prophylaxis or treatment (i.e. it might include empiric antifungal for suspected fungal sepsis versus routine prophylaxis which would depend on underlying disease). If that can’t be established I don’t think it should be included in the model.

The authors discuss “number of organ failures” but actually seem to only include SOFA score in their model. This isn’t strictly speaking the same thing and should be either removed or analysed separately.

Discussion

Line 237 -238 “Few studies have focused on neutropenic patients with cancer and sepsis or septic shock defined by Sepsis-3 criteria [8].” Please refer to the comments above, again important that these were not the only criteria used in this study as only patients with ICD coded sepsis were considered for inclusion.

Line 249. “Multidrug-resistant pathogens contributed fewer than 5% of the organisms recovered in our patients compared to nearly 25% in a 2010–2017 study from Spain confined to patients with hematological malignancies [24,30].” Suggest removing this as this reflects known differences in epidemiology in these two countries, and seems like an arbitrary comparison. (Also reference 24 is not relevant).

Strengths section: Please see above about the use of sepsis-3 criteria as a strength. Line 298 “Third, we identified a factor (combination aminoglycoside therapy) independently associated with lower hospital mortality.” It’s not really usual to describe a finding of the study as a strength of the study. Please see above re: level of emphasis this finding is given.

Limitations: Given that the second period includes the COVID period and the first period does not, does this require any comments as a potential confounding factor? (E.g. was there any change in patient mix or processes during that period, is there any other evidence of impact on outcomes from cancer patients in other studies?)

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Reviewer #1: No

Reviewer #2: No

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Neutropenic Sepsis and Septic Shock in ICU patients: a single-center experience over the Last Decade.

PONE-D-25-18837R1

Dear Dr. Canet,

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.

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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. 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

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. 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: No

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5. 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

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6. 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 authors have addressed my previous comments and the revised version of the manuscript appears significantly improve. I have no further comments.

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Reviewer #1: No

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