PONE-D-21-08617Sustained elevation of soluble B- and T- lymphocyte attenuator predicts long-term mortality in patients with bacteremia and sepsisPLOS ONE

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PLOS ONE

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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: Partly

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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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

Reviewer #3: Yes

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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

Reviewer #3: 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: This manuscript technically sound, and the data support the conclusions. The sample size seems acceptable .Data analysis was appropriate also it seems that all data are available. Various groups of patients with different types of infection was included in study , but the main limitation is the number of patients and it seems that we need more patients and also an study with a larger sample size,

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

The authors present data on serial sBTLA levels in a 2011-14 patient cohort admitted with acute illness due to confirmed bloodstream infection. Their principal finding was of an association between persistently elevated sBTLA levels at day 7 and mortality at 90 days and 12 months.

Comments

1. Could the authors please include a concise description of what is known about the biology of sBTLA? Are lymphocytes / specific lymphocyte subsets the origin? What differentiates cell surface bound from soluble BTLA? What is the fate and intravascular half-life of sBTLA? What effector cells does sBTLA act upon and to what effect? How is individual age known to affect the production and kinetics of sBTLA?

2. Could the authors please account for the apparent slow recruitment of 116 patients over 4 years and the 7 year gap between the close of recruitment and the submission of this paper?

3. Only 14 (13%) of patients were admitted to ICU during their acute hospital admission. Where any patients not admitted to ICU due to poor prognosis or for any other reason despite apparent indications for such an admission? What were the reasons for the ICU admission - specifically, how many were the consequence of the development of septic shock or acute severe organ(s) dysfunction due to the BSI that had precipitated hospital admission? How did ICU admission affect short and long term mortality risk?

4. I am surprised that the distribution of included patient ages is parametric, I would have expected it to be negatively skewed and reported as a median [IQR] - could the authors comment?

5. In Figure 1, the median value of sBTLA does appear to fall progressively over the 28 day period but by a very small increment compared to the range of measured values. If the authors analysed the delta sBTLA, and / or delta sBTLA as a percentage of the peak value, for each individual, does this provide a more insightful picture of the evolution of sBTLA levels? For example, percentage drop from peak value of both CRP and PCT are emerging as viable stopping criteria for antimicrobial therapy - hence the question.

6. The mortality data is fascinating, but requires more information. I presume that cause of death / death certification information is a matter of public record in Sweden? As such, could the authors please provide this data and factor it into their discussion. What does this data tell us about the apparent association between prolonged immune dysregulation and the pathology that causes apparent "premature" death? Or, does this data suggest that the index BSI itself occurred because of an occult pathology that would go on to cause death in the succeeding 12 months?

7. Given the association / correlation with widely used existing biomarkers, can the authors comment or speculate on the value of measuring sBTLA levels in addition to, or instead of CRP, for example. Furthermore, could the authors comment on the correlation between sBTLA levels and neutrophil : lymphocyte ratio, which is emerging as a more useful marker than absolute values of either?

8. Could the authors provide a figure that shows the differences in peak, day 7, and day 7 as a percentage of peak in sBTLA levels in survivors verses non-survivors at 28 days, 90 days and 12 months?

9. Could the authors please add more detail to their suggestions regarding what implications their findings should have in terms of the next questions / hypotheses research into sBTLA and other markers of immunosuppression should aim to address?

Reviewer #3: Dear Sirs,

I read both your papers with great interest.

Regarding the paper in review process: the new research actually expends your previous results, regarding sBTLA and sepsis/septic shock patients to the BSI patents. Were some of the patients in both studies? If so, please acknowledge that in the new study (same 31 patients in the control, or just a coincidence?)

I have some concerns regarding the fact that the statistics is too complex, and I think it should be validated by a statistician.

Row 93-95- in introduction do you state your previous research, or did you include a conclusion statement in introduction?

You have a lot of missing data, not only at admission time, but also during the data collecting process. How do you explain this fact?

Do you have a table with the demographic data of the controls? It would be interesting to compare their data with patients' data.

You have more than 100 patients in the patients' group and only 31 in the controls. Why did you decide do compare uneven groups?

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Reviewer #1: Yes: Mohsen Rajaeinejad

Reviewer #2: Yes: Jonathan Ball

Reviewer #3: Yes: Oana Antal

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Sustained elevation of soluble B- and T- lymphocyte attenuator predicts long-term mortality in patients with bacteremia and sepsis

PONE-D-21-08617R1

Dear Dr. Lange,

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.

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George Vousden

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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 #2: All comments have been addressed

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

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 #2: Yes

Reviewer #3: Yes

**********

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 #2: Yes

Reviewer #3: Yes

**********

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 #2: (No Response)

Reviewer #3: Thank you for replying to all my concerns. I have no further issues to raise, as you replayed to all I have asked for.

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7. 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 #2: Yes: Jonathan Ball

Reviewer #3: No