PONE-D-22-24326Pentraxin 3 in the cerebrospinal fluid during central nervous system infections: A retrospective cohort study.PLOS ONE

Dear Dr. Thomsen,

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: No

Reviewer #2: No

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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

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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 is a well-designed and carefully conducted study with acknowledged limitations. Control group is very well selected to match real world clinical situation. I have no major criticisms and would like to suggest correction of a few typographical errors and imprecisions in the text, and optionally to provide some additional information as specified below:

ABSTRACT: In the first page (PLOS ONE Table), "random operator curves" are mentioned - I suppose rather "receiver operating characteristic" is correct. In page 3 of the Manuscript itself, the correct abbreviation ROC is used instead.

3rd paragraph: "CSF PTX3 was ... undetectable in the control group." 4 out of 34 patients of the control group apparently had detectable CSF PTX3 concentrations (see Fig. 1), so I would recomment to change the text accordingly (e.g. "... and undetectable in 30/34 patients in the control group" or "... and undetectable in most of patients in the control group" or otherwise).

Section 2.1 For practical reasons, the readers might be interested how long the CSF PTX-3 analysis takes.

Section 2.2 Statistics: page 8, row 203: the typographic error in the formula for Youden index should be corrected (missing "-", i.e., "J = Sensitivity + Specificity - 1" is correct, not "... Specificity 1").

Discussion section: page 12, row 305: missing space between "patient" and "group"

p. 12, row 313 and 323: the abbreviation P-CRP or P-PTX3 is not explained; perhaps it is clear for most readers that "P" stands for "plasma" but please consider to explain before the first use

p. 13, row 331: "neutrophil" instead of "neutrophile"

Table 1, 1st column: perhaps it is not necessary to repeat "(IQR) if it is already stated in the Table Title/Legend; row "GCS score": symbol "(" possibly introduced by mistake; row "CSF mono": I would prefer the term "mononuclear" (or "mononuclears" or "mononuclear cells") since "mono" may be interpreted either as "mononuclear" or "monocyte" (the same applies to Table 2)

Table 1, column "Neuroborreliosis": it is quite surprising that 1/24 patients died; was the death causally related to neuroborreliosis? (response optional since it is not of significant importance for the Manuscript)

Table 3: "Haemophilus influenzae" instead of "Haemophilus influenza"; "Neuroborreliosis" instead of "Neuroorreliosis"

Table 4: cut-off values below the detection limit of the assay are of dubious importance. Am I correct if I suppose that using the LoD stated (3.2 pg/ml) as a cut-off value would result in the same sensitivity, specificity, PPV and NPV? If I understand the Method section well, no values between 1.0 pg/ml (arbitrary value for samples with undetectable PTX-3 concentration) and 3.2 pg/ml (LoD of the assay) should exist.

Figure 3 on the right, y-axis: "CSF Polynuclear cells 10^6/L" not "...10^16/L"

References:

page 23, row 489:Reference 28 is incomplete.

It would be interesting to compare sensitivity, specificity, PPV and NPV of PTX-3 and other CSF biomarkers within the same patient cohort. I would like to bring the Authors´ attention to an excellent study of prof. T. O. Kleine et al. "New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF)" (Brain Res Bull 2003; 61(3): 287-297) where it is stated that "tests with new markers were more laborious, expensive and time-consuming than CSF lactate test" (as well as other classical CSF tests). The same seems true after 20 years, and until now, none of the "new" markers studied in 2003 entered routine practice of CSF laboratories, at least not in the emergency service setting. It seems to me that with PTX-3 measured by an expensive and probably also time-consuming assay would also be quite impracticle, although such pilot studies are always welcomed and may possibly also bring new insights into disease pathophysiology.

Reviewer #2: The author needs to comment further on their case populations to other studies, especially from other areas, to compare the possible relevance of the test in other areas concerning severity, local origin and clinical case differential conditions.

Although other biomarkers are discussed, the results as compared to the other test already performed (i.e. CSF analysis reported, CSF cells and differential counts) can be compared in a diagnostic table similar to table 4 and fig3.

minor: a short title should be short

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Reviewer #1: No

Reviewer #2: No

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Pentraxin 3 in the cerebrospinal fluid during central nervous system infections: A retrospective cohort study.

PONE-D-22-24326R1

Dear Dr. Thomsen,

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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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,

Francesco Lolli, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

a few typos are evidentiated, with suggested correction, by the second referee. To be taken care in the final version

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

**********

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: Yes

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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 all comments appropriately and carefully revised their manuscript. I have found only a few formal inaccuracies remaining in the revised text that could possibly be corrected in the published version:

Page 5, line 106: "more than" is not necessary before the symbol "more or equal than"

Page 6, row 149: "3.2" instead of "3,2" (decimal point rather than decimal comma, also in Table 1, last row: <3.2)

Page 12-14, Table 4A, B, C, , 1st column under "Microbiologically confirmed pathogen and culture negative samples": "Bacterial" rather than "Bacteriel"

Page 13, Table 4B, 3rd column, line "Microbiologically confirmed and culture negative patient groups": Maximum Youdens J (mmol/L) rather than (pg/ml)

Page 14, Table 4C, 3rd column, line "Microbiologically confirmed and culture negative patient groups": Maximum Youdens J (x10^6/L) rather than (pg/ml)

Page 17, line 314: "slightly better" rather than "slight better"

Page 19, line 358: two commas instead of one after the word "studies"

Finally, I would like to express my gratitude to have the opportunity to review this interesting and carefully written manuscript and to wish the Authors many success in their future research.

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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 #1: No

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