PONE-D-21-15104

Deleterious neurological impact of diagnostic delay in immune-mediated thrombotic thrombocytopenic purpura

PLOS ONE

Dear Dr. Renaud,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

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

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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: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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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: In this manuscript, the authors investigated the effects of diagnostic delay on neurological in patients with iTTP. Based on their results, Renaud et al. concluded that diagnostic delay had a significant impact on neurological outcome. Although the results of this study add a little new information to current literatures, the retrospective nature and small number of cases make it difficult to draw a definite conclusion that “diagnostic delay has an impact on neurological outcomes in iTTP”. My comments:

1. Why the cutoff value of 24h was used to group classification ? Please add the number of patients in group 1 and group 2.

2. Please add references for the definition of iTTP.

3. Please add details on the treatment of iTTP.

4. How to define “brain dysfunction” and “brain dysfunction free survival” ? and related references should be provided.

5. The authors did not observe the effect of diagnostic delay on mortality. Why ?

Reviewer #2: The current article from Renaud and colleagues investigates the effect and reasonings of diagnostic delay of TTP and neurological outcomes in affected patients. Outlining the diagnostic during the differential diagnosis between TTP and other diseases is of great interest; however, several significant questions are raised. Moreover, the manuscript at this stage provides only confirmatory results that >24h delay markedly increase negative consequences. The delay in diagnosis directly correlates with the delay in a specific treatment, and the consequences of the latter are reported by Sawler et al., 2020

Major comments:

1. Although the diagnosis establishment is essential, how does it correlate with the plasma exchange therapy start? Are there patients from the group with the immediate diagnosis but delayed plasma transfusions?

2. How was the cut-off for the delayed and immediate diagnosis determined?

3. In what number of patients were the ADAMTS13 levels determined before or shortly after the plasma exchange therapy?

4. The authors state that different therapeutic approaches were used. Please, specify what treatment patients received in different groups and their counts.

5. Several prediction scores were developed to assess TTP risks. Did clinicians use them to evaluate the probability of TTP? It is interesting to check if they are significantly different between derived groups.

6. The Clinical-biological determinants of diagnostic delay section raise several comments:

a. Although the authors state that the group has statistically different PLT counts, one would argue that both levels might be considered as severe thrombocytopenia.

b. Mixing values from total counts and delayed group when analyzing schistocytes strongly confuses the reader

Minor comments:

1. Please, specify the ADAMTS13 assay type used in the study.

2. Table 1 and Table 2 content is not immediately straightforward for the reader. Two subcolumns are reported in each section; however, it’s not apparent what is reported in each one and in what units. For example, Women 26 (68). I strongly recommend reformating the tables to include all the numbers

3. The manuscript requires proof-reading by an English native person

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-15104R1Deleterious neurological impact of diagnostic delay in immune-mediated thrombotic thrombocytopenic purpuraPLOS ONE

Dear Dr. Renaud,

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 Nov 13 2021 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

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.

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 #3: (No Response)

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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 #3: Partly

**********

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

Reviewer #3: 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 #3: 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 #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 #3: ABSTRACT

> Unexpectedly, recent studies suggest that a slight delay in TPE initiation has no significant impact on patients’ outcome.

Some other expressions like "However, the exact impact of a slight delay in TPE initiation on the subsequent patients’ outcome is still controversial” would be better.

> delayed (>24h, group 1) and immediate diagnosis (≤24h, group 2).

24 hours from when? From the clinical onset, or from the first hospital visit?

> Conclusion: Diagnostic delay is highly prevalent in iTTP, with a significant impact on neurological outcome.

The shown results imply that the occurrence of stroke/TIA during hospitalization may be slightly higher in “delayed” group, whereas the occurrence of irreversible neurological sequelae was not significantly different (p=0.22) between the groups. Thus, this conclusion is misleading. The swift performance of TPE may suppress the occurrence of stroke/TIA, but it may not improve the neurological outcome.

> Interdisciplinary efforts are necessary in order to increase first-line physicians’ awareness regarding the early clinical-biological presentation of iTTP.

What is the author’s specific message regarding the suggested factors of delayed diagnosis? Please describe more specifically. Is there a supporting data to say that the “unawareness” among the first-line physicians of the disease concept of “TTP” caused the delayed diagnoses in your cohort?

METHODS

Graph Pad Prism software 6.0 >> GraphPad Prism software 6.0

Please add the information about the manufacturer of GraphPad Software.

e.g., (GraphPad Software, Inc., San Diego, CA)

I cannot find the criteria and rationale to divide the cohort to the “delayed” group (>24h) and “immediate” group (<24h) in the METHODS section. From when the “24 hours” was counted? From the clinical onset? Why the cutoff time of 24 hours was set? Did previous studies support the cutoff at 24 hours of TPE initiation from onset to influence the clinical outcome?

RESULTS

> Clinical- biological determinants of diagnostic delay

How about performing a multiple regression analysis by using the required days from onset to TPE initiation as the dependent variable? Currently, the authors only performed univariate analyses to search for the determinants of diagnostic delay.

TABLES

Table 1:

How were the data regarding the prevalence of fever at the first hospital visit in the two groups?

> no. (%)

What is “no”? Maybe, “n” would be better, if the authors intended to show the numbers.

> points (IQR)

Are the shown values median or mean?

(N=38) (N=20) (N=18) >> (n=38) (n=20) (n=18)

“N” and “n” have different meanings.

Table 2:

> Table 2. Comparison of neurological outcomes from disease onset to hospital discharge

I think the table should compare the neurological outcomes from “TPE initiation” to hospital discharge, because this section intends to show the “Deleterious neurological impact of diagnostic delay”. If they include the time “from disease onset” in this table, the numbers overlap with those in Table 1.

> a Number of neurological events [number of patients].

Which of the “number of events” or “number of patients” was used to calculate the p-values by performing chi square or Fisher test?

> Stroke/TIA [n] a

Please separately show the numbers for “stroke” and “TIA”. Did skilled neurologists diagnosed the TIA conditions? Were all episodes of stroke confirmed by brain MRI scan?

Table 3:

> TPE per patient – no. (IQR)b

Maybe, TPE “cycles” per patient?

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Reviewer #3: 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.

Deleterious neurological impact of diagnostic delay in immune-mediated thrombotic thrombocytopenic purpura

PONE-D-21-15104R2

Dear Dr. Renaud,

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,

Massimo Cugno, M.D.

Academic Editor

PLOS ONE

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

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 #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: 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

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 #1: 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 #1: All of my comments have been addressed by the authors. The manuscript could be accepted for publication.

Reviewer #3: Thank you for the thorough modifications.

I think the authors have addressed all my concerns correctly.

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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

Reviewer #3: No