-->PONE-D-26-14642-->-->Diagnostic yield and complication rate of transbronchial lung cryobiopsy using 1.1mm probe in patients with interstitial lung disease-->-->PLOS One

Dear Dr. Adams,

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.

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Kartikeya Rajdev, MD

Academic Editor

PLOS One

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7. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

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: Thank you for submitting this manuscript. As mentioned in the manuscript, the main limitation of this study is the retrospective nature of the study and the lack of control arm. Despite reduced bleeding risk with 1.1 mm cryo probe compared to 1.9 mm and 2.4 mm probes the diagnostic yield is significantly reduced thus reducing the utility of the 1.1 mm probe particularly with only a rare risk of major bleeding with the larger probes. Also the smaller probe had slightly increased risk of pneumothorax. At this time I am not convinced that the smaller probe offers any significant advantages over the larger ones. Future prospective multisite study/studies comparing different size probes with a control arm is needed.

Reviewer #2: This manuscript evaluates the diagnostic yield and complication rate of transbronchial lung cryobiopsy using a 1.1 mm cryoprobe with robotic bronchoscopy guidance in patients undergoing evaluation for interstitial lung disease. The topic is clinically relevant, especially as smaller cryoprobes and robotic bronchoscopy are being used more frequently to improve safety while maintaining diagnostic yield. The study provides useful procedural details and complication data from a real-world academic center experience.

However, several points need clarification. The study is described as both prospective and retrospective in different parts of the manuscript, and this should be clarified for consistency. The definition of diagnostic yield is not clearly explained and appears to be based on change in multidisciplinary diagnosis after BAL and TBLC rather than biopsy diagnostic adequacy alone, which is different from how diagnostic yield is usually reported in prior TBLC studies. This should be clarified. In addition, the conclusions comparing diagnostic yield and complication rates of the 1.1 mm probe with larger cryoprobes should be interpreted more cautiously since there is no direct comparison group in this study. The regression analysis exploring predictors of diagnostic yield is interesting, but the relatively small sample size may limit the strength of these conclusions. Minor grammar and wording edits would also improve clarity in several sections of the manuscript.

Overall, this is a useful and clinically relevant study that adds practical experience with the 1.1 mm cryoprobe and robotic bronchoscopy platform. The manuscript would be suitable for publication after clarification of the study design, clearer definition of diagnostic yield, and moderation of some conclusions.

Reviewer #3: Reviewer Comment — Study Design Clarification:

There is an inconsistency in how the study design is described that needs to be addressed. The Methods section describes patients as "prospectively identified," yet the ethics statement refers to this as a "retrospective study" and notes that consent was waived on that basis. The authors likely conducted a retrospective analysis of a prospectively maintained registry, but this is not clearly stated. Additionally, the ethics section lists a data collection period of January 2025–February 2026, while the procedural period spans 2022–2026, with no explanation for the discrepancy. Please add one to two sentences clearly describing the study design and clarifying what each date range refers to. Consistent use of a single term, such as "retrospective cohort study using a prospectively maintained registry" throughout the abstract and Methods could resolve this.

Reviewer Comment — Discussion: Yield Comparison with Prior Studies:

The discussion states that "studies of 1.1mm touch probes have >80% diagnostic yield, which is much higher than expected, indicating the need for additional studies." While the introduction appropriately notes that Bian et al. and Zhang et al. used conventional bronchoscopy, the discussion does not carry this context forward when comparing yields. The lower diagnostic yield in the present study (43.5%) compared to prior 1.1mm probe studies could be due to a few reasons that are not acknowledged at this point in the manuscript. I suggest the authors add a sentence explaining this, for example: "The lower yield observed in the present study compared to prior 1.1mm probe studies could be due to differences in bronchoscopic platform (ssRAB vs. conventional flexible bronchoscopy), patient population complexity (90.3% unclassifiable ILD vs. broader ILD cohorts), and definition of diagnostic yield (change in diagnosis vs. MDD-confirmed diagnosis), among other causes.

Reviewer Comment — Table 5 Formatting Errors:

A few OR values in Table 5 appear to have typographic errors. "Antigen exposure" shows OR 9.92 (0.3–2.5) and "Age" shows OR 9.99 (0.9–1.0), both not possible given their non-significant p-values and confidence intervals that cross 1.0. The "9." is likely a formatting artifact, with the true values being 0.92 and 0.99 respectively. Please verify and correct all OR values in Table 5 to ensure they are consistent with the reported p-values and confidence intervals.

I appreciated the opportunity to review this manuscript and believe it makes a valuable contribution to the interventional pulmonology literature. With targeted revisions, this manuscript will be strengthened and ready for publication.

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-->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.

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Reviewer #1: Yes: Shais Jallu

Reviewer #2: Yes: Abhishek Singh

Reviewer #3: Yes: Narayana Gandham

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-->

-->PONE-D-26-14642R1-->-->Diagnostic yield and complication rate of transbronchial lung cryobiopsy using 1.1mm probe in patients with interstitial lung disease-->-->PLOS One

Dear Dr. Adams,

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 Aug 01 2026 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 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.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Kartikeya Rajdev, MD

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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. 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 #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

-->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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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 #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 #1: Yes

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 #1: Thank you for submitting the revision. Respone to the reviewers comments is appreciated. I feel this manuscript will make a significant contribution to IP literature.

Reviewer #2: The authors have adequately addressed the major concerns raised during the prior review. The study design is now clearly described as a retrospective cohort study using a prospectively maintained registry, and the distinction between the procedure period and data collection period has been clarified.

The definition of diagnostic yield has also been clarified. The authors now explain that BAL and TBLC were considered diagnostic in 27 patients, and that all of these patients had a change in diagnosis after bronchoscopy.

The conclusions are now more appropriately cautious. The authors acknowledge that there was no direct comparison group using larger cryoprobes, surgical lung biopsy, or another control arm. This is important because the study cannot definitively prove superiority or noninferiority of the 1.1 mm probe compared with larger probes.

The added discussion about why the diagnostic yield in this study was lower than prior 1.1 mm cryoprobe studies is also useful. Differences in bronchoscopic platform, patient complexity, and definition of diagnostic yield are reasonable explanations.

The authors also corrected the apparent typographic errors in Table 5 and reviewed the odds ratios. This resolves a key presentation issue from the prior version.

Overall, this is a clinically relevant and useful study. It adds practical data on the diagnostic yield and complication rate of 1.1 mm transbronchial lung cryobiopsy using robotic bronchoscopy guidance in patients with ILD. The main limitations remain the retrospective design, small sample size, lack of a control group, and single-center experience, but these are now clearly acknowledged. The conclusions are supported by the data as revised. I believe the manuscript is suitable for publication.

Reviewer #3: - The pre-TBLC hypersensitivity pneumonitis (HP) threshold appears conservative but guideline-consistent. That is reasonable, but it likely contributes to the large apparent post-TBLC shift toward HP (since many patients with antigen exposure and suggestive features were initially classified as unclassifiable ILD until tissue sampling increased diagnostic confidence). I would encourage the authors to acknowledge that this could be an important limitation of the baseline classification scheme of HP and not imply that all post-TBLC diagnostic movement, especially in this category, reflects newly discovered disease.

- Typo TLBC was noted, please change that to TBLC

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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: Yes: Shais Jallu

Reviewer #2: Yes: Abhishek Singh, MD

Reviewer #3: Yes: Narayana Gandham

**********

[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.]

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-->

Diagnostic yield and complication rate of transbronchial lung cryobiopsy using 1.1mm probe in patients with interstitial lung disease

PONE-D-26-14642R2

Dear Dr. Adams,

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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Kind regards,

Kartikeya Rajdev, MD

Academic Editor

PLOS One

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