PONE-D-26-11568 Inhaled Nitric Oxide in Fibrotic and Advanced Interstitial Lung Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials PLOS One

Dear Dr. Nakahara,

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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One of the reviewers questioned the need for this systematic review and the value of the study. I suggest the authors to highlight the significance of this study and emphasize the new findings that have not been reported previously. Add additional insights into the discussion and make compelling arguments to justify this study.

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Kind regards,

Selvakumar Subbian, Ph.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: 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: Yes

Reviewer #2: 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

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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 manuscript “Inhaled Nitric Oxide in Fibrotic and Advanced Interstitial Lung Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” is well written but requires revisions to benefit the readers.

1. Inclusion of current treatment modalities across different age groups of ILD

2. The authors could justify how the analysis was performed to include both short (20 min)and long term (weeks) of iNO exposure. The authors could include the effects of the same as well as the advantages and disadvantages of short and long term iNO exposure from a clinician perspective in the discussion.

3. The authors have stated “For MVPA, the certainty of evidence was downgraded for serious inconsistency due to substantial heterogeneity”. Please discuss the possible reasons for the same in previous RCTs.

4. The majority of the population were adults over 60 years and male. Please discuss the same in the context of ILD and iNO therapy. Does the conclusion of no clinical improvement be attributed to the population considered. Is iNO administered to any other age group?

5. Would the author recommend the feasibility of inclusion of iNO in routine therapy – in light of advantages and disadvantages considering no safety issue. What are the drawbacks for iNO considering the routine therapy wherever considered. Why were the same restricted to adults in RCTs.

6. To benefit the reader, the final conclusion could include authors perspective and recommendation on use of iNO for ILD

Reviewer #2: GENERAL COMMENTS:

The authors conducted a systematic review of the literature to compare the efficacy and safety of inhaled nitric oxide (iNO) versus placebo in patients with interstitial lung disease (ILD). They identified four randomized controlled trials (RCTs), including one crossover trial, involving 274 patients for analysis. Pooled analyses revealed that iNO likely results in little to no difference in 6-minute walk distance (6MWD) compared with placebo, and may also result in little to no difference in adverse events or moderate-to-vigorous physical activity (MVPA). The authors concluded that iNO did not demonstrate improvements in 6MWD or MVPA. While this report includes valuable information, it raises several concerns.

MAJOR COMMENTS:

1. Rationale of the study

The authors state that previous RCTs have demonstrated increases in MVPA, alongside improvements in dyspnea, quality-of-life measures, and oxygenation. However, a phase-3 trial in patients with fILD found no significant differences in activity level, 6MWD or patient-reported outcomes. They justify their study on the basis that the available evidence regarding iNO in ILD is inconsistent and limited to small-scale trials.

King et al. conducted a phase 2 exploratory randomized controlled trial and found that INOpulse was well tolerated and associated with the maintenance of physical activity and an improvement in symptoms in patients with ILD requiring supplemental oxygen (AnnalsATS, 2021). They then conducted a randomized, double-blind, placebo-controlled trial to validate the benefit of ambulatory iNO in patients with fILD requiring supplemental oxygen, concluding that there was no demonstrable benefit to iNO in patients with the disorder (AnnalsATS, 2024).

Are a further systematic review and meta-analysis necessary?

2. Studies included in review

The authors included four RCTs in this systematic review and meta-analysis. The first RCT was conducted by Nathan et al. and enrolled 41 patients. The second RCT was reported by King et al., although Nathan contributed to the study design, data analysis, and manuscript preparation and revision. The third RCT was performed by Nathan et al. to validate the benefits of ambulatory iNO. Thus, these three RCTs were all conducted by the same group. The fourth study was conducted independently of the others. However, this study only included 44 patients. Is it therefore reasonable to conduct a systematic review and meta-analysis?

3. Baseline patient and study characteristics

According to Table 1, Freidkin et al. administered iNO for 20 minutes once. In contrast, Nathan’s group delivered NO consistently for 8 to 16 weeks (at a daily usage rate of >12 hours). Are the results of the study by Freidkin et al. comparable to those of Nathan’s group?

MINOR COMMENTS:

1. Supplementary Table 5

The study by Freidkin et al. was conducted in Israel rather than the United States.

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Reviewer #1: Yes: Radha Gopalaswamy

Reviewer #2: Yes: Toshinori Takada

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Inhaled Nitric Oxide in Fibrotic and Advanced Interstitial Lung Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

PONE-D-26-11568R1

Dear Dr. Nakahara,

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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Kind regards,

Selvakumar Subbian, Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

In the revised version, the authors have satisfactorily addressed the concerns raised by the reviewers.

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: N/A

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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: 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: (No Response)

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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: Radha Gopalaswamy

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