PONE-D-21-04098

The Role of Interleukin-6 as a Prognostic Biomarker for Predicting Acute Exacerbation in Interstitial Lung Diseases

PLOS ONE

Dear Dr. Kim,

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.

Comments:

1. Table 1 & 2: Add % to the patient characteristic population ratio even explained at the bottom of the table, for example,  IPF, n (%)--- 57 (68.7).
2. Figure 2: survival analysis, please correct mislabeling (IL6 level).
3. As a predictive factor for AE in the CTD-group, n=3 is too small for biomarker study. I agree to the reviewer’s comments to remove CTD group from study.

     I hope reviewer's comments is helpful for improving manuscript.

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Minghua Wu, M.D., 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: No

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

Reviewer #1: Yes

Reviewer #2: No

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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: 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 by Dr. Lee et al demonstrated a Role of Interleukin-6 as a Prognostic Biomarker for Predicting Acute Exacerbation in Interstitial Lung Diseases. The authors followed up 83 patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea. They measured the lung functional parameters and the serum levels of IL-6 at diagnosis with ILD and sequentially at follow-up visits. From the studies, the authors demonstrated that high levels of IL6 (OR 1.014, 95% CI: 1.001–1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. They also performed the receiver operating characteristic curve analysis, and found that the serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. Finally, the authors concluded that a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

This manuscript demonstrated an important role of IL-6 as a biomarker for IPF-AE. Since the increased serum IL-6 and IL-8 level has already been reported (Papiris SA et al, Cytokine. 2018 Feb;102:168-172), the manuscript is somehow lack of novelty. However, the authors performed a longitudinal study to check IL-6 levels overtime. If the authors have already have the data, it will be interesting to show IL-6 levels overtime to see the dynamic changes of IL6 before the onset of the AE.

Minor comments.

Figure 2. Is the labels for “Peak IL-6 level>25.20” and “Peak IL-6 level<25.20” flipped?

Reviewer #2: Review of the manuscript: “The Role of Interleukin-6 as a Prognostic Biomarker for Predicting Acute Exacerbation in Interstitial Lung Diseases”

This retrospective study aimed to assess the merit of IL-6 to predict acute exacerbation (AE) of intestinal lung disease (ILD).

Comments

- Limitation: an important limitation of the paper is the low number of patients, with probable insufficient power (the power of the study sample needs to be determined) and the heterogeneity of included diseases Moreover, the OR and HR of IL6 to predict the occurrence of AE were low, close to 1, the question is their relevance in clinical pertinence

- Please precise the number of screened patients, those who fulfilled inclusion and exclusion criteria leading to the final number of recruited patients

- The ILD pattern on HRCT scan should me precised: UIP, NSIP…

- Please provide the detailed causes of AE. Please confirm that infections have been formally ruled out. It is important since infections may increase CRP and thus, IL-6 levels.

- Logistic regression analysis: please explain how were entered the different covariates in the model (stepwise, backward…). In this model, IL-6 was entered as a continuous variable; it would be interesting to consider IL-6 as a dichotomous variable (Lower/higher)

- Multivariate analyses: gender, disease duration, and HRCT scan pattern should be included in the models

- The pertinence to include in the models both CRP and IL-6 is questionable given the strong relationship between these 2 variables

- Kaplan-Meier survival curve: a table with the number of patients should be added below the figure

- Given the very low number of patients with CTD-ILD, and the low frequency of AE, the reviewer suggests the deletion of the sub analysis of the CTD-group

- How were Handled missing data?

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Reviewer #1: No

Reviewer #2: No

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The Role of Interleukin-6 as a Prognostic Biomarker for Predicting Acute Exacerbation in Interstitial Lung Diseases

PONE-D-21-04098R1

Dear Dr. Kim,

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,

Minghua Wu, M.D., Ph.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 #2: 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 #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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

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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

Reviewer #2: 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: I would like to thank the authors for addressing my questions! I have no other concerns and comments.

Reviewer #2: The authors have adequately answered to all the raised comments. The manuscript has been significantly improved.

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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 #2: No