PONE-D-19-31648

Incidence and etiology of chronic pulmonary infections in patients with idiopathic pulmonary fibrosis

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https://doi.org/10.1164/rccm.201807-1255ST

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Reviewer #2: No

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Reviewer #1: Incidence and etiology of chronic pulmonary infections in patients with idiopathic pulmonary fibrosis

Authors : Odashima K et al.

This study is a retrospective study on the chronic pulmonary infections in patients with IPF. Study is very well done and has its own limitation due to the retrospective nature of it which authors have acknowledged in the manuscript.

I have few minor comments

“Five- and ten-year mortality rates of patients with and without CPI development were 43.4%

and 33.0%, and 68.9% and 72.8%, respectively.” In this statement in mortality section, are they trying to say that mortality is higher in those without infections? Although there was no difference in the KM curve. Please explain

The authors found KL 6 levels to be associated with survival in those with CPI. How do they explain this finding when KL6 level was elevated with diagnosis of IPF.

I would recommend to add a separate table on KL6 data findings. Showing how its different in each group and the trend in those who had CPI. This is an interesting finding of this paper as KL6 is not routinely used for treatment or evaluation of IPF world wide.

Regarding diagnosis of IPF, the authors have mentioned using ATS criteria. By which I am assuming all these patients had HRCT and a multidisciplinary evaluation. If yes, it would be informative to know how many of these were definite IPF or probable or possible and then showing the prevalence of these infection based on the type of IPF.

Reviewer #2: In this manuscript Odashima et al. describe the incidence and etiology of chronic pulmonary infections in patients with idiopathic pulmonary fibrosis. The authors define chronic pulmonary infection and as infection that was diagnosed 1 or more months after the onset of symptoms or upon the appearance of new shadows on pulmonary radiologic images, and note that nontuberculous mycobacteria, Mycobacterium tuberculosis, aspergillosis and nocardia were therefore most frequent etiologies of chronic pulmonary infection in patients with idiopathic pulmonary fibrosis.

The authors make a very good observation regarding chronic infections in patients with interstitial lung disease. This is been well described in patients with other chronic lung conditions such as chronic obstructive pulmonary disease, but much less so in the interstitial lung diseases. However, I have the following concerns and questions regarding the manuscript which need to be addressed.

The authors institution is a tertiary referral care for non-tuberculosis respiratory diseases and tuberculosis. Given that, it is probably reasonable to resume that it is also a referral center for complex patients with nontuberculous mycobacteria and other chronic infections. Given that older patients may be predisposed to these infections, and that the same population group is at a high risk for idiopathic pulmonary fibrosis as well, unless we can factor in the denominator, in addition to the expected baseline rate of idiopathic pulmonary fibrosis, nontuberculous mycobacteria, tuberculosis and other infections, one can question whether the association between idiopathic pulmonary fibrosis and chronic infections is spurious, and is secondary to a referral bias. For example, if the expected prevalence of idiopathic pulmonary fibrosis in a population is 10% and the expected prevalence of chronic infections is 5%, then just by chance alone, 0.5% of patients will have both the diseases, and if these patients are somehow referred to a single institution, simply analyzing these patients with both diseases can give a false impression that there is an association when there actually is not. This could be a difficult task to accomplish but the authors should try to address this in the manuscript.

The authors have divided the groups based on when IPF and CPI respectively were diagnosed in relationship to each other. Table 1 mentions steroids and immunosuppressants in these patients without alluding to the temporal relationship between the infection and immunosuppression. It probably makes more sense to divide the groups based on whether these patients had no risk factors, or had risk factors such as being immunosuppressed, or receiving corticosteroids before a diagnosis of CPI was made. These subgroups can be further divided based on the whether the IPF was diagnosed first, CPI, or at the same time.

Group C includes patients who had chronic infections at the time of diagnosis but none at the time of follow-up. Is this because these infections were treated? Or do they represent false positives?

Table 3. Multivariate Cox progression final model. E SR. It is unclear why there are multiple groups for this. Perhaps best to ignore those with unknown ESR and divide the rest into 2 groups only, less than 20, and more or equal to 20.

Figure 3. If the difference between these 2 groups is not significant, it is unclear how this figure adds to the manuscript.

Figure 4. Given the numerous factors affecting mortality in this group, this is likely not needed.

Table 4. To patients with microscopic polyangiitis were included in the group. Usual interstitial pneumonia pattern has been well described in patients with microscopic polyangiitis, and can in fact precede the diagnosis of microscopic polyangiitis. This patients do not have IPF and should not be included in the group.

Did all the patients with the organism isolates meet relevant clinical criteria for infection?

The authors should speculate on the reason for CPI in patients with IPF and hypothesize on possible mechanisms.

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Reviewer #1: No

Reviewer #2: No

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Incidence and etiology of chronic pulmonary infections in patients with idiopathic pulmonary fibrosis

PONE-D-19-31648R1

Dear Dr. Odashima,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Vinicio A. de Jesus Perez, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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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 the comments raised by me appropriately. Although, authors have not provided a separate table for KL6 in each group and I acknowledge their explanation but I feel its important to know in general. May be a table can be added as a supplementary data if not in main manuscript.

Apart from this I do not have any further comments.

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Reviewer #1: Yes: Sandeep Sahay