PONE-D-21-05271

Vulnerability to recurrent episodes of acute decompensation/ acute-on-chronic liver failure characterizes those triggered by indeterminate precipitants in patients with liver cirrhosis

PLOS ONE

Dear Dr. Po-sung Chu,

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Reviewers' comments:

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Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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: Hoshi H and co authors in the current paper examined cirrhotic patients outcome as a function of recurrent episodes of acute decompensation (AD) and/or acute on chronic liver failure (ACLF). From their data the authors conclude that AD/ACLF of indeterminate origin: i) accounted for the most of the cases (28%); ii) had a better survival; iii) exposed patients to an increased incidence of AD/ACLF recurrence during time.

This study raises the following comments:

1) The authors pooled together the data coming from AD patient and patients with ACLF. I do not think this should be considered correct. In fact as observed in the CANONIC study several statistical differences exist between these two groups. Moreover, also changes occur among different ACLF grades. Since this research mainly includes patients with no ACLF (83% of cases) I would suggest the author to restrict their analysis and conclusions on these subjects.

2) The prevalence of an indeterminate cause for decompensation was higher in the CANONIC study (58.9% no ACLF, 43.6% ACLF) in comparison with what observed by the authors (28% pooled). This finding however was not commented or explained in the discussion. Please comment

3) I suspect that the episodes of AD/ACLFIND observed by the authors mainly include cases of ascites and encephalopathy (data on this point should be reported). In this case the results observed by the authors would be probably more dependent to the prevalence of these complications (that typically have an abrupt onset, an unclear trigger, frequent recurrence and reduced mortality) in this group, rather than the occult origin of decompensation. Please comment and report data.

Minor

Figures need to be improved

Reviewer #2: Chu et al conducted a single-center observational study, in which a total of 466 events of AD/ACLF in 285 patients, including their 285 first indexed AD/ACLF were analyzed to characterize the AD/ACLF that precipitated by “Indeterminate” factors. By stratified analysis of different acute precipitants, they demonstrated that the patients with AD/ACLFIND are more vulnerable to suffer from subsequent AD/ACLF and tended to developed AD/ACLF associated organ failure when compared to the AD/ACLF induced by other precipitants such as bacterial infection (AD/ACLFBAC), gastrointestinal bleeding, and active alcoholism et al. One of the major meaningful messages from this study could be that the clinicians may need apply different prognostic systems to predict the outcome of the AD/ACLF that triggered by different etiology.

The authors noticed that, although EASL CLIF-C ACLF grades (No ACLF vs. grade 1-3) significantly correlated with survival outcomes in AD/ACLFBAC, they did not significantly predict survival outcomes in AD/ACLFIND or AD/ACLFGIB or AD/ACLFALC (Fig1D).

Could the authors further deliberated the cause of it? How about using other model such as MELD.

In table 3, the patients with AD/ACLFBAC were associated with both leukocytosis (WBC count 7.4[4.6-11.8]) and hyperbilirubinemia (4.1[1.7-8.0]). However, in FigS4B, the Spearman’s correlation analysis of serum level of total bilirubin and white blood cell count demonstrated there is no correlation of this 2 factors with transplant-free survival and liver transplanted/dead. Is there any conflicts in at here, or with any previous publications?

Minor issue

1. Page17. line 296, “Figs 3A-B”, should be changed to “Fig 3A-B”

2. Page, Line 328, “(S2C Fig)”, should be changed “(Fig S2C)”

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Vulnerability to recurrent episodes of acute decompensation/ acute-on-chronic liver failure characterizes those triggered by indeterminate precipitants in patients with liver cirrhosis

PONE-D-21-05271R1

Dear Dr. Po-sung Chu,

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,

Gianfranco D. Alpini

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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: Yes

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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: (No Response)

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: (No Response)

Reviewer #2: 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)

Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: No