PONE-D-20-35972

Clinical significance of hypoalbuminemia in patients with scrub typhus complicated by acute kidney injury

PLOS ONE

Dear Dr.In O Sun

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PLOS ONE

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- https://e-sciencecentral.org/articles/pubreader/SC000036783

- https://www.jiac-j.com/article/S1341-321X(13)00033-0/fulltext

- https://synapse.koreamed.org/articles/1128479

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Partly

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: I Don't Know

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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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: This article poses a clear hypothesis that is fully supported by the data and statistical analysis. The article is clearly written, exhibits good grammar and prose, and the results are clinically relevant. Clinicians may potentially use the findings to direct the level of monitoring various patients receive. Would recommend for publication.

Reviewer #2: The authors present a case series of patients diagnosed with scrub typhus admitted to a medical center in South Korea. They demonstrate that hypoalbuminemia detected on presentation was associated with acute kidney injury, correlated well with severity of the AKI by RIFLE criteria, and was associated with other systemic complications. They further state that multiple clinical and laboratory findings were predictive of AKI by multivariate analysis, which may warrant change to assessment, monitoring, or therapeutic approach.

My assessment of their submission is hampered by duplication of Table 1 in the listed Table 2.

The introduction discusses other publications addressing scrub typhus, its complications, association with renal failure specifically, and association with other complications. The strengths of this analysis by comparison included a larger sample size and use of RIFLE criteria to demonstrate correlation of severity of AKI with severity of hypoalbuminemia. It is interesting that the rate of hypoalbuminemia in this study was lower than others. I would explicitly state whether others included inpatients, outpatients, or both as that is an important limitation of this study.

The section on patient selection should explicitly state whether patients were inpatients, outpatients, or both, and whether they included patients transferred in from another facility. Later in the manuscript, it is stated they excluded outpatients. Also, they exclude patients transferred to other facilities, but it would be helpful to state if it is known why those patients were transferred, especially if it was to a higher level of care.

Elevation of cardiac biomarkers was stated to define myocarditis--this is not accurate and could be stated more accurately as a marker of such. Respiratory complications included ARDS and various imaging findings, but not respiratory failure or mechanical ventilation.

Table 3 should include definition of terms by cutoff values. FENa has a marker for footnote 'a' but no associated footnote and n(%) appear incorrect. If a large number of cases did not have FENa or urinalysis available, I question the value of including that information. Was it assessed whether these cases are representative of the population?

A bigger question is whether HA as an independent biomarker of AKI risk is significant in this setting. It correlated well with AKI and other poor outcomes, but as a negative acute phase reactant, one would expect that to be true. The homeostasis of albumin is affected by numerous factors other than vascular permeability. During acute inflammatory syndromes, synthesis is suppressed and catabolism increased in addition to increased volume of distribution. The "central pathomechanism" comment is incomplete. I would direct to the discussion cited as a reference in Lee, et al. (BMC Infect Dis 2010).

The fact that almost all cases with AKI were present on admission makes HA a marker for a condition that was already present on admission, not a predictor that it will occur. Does HA predict which cases with AKI will progress to a more significant degree of AKI, or which cases that present with HA and normal renal function will progress to AKI? Would it predict which of the 2% of cases will not recover?

Reviewer #3: The authors must be complemented on writing about this very important infectious disease.

I had a few queries:

1. In page 11 could you elaborate further and explain how definiitons for cardiac and respiratory complications were arrived at

2. How was meningoencephalitis identified

3. Under discussion : "The development of HA in

patients with scrub typhus seems to be due to the central pathomechanism of scrub typhus,

which is vasculitis or perivasculitis of multiple organs resulting in increased vascular

permeability". Could you please provide a reference.

4. Further explanation of who were included in the study is warranted. We would like to know what work up was done for patients presenting with fever and a rash. What other causes were ruled out.

5.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Clinical significance of hypoalbuminemia in patients with scrub typhus complicated by acute kidney injury

PONE-D-20-35972R1

Dear Dr. Sun,

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,

Bhagwan Dass, MD

Academic Editor

PLOS ONE

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