Dear Mr Paul:

Thank you very much for submitting your manuscript "Hepatitis E as a cause of adult hospitalization in Bangladesh: Results from an acute jaundice surveillance study in six tertiary hospitals, 2014-2017" (PNTD-D-19-01051) for review by PLOS Neglected Tropical Diseases. Your manuscript was fully evaluated at the editorial level and by independent peer reviewers. The reviewers appreciated the attention to an important topic but identified some aspects of the manuscript that should be improved.

We therefore ask you to modify the manuscript according to the review recommendations before we can consider your manuscript for acceptance. Your revisions should address the specific points made by each reviewer.

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(4) Appropriate Figure Files

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We hope to receive your revised manuscript by Nov 19 2019 11:59PM. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by replying to this email.

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If you have any questions or concerns while you make these revisions, please let us know.

Sincerely,

Alan L Rothman, MD

Associate Editor

PLOS Neglected Tropical Diseases

Samuel Scarpino

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objectives were clear and the method appropriate. There was a robust sample size well distributed throughout the country to represent a national burden for severe hospitalized jaundice. As acknowledged by the authors, the design did not allow for estimates of milder disease, or those with severe disease but seeking traditional medicine.

Reviewer #2: The objective of this study was to estimate the prevalence of HEV infection among jaundice patients aged >=14 ansadmitted in tertiary hospitals in Bangladesh, estimate the case-fatality rate and estimate factors associate with mortality, as well as describe seasonal and geographical trends

The descrition of objective is very complex. Which is the main objective of the study? Please rewrite this section and specify the main objective.

The study is well designed, but please insert the list of items included in the case report (line 138) and a schema of the method of enrollement of patients

The sample size was not reported in the method section, please add

The discussion and conclusion were based on univariate analysis. Please add multivariate analysis to validate results or univariate analysis

Please add number of ethic autorisation

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are clearly represented. It seems that all causes of jaundice have a negative impact on pregnancies. Although there were more neonatal deaths with HEV + pregnant women, maternal mortality and miscarriage were equally bad among HEV+ and HEV- pregnant women. This might have been brought up in the discussion more fully. Hepatitis is bad for maternal and fetal outcomes regardless the type.

Reviewer #2: As mentioned in method section authors have to add a multivariate analysis in order to validate results of the univariate analysis

Please add median age and Min and Max in Table 1

In Figure 2 authors declared that the proportions of patients anti-HEV IgM declined significatly with time after two months but IC95% from the week 2 to four overlap. Please modify this sentence.

Figure 3: How do you explain the increase of the number of IgM positive cases during the 2016 summer?

Line 304-305 please place after line 301

Table 4: pvalue of live birth/still birth are missed?

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported by the evidence and the limitations nicely acknowledged.

Reviewer #2: The authors need to improve statistical analysis

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: none

Reviewer #2: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: This is an important paper which well describes the burden of HEV among severe jaundice cases seeking hospital care in Bangladesh. While the lack of quality burden of disease data is an important reason why there is not clear and strong guidance regarding use of the HEV vaccine, it is not the only limitation. There is insufficient experience with the vaccine in high risk populations , like pregnant women or those in humanitarian emergency settings or other areas (like Bangladesh) where genotype 1 and fecal-oral transmission is the common route.

It is unfortunate that those under 14 yo and hospitalized with jaundice could not be included, or that families were not investigated to find additional mild or asymptomatic cases. But I understand the limitations of funding. Hopefully these important results will lead to additional studies to extend the understanding of HEV transmission into the household and to younger ages. If vaccines are to be used most effectively, the entire transmission cycle should be known.

Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: No

Dear Mr Paul,

We are pleased to inform you that your manuscript, "Hepatitis E as a cause of adult hospitalization in Bangladesh: Results from an acute jaundice surveillance study in six tertiary hospitals, 2014-2017", has been editorially accepted for publication at PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted and sent to production you will need to complete our formatting changes, which you will receive in a follow up email. Please note: your manuscript will not be scheduled for publication until you have made the required changes.

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Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Alan L Rothman, MD

Associate Editor

PLOS Neglected Tropical Diseases

Samuel Scarpino

Deputy Editor

PLOS Neglected Tropical Diseases

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