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PONE-D-19-25327

Primary Epstein-Barr virus infection with and without infectious mononucleosis

PLOS ONE

Dear Mr. Rostgaard,

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

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: It would be useful to report the number of individuals included in the study, and a descriptive table showing the number of individuals who are EBV positive or negative at each age. A multiple-decrement life table could provide at a glance a good sense of the infection and disease process, and thus a more convincing presentation of the results presented.

Reviewer #2: Manuscript Nr.: PONE-D-19-25327

Rostgaard et al., "Primary Epstein-Barr virus infection with and without infectious mononucleosis"

The authors evaluate the age and sex dependency of infectious mononucleosis (IM) in the Danish population between 2006 and 2011 for the ages between 0 and 29 years. IM is identified by hospitalization or self-reporting. The Epstein Barr virus (EBV) serostatus is assessed by IgG and IgM responses to virus capsid antigen (VCA) and IgG to the nuclear antigen 1 of EBV (EBNA1). They report that the cumulative IM risk for males before 30 years of age is 13% and for females 22%. IM peaks during puberty at 16.3 years earlier in girls than with 17.3 years in boys. The authors suggest that alterations in the immune system during puberty might account for the increased risk to develop the immunopathology of IM in response to primary EBV infection.

The reported data and the differences between girls and boys are interesting. One wonders if however quantitative data could be obtained from the assessed serotests and if other virus specific serologies were reported in at least a subgroup of individuals.

Major comments:

1. As pointed out by the authors overall viral loads do not differ between individuals with asymptomatic or symptomatic EBV infection. However, the composition of the primary infection might be altered during IM. Do the authors find any evidence that seroconversion during adolescence irrespective of IM results in an altered ratio of VCA (lytic infection) versus EBNA1 (latent and lytic infection) specific antibody titers?

2. Additional infections have been proposed to mature or alter the human immune system. Was the serostatus to other pathogens assessed and shows a similar bimodal distribution with two peaks of acquisition (0-2 years and during puberty)?

3. The increased rate of IM related hospitalization in males compared to females despite higher IM incidence in females is puzzling and could point towards more severe immunopathology in males during IM. Do the authors observe higher immunoglobulin titers against EBV antigens in males compared to females?

Minor comments:

1. In their results the authors often stay vague by just stating that one incidence rate is higher than another etc. I think it would be helpful if the manuscript would indicate the actual numbers that the deployed modelling generated.

In summary, this is an interesting manuscript on IM in the Danish population, reporting a surprisingly high cumulative risk in females with a fairly narrow IM peak around puberty. The study could be further improved by reporting some of the available immune parameters quantitatively.

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Reviewer #1: No

Reviewer #2: No

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Primary Epstein-Barr virus infection with and without infectious mononucleosis

PONE-D-19-25327R1

Dear Dr. Rostgaard,

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.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Gulfaraz Khan, PhD, FRCPath

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: Manuscript Nr.: PONE-D-19-25327R1

Rostgaard et al., "Primary Epstein-Barr virus infection with and without infectious mononucleosis"

The authors evaluate the age and sex dependency of infectious mononucleosis (IM) in the Danish population between 2006 and 2011 for the ages between 0 and 29 years. IM is identified by hospitalization or self-reporting. The Epstein Barr virus (EBV) serostatus is assessed by IgG and IgM responses to virus capsid antigen (VCA) and IgG to the nuclear antigen 1 of EBV (EBNA1). They report that the cumulative IM risk for males before 30 years of age is 13% and for females 22%. IM peaks during puberty at 16.3 years earlier in girls than with 17.3 years in boys. The authors suggest that alterations in the immune system during puberty might account for the increased risk to develop the immunopathology of IM in response to primary EBV infection.

The revised manuscript version continues to report an interesting dichotomy between girls and boys for IM with a higher frequency and earlier onset in girls, but more frequent hospitalization of boys. Even so the authors could not provide quantitative data on the measured serologies, they have discussed these outstanding issues and now report their data more quantitatively. Therefore, the revised manuscript is improved.

Minor comment:

1. The title could be more informative and reflect some findings of the manuscript. Something along the lines of “Earlier onset and higher frequency of infectious mononucleosis in Danish females than males” would seem appropriate.

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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: Yes: Christian Münz