Reviewer ’s report  
 
Title: Epstein -Barr virus infection is associated  with a higher Child -Pugh score and may predict 
poor prognoses for patients with liver cirrhosis  
 
Version: 0 Date: 03 Oct 2018  
 
Reviewer: Reviewer 2  
 
Reviewer's report:  
 
PEER REVIEWER COMMENTS: To view the full report from the academic peer reviewer, 
please see the attached file.  
 
REVIEWER COMMENTS FROM REPORT: Title: Epstein -Barr virus infection is associated 
with a higher Child -Pugh score and may predict poor prognoses for patients with liver cirrhosis  
Brief summary of the results of the study presented in the manuscript  
The p resent study aimed to analyze EBV infection rates, the effects on liver function, mortality 
risk factors in patients with liver cirrhosis. The authors have shown that patients with liver 
cirrhosis had higher EBV infection rates and liver injury was aggrava ted in EBV -infected 
patients.  
 
Introduction  
Introduction section is supported by the relevant references. However, there are several relevant 
publications on hepatitis caused by EBV infection, which the authors may consider to add as 
references. With rega rd to the liver infection caused by EBV, Vine et al. have described the 
features and natural history of EBV hepatitis (Vine et al. Characteristics of Epstein -Barr virus 
hepatitis among patients with jaundice or acute hepatitis. Aliment Pharmacol Ther. 2012 ). 
Also, Ulug et al. have reported a case of acute hepatitis associated with acute EBV infection 
Ulug et al. Acute hepatitis: a rare complication of Epstein -Barr virus (EBV) infection. J Infect 
Dev Ctries. 2010). Also, Gupta et al. have described two cases  of acute hepatitis after EBV 
infection (Gupta et al. Epstein -Barr virus associated acute hepatitis with cross -reacting antibodies 
to other herpes viruses in immunocompetent patients: report of two cases. J Med Virol 2013).  
 
 
Methods  
The authors used approp riate statistical methods.  
As to qPCR analysis, the authors should include primer sequences either in the text or as a 
separate table.  
 
Results and Discussion  
The Results are clearly presented. It would be valuable to see whether there were also 
histologic al signs of more severe liver damage in EBV -infected patients, if the authors would 
have access to the liver biopsies. Also, have the authors tried to determine the type of EBV 
infection (lytic or latent 0 -IV) and potential correlation with the degree of l iver damage in the 
analyzed patients with cirrhosis?  
Also, in the Discussion section it might be important to mention that although EBV has not been 
clearly shown in hepatocytes, increased levels of EBV DNA encoding transcripts have been 
found in lymphocy tes infiltrating the liver and inducing inflammation and chronic hepatitis 
(Petrova et al. Chronic Epstein -Barr virus -related hepatitis in immunocompetent patients. World 
J Gastroenterol. 2006).  
With regard to data presentation, the authors may consider to  complement the data presentation 
in tables with a figure (figures) showing survival curves for the Child -Pugh score (and for other 
risk factors).  
Because EBV has not been clearly demon -strated in human liver cells, although one study 
didshow evidence of  EBV replication in the hepatocytes  of mice . Increased levels of DNA 
encoding viral anti -gens and EBV encoding region transcripts have been  found in lymphocytes 
inﬁltrating the liver, which  might cause inﬂammatory damage to the liver and  chronic diseas  
 
Ethical permit  
With regard to the ethical permit for the study, it is recommended to include the number and the 
year of the ethical approval.  
 
Editing corrections and suggestions  
Page 11, line 253  
Instead of "The ages of the EBV -infected patients were old er than the non -infected patients", it is 
better to write just: "The EBV -infected patients were older than the non -infected patients".  
Page 12, line 274  
Instead of "180 -day mortality rate. which is in agreement", it should be: "180 -day mortality rate, 
which is in agreement" (coma instead of dot).  
 
Overall conclusion  
In summary, the described research is performed according to the relevant research and ethical 
standards. The results of the study would be interesting for both gastroenterologists and 
virolog ists. The paper can be published in a relevant gastroenterology or clinical virology journal 
with a moderate impact factor.  
 
REQUESTED REVISIONS:  
See comments above  
 
ADDITIONAL REQUESTS/SUGGESTIONS:  
The authors may consider suggestions for the references  and several corrections described in the 
peer review.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
  
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
This reviewer has been recruited by a partner organization, Research Square. Reviewers with 
declared or apparent competing interests are not utilized for these reviews. This reviewer has 
agreed to publi cation of their comments online under a Creative Commons Attribution License 
attributed to Research Square and was paid a small honorarium for completing the review within 
a specified timeframe. Honoraria for reviews such as this are paid regardless of the  reviewer 
recommendation.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named rep ort 
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understa nd that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Epstein -Barr virus infection is associated  with a higher Child -Pugh score and may predict 
poor prognoses for patients with liver cirrhosis  
 
Version: 0 Date: 03 Oct 2018  
 
Reviewer: Reviewer 2  
 
Reviewer's report:  
 
PEER REVIEWER COMMENTS: To view the full report from the academic peer reviewer, 
please see the attached file.  
 
REVIEWER COMMENTS FROM REPORT: Title: Epstein -Barr virus infection is associated 
with a higher Child -Pugh score and may predict poor prognoses for patients with liver cirrhosis  
Brief summary of the results of the study presented in the manuscript  
The p resent study aimed to analyze EBV infection rates, the effects on liver function, mortality 
risk factors in patients with liver cirrhosis. The authors have shown that patients with liver 
cirrhosis had higher EBV infection rates and liver injury was aggrava ted in EBV -infected 
patients.  
 
Introduction  
Introduction section is supported by the relevant references. However, there are several relevant 
publications on hepatitis caused by EBV infection, which the authors may consider to add as 
references. With rega rd to the liver infection caused by EBV, Vine et al. have described the 
features and natural history of EBV hepatitis (Vine et al. Characteristics of Epstein -Barr virus 
hepatitis among patients with jaundice or acute hepatitis. Aliment Pharmacol Ther. 2012 ). 
Also, Ulug et al. have reported a case of acute hepatitis associated with acute EBV infection 
Ulug et al. Acute hepatitis: a rare complication of Epstein -Barr virus (EBV) infection. J Infect 
Dev Ctries. 2010). Also, Gupta et al. have described two cases  of acute hepatitis after EBV 
infection (Gupta et al. Epstein -Barr virus associated acute hepatitis with cross -reacting antibodies 
to other herpes viruses in immunocompetent patients: report of two cases. J Med Virol 2013).  
 
 
Methods  
The authors used approp riate statistical methods.  
As to qPCR analysis, the authors should include primer sequences either in the text or as a 
separate table.  
 
Results and Discussion  
The Results are clearly presented. It would be valuable to see whether there were also 
histologic al signs of more severe liver damage in EBV -infected patients, if the authors would 
have access to the liver biopsies. Also, have the authors tried to determine the type of EBV 
infection (lytic or latent 0 -IV) and potential correlation with the degree of l iver damage in the 
analyzed patients with cirrhosis?  
Also, in the Discussion section it might be important to mention that although EBV has not been 
clearly shown in hepatocytes, increased levels of EBV DNA encoding transcripts have been 
found in lymphocy tes infiltrating the liver and inducing inflammation and chronic hepatitis 
(Petrova et al. Chronic Epstein -Barr virus -related hepatitis in immunocompetent patients. World 
J Gastroenterol. 2006).  
With regard to data presentation, the authors may consider to  complement the data presentation 
in tables with a figure (figures) showing survival curves for the Child -Pugh score (and for other 
risk factors).  
Because EBV has not been clearly demon -strated in human liver cells, although one study 
didshow evidence of  EBV replication in the hepatocytes  of mice . Increased levels of DNA 
encoding viral anti -gens and EBV encoding region transcripts have been  found in lymphocytes 
inﬁltrating the liver, which  might cause inﬂammatory damage to the liver and  chronic diseas  
 
Ethical permit  
With regard to the ethical permit for the study, it is recommended to include the number and the 
year of the ethical approval.  
 
Editing corrections and suggestions  
Page 11, line 253  
Instead of "The ages of the EBV -infected patients were old er than the non -infected patients", it is 
better to write just: "The EBV -infected patients were older than the non -infected patients".  
Page 12, line 274  
Instead of "180 -day mortality rate. which is in agreement", it should be: "180 -day mortality rate, 
which is in agreement" (coma instead of dot).  
 
Overall conclusion  
In summary, the described research is performed according to the relevant research and ethical 
standards. The results of the study would be interesting for both gastroenterologists and 
virolog ists. The paper can be published in a relevant gastroenterology or clinical virology journal 
with a moderate impact factor.  
 
REQUESTED REVISIONS:  
See comments above  
 
ADDITIONAL REQUESTS/SUGGESTIONS:  
The authors may consider suggestions for the references  and several corrections described in the 
peer review.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
  
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
This reviewer has been recruited by a partner organization, Research Square. Reviewers with 
declared or apparent competing interests are not utilized for these reviews. This reviewer has 
agreed to publi cation of their comments online under a Creative Commons Attribution License 
attributed to Research Square and was paid a small honorarium for completing the review within 
a specified timeframe. Honoraria for reviews such as this are paid regardless of the  reviewer 
recommendation.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named rep ort 
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understa nd that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Epstein -Barr virus infection is associated  with a higher Child -Pugh score and may predict 
poor prognoses for patients with liver cirrhosis  
 
Version: 0 Date: 03 Oct 2018  
 
Reviewer: Reviewer 2  
 
Reviewer's report:  
 
PEER REVIEWER COMMENTS: To view the full report from the academic peer reviewer, 
please see the attached file.  
 
REVIEWER COMMENTS FROM REPORT: Title: Epstein -Barr virus infection is associated 
with a higher Child -Pugh score and may predict poor prognoses for patients with liver cirrhosis  
Brief summary of the results of the study presented in the manuscript  
The p resent study aimed to analyze EBV infection rates, the effects on liver function, mortality 
risk factors in patients with liver cirrhosis. The authors have shown that patients with liver 
cirrhosis had higher EBV infection rates and liver injury was aggrava ted in EBV -infected 
patients.  
 
Introduction  
Introduction section is supported by the relevant references. However, there are several relevant 
publications on hepatitis caused by EBV infection, which the authors may consider to add as 
references. With rega rd to the liver infection caused by EBV, Vine et al. have described the 
features and natural history of EBV hepatitis (Vine et al. Characteristics of Epstein -Barr virus 
hepatitis among patients with jaundice or acute hepatitis. Aliment Pharmacol Ther. 2012 ). 
Also, Ulug et al. have reported a case of acute hepatitis associated with acute EBV infection 
Ulug et al. Acute hepatitis: a rare complication of Epstein -Barr virus (EBV) infection. J Infect 
Dev Ctries. 2010). Also, Gupta et al. have described two cases  of acute hepatitis after EBV 
infection (Gupta et al. Epstein -Barr virus associated acute hepatitis with cross -reacting antibodies 
to other herpes viruses in immunocompetent patients: report of two cases. J Med Virol 2013).  
 
 
Methods  
The authors used approp riate statistical methods.  
As to qPCR analysis, the authors should include primer sequences either in the text or as a 
separate table.  
 
Results and Discussion  
The Results are clearly presented. It would be valuable to see whether there were also 
histologic al signs of more severe liver damage in EBV -infected patients, if the authors would 
have access to the liver biopsies. Also, have the authors tried to determine the type of EBV 
infection (lytic or latent 0 -IV) and potential correlation with the degree of l iver damage in the 
analyzed patients with cirrhosis?  
Also, in the Discussion section it might be important to mention that although EBV has not been 
clearly shown in hepatocytes, increased levels of EBV DNA encoding transcripts have been 
found in lymphocy tes infiltrating the liver and inducing inflammation and chronic hepatitis 
(Petrova et al. Chronic Epstein -Barr virus -related hepatitis in immunocompetent patients. World 
J Gastroenterol. 2006).  
With regard to data presentation, the authors may consider to  complement the data presentation 
in tables with a figure (figures) showing survival curves for the Child -Pugh score (and for other 
risk factors).  
Because EBV has not been clearly demon -strated in human liver cells, although one study 
didshow evidence of  EBV replication in the hepatocytes  of mice . Increased levels of DNA 
encoding viral anti -gens and EBV encoding region transcripts have been  found in lymphocytes 
inﬁltrating the liver, which  might cause inﬂammatory damage to the liver and  chronic diseas  
 
Ethical permit  
With regard to the ethical permit for the study, it is recommended to include the number and the 
year of the ethical approval.  
 
Editing corrections and suggestions  
Page 11, line 253  
Instead of "The ages of the EBV -infected patients were old er than the non -infected patients", it is 
better to write just: "The EBV -infected patients were older than the non -infected patients".  
Page 12, line 274  
Instead of "180 -day mortality rate. which is in agreement", it should be: "180 -day mortality rate, 
which is in agreement" (coma instead of dot).  
 
Overall conclusion  
In summary, the described research is performed according to the relevant research and ethical 
standards. The results of the study would be interesting for both gastroenterologists and 
virolog ists. The paper can be published in a relevant gastroenterology or clinical virology journal 
with a moderate impact factor.  
 
REQUESTED REVISIONS:  
See comments above  
 
ADDITIONAL REQUESTS/SUGGESTIONS:  
The authors may consider suggestions for the references  and several corrections described in the 
peer review.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
  
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publi cation of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
This reviewer has been recruited by a partner organization, Research Square. Reviewers with 
declared or apparent competing interests are not utilized for these reviews. This reviewer has 
agreed to publi cation of their comments online under a Creative Commons Attribution License 
attributed to Research Square and was paid a small honorarium for completing the review within 
a specified timeframe. Honoraria for reviews such as this are paid regardless of the  reviewer 
recommendation.  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named rep ort 
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understa nd that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant