Reviewer ’s report  
Title: Villous atrophy in the terminal ileum is a specific end oscopic finding correlated with 
histological evidence and poor prognosis in acute graft -versus -host disease after 
allohematopoietic stem cell transplantation  
 
Version: 0 Date: 21 Jan 2018  
 
Reviewer: John Louis -Auguste  
 
Reviewer's report:  
GENERAL COMMENTS:  
This clinically relevant retrospective study describes a potentially useful endoscopic sign of 
severe intestinal acute GvHD, which may permit earlier diagnosis and therapy. In multivariate 
analysis endoscopic villous atrophy (VA) remained a predictor of ac ute GVHD.  
The rationale for the study and methods (with the following caveats) are appropriate. However, 
the results as presented require significant clarification / modifications before they can fully 
support the stated conclusions.  
 
MAJOR:  
 
Introduction : 
Please state why existing endoscopic scoring systems are not suitable / require improvement.  
Other endoscopic scoring systems e.g. Freiburg (as referenced in Kreisel et al / ref. 7) do not 
incorporate villous atrophy. The central argument that VA is a u seful endoscopic sign would be 
much stronger if its performance could be compared against Freiburg, or even incorporated with 
it. This should be possible as endoscopic photos for each case are available allowing both scores 
to be calculated. If this is not  possible I think this should at least be discussed as an avenue for 
future work.  
Likewise, as the authors clearly have high quality outcome / follow -up data, could they also 
incorporate Freiburg score (for example) into outcome, which as far as I am aware  has not been 
studied?  
Methods:  
Please clarify how VA scoring was done (independence; blinding). Please include a measure of 
inter-observer reproducibility.  
Please describe how the VA scoring system was derived.  
Figure 3 a and b: Are further representativ e images available? Both a and b appear to show 
complete mucosal denudation with 'islands' of unaffected villi, rather than atrophy (the visible 
villi may be somewhat blunted but the images provided do not allow the reader to determine this 
confidently; fu rthermore I cannot see any differences between the villi in 'a' and 'c'). Please could 
this be explained and the descriptions modified if required?  
Furthermore, the essential differences between a and b are not clear - arrows / annotations would 
be helpful .  
 
Results:  
Please indicate which statistical tests were used for each result provided.  
I am unfamiliar with the Jonckheere -Terpstra and Cochran -Armitage tests.  
In the methods, the authors state that biopsies were taken from all patients and from each of 6 
segments - i.e. there should be approx. 50 biopsies per segment, and approx. 300 biopsies in 
total. However only 100 biopsies were taken. This needs to be explained / discussed.  
Only 27/51 had TI biopsies taken. Presumably there are therefore a number of  patients with 
colonic GvHD who did not have TI biopsies taken. Please could this be discussed and numbers 
given, as it may significantly weaken the central argument.  
What proportion of TI were endoscopically normal?  
 
MINOR:  
Please clarify which author(s) reviewed the endoscopic images (not just which authors scored 
villous atrophy).  
I think figure 1 (study flowchart) should be included in results and not methods.  
I would suggest using normal / mild / severe classification in the methods and in figure 3, as 
otherwise it is unclear what from the descriptions what S/N/M refer to  
p8 line 16: unclear meaning  
p15 line 4: 'more likely to require treatment...although there was no significant difference'. A P 
value of 0.02 is then give n. Does the P value refer to requirement for 2nd line treatment for 
steroid refractory disease? If so then there does appear to be a significant difference. If there is 
no significant difference then it cannot be stated that a certain group was more likely  to require 
treatment. Please clarify.  
Table 3 - numbers exceed number of patients, presumably because more than one abnormality is 
present. This should be explained.  
Table 5: please provide P values for all comparisons rather than 'NS'  
Figure 2: are these  images from colon or TI?  
I cannot find reference 8 (Mashiba et al. 2003) on Pubmed. 3 
 
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 contr ols 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 recomme nd an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additional statistical review  
Quality of written English  
Please indicate t he 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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation that may in an y way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fees, funding, or salary from an organiza tion 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 com peting 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.  
 
I declare that I have no competing interests  
 
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 nam ed report 
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 un derstand 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: Villous atrophy in the terminal ileum is a specific end oscopic finding correlated with 
histological evidence and poor prognosis in acute graft -versus -host disease after 
allohematopoietic stem cell transplantation  
 
Version: 0 Date: 21 Jan 2018  
 
Reviewer: John Louis -Auguste  
 
Reviewer's report:  
GENERAL COMMENTS:  
This clinically relevant retrospective study describes a potentially useful endoscopic sign of 
severe intestinal acute GvHD, which may permit earlier diagnosis and therapy. In multivariate 
analysis endoscopic villous atrophy (VA) remained a predictor of ac ute GVHD.  
The rationale for the study and methods (with the following caveats) are appropriate. However, 
the results as presented require significant clarification / modifications before they can fully 
support the stated conclusions.  
 
MAJOR:  
 
Introduction : 
Please state why existing endoscopic scoring systems are not suitable / require improvement.  
Other endoscopic scoring systems e.g. Freiburg (as referenced in Kreisel et al / ref. 7) do not 
incorporate villous atrophy. The central argument that VA is a u seful endoscopic sign would be 
much stronger if its performance could be compared against Freiburg, or even incorporated with 
it. This should be possible as endoscopic photos for each case are available allowing both scores 
to be calculated. If this is not  possible I think this should at least be discussed as an avenue for 
future work.  
Likewise, as the authors clearly have high quality outcome / follow -up data, could they also 
incorporate Freiburg score (for example) into outcome, which as far as I am aware  has not been 
studied?  
Methods:  
Please clarify how VA scoring was done (independence; blinding). Please include a measure of 
inter-observer reproducibility.  
Please describe how the VA scoring system was derived.  
Figure 3 a and b: Are further representativ e images available? Both a and b appear to show 
complete mucosal denudation with 'islands' of unaffected villi, rather than atrophy (the visible 
villi may be somewhat blunted but the images provided do not allow the reader to determine this 
confidently; fu rthermore I cannot see any differences between the villi in 'a' and 'c'). Please could 
this be explained and the descriptions modified if required?  
Furthermore, the essential differences between a and b are not clear - arrows / annotations would 
be helpful .  
 
Results:  
Please indicate which statistical tests were used for each result provided.  
I am unfamiliar with the Jonckheere -Terpstra and Cochran -Armitage tests.  
In the methods, the authors state that biopsies were taken from all patients and from each of 6 
segments - i.e. there should be approx. 50 biopsies per segment, and approx. 300 biopsies in 
total. However only 100 biopsies were taken. This needs to be explained / discussed.  
Only 27/51 had TI biopsies taken. Presumably there are therefore a number of  patients with 
colonic GvHD who did not have TI biopsies taken. Please could this be discussed and numbers 
given, as it may significantly weaken the central argument.  
What proportion of TI were endoscopically normal?  
 
MINOR:  
Please clarify which author(s) reviewed the endoscopic images (not just which authors scored 
villous atrophy).  
I think figure 1 (study flowchart) should be included in results and not methods.  
I would suggest using normal / mild / severe classification in the methods and in figure 3, as 
otherwise it is unclear what from the descriptions what S/N/M refer to  
p8 line 16: unclear meaning  
p15 line 4: 'more likely to require treatment...although there was no significant difference'. A P 
value of 0.02 is then give n. Does the P value refer to requirement for 2nd line treatment for 
steroid refractory disease? If so then there does appear to be a significant difference. If there is 
no significant difference then it cannot be stated that a certain group was more likely  to require 
treatment. Please clarify.  
Table 3 - numbers exceed number of patients, presumably because more than one abnormality is 
present. This should be explained.  
Table 5: please provide P values for all comparisons rather than 'NS'  
Figure 2: are these  images from colon or TI?  
I cannot find reference 8 (Mashiba et al. 2003) on Pubmed. 3 
 
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 contr ols 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 recomme nd an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additional statistical review  
Quality of written English  
Please indicate t he 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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation that may in an y way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fees, funding, or salary from an organiza tion 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 com peting 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.  
 
I declare that I have no competing interests  
 
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 nam ed report 
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 un derstand 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: Villous atrophy in the terminal ileum is a specific end oscopic finding correlated with 
histological evidence and poor prognosis in acute graft -versus -host disease after 
allohematopoietic stem cell transplantation  
 
Version: 0 Date: 21 Jan 2018  
 
Reviewer: John Louis -Auguste  
 
Reviewer's report:  
GENERAL COMMENTS:  
This clinically relevant retrospective study describes a potentially useful endoscopic sign of 
severe intestinal acute GvHD, which may permit earlier diagnosis and therapy. In multivariate 
analysis endoscopic villous atrophy (VA) remained a predictor of ac ute GVHD.  
The rationale for the study and methods (with the following caveats) are appropriate. However, 
the results as presented require significant clarification / modifications before they can fully 
support the stated conclusions.  
 
MAJOR:  
 
Introduction : 
Please state why existing endoscopic scoring systems are not suitable / require improvement.  
Other endoscopic scoring systems e.g. Freiburg (as referenced in Kreisel et al / ref. 7) do not 
incorporate villous atrophy. The central argument that VA is a u seful endoscopic sign would be 
much stronger if its performance could be compared against Freiburg, or even incorporated with 
it. This should be possible as endoscopic photos for each case are available allowing both scores 
to be calculated. If this is not  possible I think this should at least be discussed as an avenue for 
future work.  
Likewise, as the authors clearly have high quality outcome / follow -up data, could they also 
incorporate Freiburg score (for example) into outcome, which as far as I am aware  has not been 
studied?  
Methods:  
Please clarify how VA scoring was done (independence; blinding). Please include a measure of 
inter-observer reproducibility.  
Please describe how the VA scoring system was derived.  
Figure 3 a and b: Are further representativ e images available? Both a and b appear to show 
complete mucosal denudation with 'islands' of unaffected villi, rather than atrophy (the visible 
villi may be somewhat blunted but the images provided do not allow the reader to determine this 
confidently; fu rthermore I cannot see any differences between the villi in 'a' and 'c'). Please could 
this be explained and the descriptions modified if required?  
Furthermore, the essential differences between a and b are not clear - arrows / annotations would 
be helpful .  
 
Results:  
Please indicate which statistical tests were used for each result provided.  
I am unfamiliar with the Jonckheere -Terpstra and Cochran -Armitage tests.  
In the methods, the authors state that biopsies were taken from all patients and from each of 6 
segments - i.e. there should be approx. 50 biopsies per segment, and approx. 300 biopsies in 
total. However only 100 biopsies were taken. This needs to be explained / discussed.  
Only 27/51 had TI biopsies taken. Presumably there are therefore a number of  patients with 
colonic GvHD who did not have TI biopsies taken. Please could this be discussed and numbers 
given, as it may significantly weaken the central argument.  
What proportion of TI were endoscopically normal?  
 
MINOR:  
Please clarify which author(s) reviewed the endoscopic images (not just which authors scored 
villous atrophy).  
I think figure 1 (study flowchart) should be included in results and not methods.  
I would suggest using normal / mild / severe classification in the methods and in figure 3, as 
otherwise it is unclear what from the descriptions what S/N/M refer to  
p8 line 16: unclear meaning  
p15 line 4: 'more likely to require treatment...although there was no significant difference'. A P 
value of 0.02 is then give n. Does the P value refer to requirement for 2nd line treatment for 
steroid refractory disease? If so then there does appear to be a significant difference. If there is 
no significant difference then it cannot be stated that a certain group was more likely  to require 
treatment. Please clarify.  
Table 3 - numbers exceed number of patients, presumably because more than one abnormality is 
present. This should be explained.  
Table 5: please provide P values for all comparisons rather than 'NS'  
Figure 2: are these  images from colon or TI?  
I cannot find reference 8 (Mashiba et al. 2003) on Pubmed. 3 
 
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 contr ols 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 recomme nd an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additional statistical review  
Quality of written English  
Please indicate t he 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, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation that may in an y way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fees, funding, or salary from an organiza tion 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 com peting 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.  
 
I declare that I have no competing interests  
 
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 nam ed report 
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 un derstand 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