Reviewer ’s report  
 
Title: Exclusive enteral nutrition induction with concomitant early thiopurine use is effective in 
maintaining steroid free remission in a Southeast Asian cohort of children with Crohn's Disease  
 
Version: 0 Date: 06 Jan 2018  
 
Reviewer: Andrew Day  
 
Reviewer's report:  
 
This manuscript describes a retrospective assessment of the outcomes of EEN in a cohort of 
children diagnosed with CD in Singapore  
 
SPECIFIC COMMENTS  
1. The authors should revise the way they describe children with Crohn disease. The APA 
guidelines should be considered here (children with CD should be used instead of CD 
children or other patterns). The TITLE might be reworded accordi ngly 
 
2. The methods section of the ABSTRACT refers to the number of children: this is a result and 
should be moved  
 
3. Early AZA usage is not defined here  
 
4. The description of the PCDAI scores in the results of the ABSTRACT is unusual and should 
revised  
 
5. The results section of the ABSTRACT mentions multiple data points and then only one p 
value: did all these relationships have the same p value?  
 
6. With reference to the last sentence of the ABSTRACT, one would removing "our" and using 
an impersonal phrase  instead (same comment for later in the manuscript)  
 
7. On page 5 (METHODS AND INTRODUCTION) the word "is" should be "was"  
 
8. The METHODS notes that all patients were also treated with 5 -ASA. One assumes that this 
was directly after diagnosis? What was the indication to commence 5 -ASA? did all children 
continue 5 -ASA through the whole period of the study? this is relevant as it may have 
modified the response to EEN and also contributed to the longer term disease course  
 
9. It is not clear if all patients diag nosed with CD during the period of observation were treated 
with EEN? Or was this just a subset of the total group diagnosed?  
 
10. The details about Modulen should also include the city/country of the company (as per 
standard practice)  
 
11. Although the pati ents with stricturing disease did not enter remission with EEN, did they in 
fact have improved nutrition or inflammatory status regardless? The patients with sticturing 
and penetrating disease evidently did respond to EEN?  
 
12. There have been various repor ts of EEN for penetrating CD and for perianal CD: did the 
patients with perianal disease all respond (the same of those without)?  
 
13. In the section "response to EEN induction" are the values mentioned for all 33 children? (or 
just those who entered remiss ion) 
 
14. The authors report a delta on height of around 2 cms: this is within an 8 week period. Is this 
correct?  
 
15. The second part of this section lists the changes in various inflammatory markers. This data 
would be better presented in Table form (with a summary sentence in the text of the 
manuscript referring to the impressive changes)  
 
16. In page 10, with regards the use of AZA, was the early introduction related to specific 
clinical indications (unstated) or purely due to clinician preference? How lon g after diagnosis 
was AZA commenced in the late group? The mean time after diagnosis (with range) would 
be helpful. Commencement after 8 -9 months may not have had much impact within the 12 
months of observation  
 
17. The maintenance of remission section refe rs to those in remission at 6 and 12 months. Do 
these numbers indicate those who had continuous remission from induction with EEN (with 
no relapses in the intervening time at all), or were these data just the number of children who 
happened to be in remiss ion (regardless of how many relapses in the interim)  
 
18. In line 48 in this section, the authors refer the duration of remission in the early and late 
groups and mention a p value. This sentence should include the mean/SD of each duration for 
direct comparison. Was the difference actually clinically relevant ?? 
 
19. Did any of the children receive maintenance enteral nutrition after the completion of EEN?  
 
20. On page 11 the authors refer to the population of the current study being predominantly SEA 
ethnicity. Earlier it was stated that ALL the children were SE A 
 
21. The discussion could be shortened a little, with enhanced flow  
 
22. There are numerous errors in the references, with some being unrecognizable  
 
23. The titles and legends of all TABLES could be improved. These are currently dependent on 
the text of th e manuscript - revision could make them more independent  
 
24. TABLE 3 includes all 33 children. Should the 3 children who did not respond to EEN be 
considered here? One would favour their exclusion from this analysis  
 
25. The figure used the word "enrolled" which implies that they were recruited prospectively  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work inclu de the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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.  
 
I am able to assess the statistics  
 
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 inter ests, 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 publication 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 currently applying for any patents relating to the c ontent 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.  
 
'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 named report  
including any a ttachments 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 understand that any comment s 
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: Exclusive enteral nutrition induction with concomitant early thiopurine use is effective in 
maintaining steroid free remission in a Southeast Asian cohort of children with Crohn's Disease  
 
Version: 0 Date: 06 Jan 2018  
 
Reviewer: Andrew Day  
 
Reviewer's report:  
 
This manuscript describes a retrospective assessment of the outcomes of EEN in a cohort of 
children diagnosed with CD in Singapore  
 
SPECIFIC COMMENTS  
1. The authors should revise the way they describe children with Crohn disease. The APA 
guidelines should be considered here (children with CD should be used instead of CD 
children or other patterns). The TITLE might be reworded accordi ngly 
 
2. The methods section of the ABSTRACT refers to the number of children: this is a result and 
should be moved  
 
3. Early AZA usage is not defined here  
 
4. The description of the PCDAI scores in the results of the ABSTRACT is unusual and should 
revised  
 
5. The results section of the ABSTRACT mentions multiple data points and then only one p 
value: did all these relationships have the same p value?  
 
6. With reference to the last sentence of the ABSTRACT, one would removing "our" and using 
an impersonal phrase  instead (same comment for later in the manuscript)  
 
7. On page 5 (METHODS AND INTRODUCTION) the word "is" should be "was"  
 
8. The METHODS notes that all patients were also treated with 5 -ASA. One assumes that this 
was directly after diagnosis? What was the indication to commence 5 -ASA? did all children 
continue 5 -ASA through the whole period of the study? this is relevant as it may have 
modified the response to EEN and also contributed to the longer term disease course  
 
9. It is not clear if all patients diag nosed with CD during the period of observation were treated 
with EEN? Or was this just a subset of the total group diagnosed?  
 
10. The details about Modulen should also include the city/country of the company (as per 
standard practice)  
 
11. Although the pati ents with stricturing disease did not enter remission with EEN, did they in 
fact have improved nutrition or inflammatory status regardless? The patients with sticturing 
and penetrating disease evidently did respond to EEN?  
 
12. There have been various repor ts of EEN for penetrating CD and for perianal CD: did the 
patients with perianal disease all respond (the same of those without)?  
 
13. In the section "response to EEN induction" are the values mentioned for all 33 children? (or 
just those who entered remiss ion) 
 
14. The authors report a delta on height of around 2 cms: this is within an 8 week period. Is this 
correct?  
 
15. The second part of this section lists the changes in various inflammatory markers. This data 
would be better presented in Table form (with a summary sentence in the text of the 
manuscript referring to the impressive changes)  
 
16. In page 10, with regards the use of AZA, was the early introduction related to specific 
clinical indications (unstated) or purely due to clinician preference? How lon g after diagnosis 
was AZA commenced in the late group? The mean time after diagnosis (with range) would 
be helpful. Commencement after 8 -9 months may not have had much impact within the 12 
months of observation  
 
17. The maintenance of remission section refe rs to those in remission at 6 and 12 months. Do 
these numbers indicate those who had continuous remission from induction with EEN (with 
no relapses in the intervening time at all), or were these data just the number of children who 
happened to be in remiss ion (regardless of how many relapses in the interim)  
 
18. In line 48 in this section, the authors refer the duration of remission in the early and late 
groups and mention a p value. This sentence should include the mean/SD of each duration for 
direct comparison. Was the difference actually clinically relevant ?? 
 
19. Did any of the children receive maintenance enteral nutrition after the completion of EEN?  
 
20. On page 11 the authors refer to the population of the current study being predominantly SEA 
ethnicity. Earlier it was stated that ALL the children were SE A 
 
21. The discussion could be shortened a little, with enhanced flow  
 
22. There are numerous errors in the references, with some being unrecognizable  
 
23. The titles and legends of all TABLES could be improved. These are currently dependent on 
the text of th e manuscript - revision could make them more independent  
 
24. TABLE 3 includes all 33 children. Should the 3 children who did not respond to EEN be 
considered here? One would favour their exclusion from this analysis  
 
25. The figure used the word "enrolled" which implies that they were recruited prospectively  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work inclu de the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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.  
 
I am able to assess the statistics  
 
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 inter ests, 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 publication 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 currently applying for any patents relating to the c ontent 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.  
 
'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 named report  
including any a ttachments 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 understand that any comment s 
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: Exclusive enteral nutrition induction with concomitant early thiopurine use is effective in 
maintaining steroid free remission in a Southeast Asian cohort of children with Crohn's Disease  
 
Version: 0 Date: 06 Jan 2018  
 
Reviewer: Andrew Day  
 
Reviewer's report:  
 
This manuscript describes a retrospective assessment of the outcomes of EEN in a cohort of 
children diagnosed with CD in Singapore  
 
SPECIFIC COMMENTS  
1. The authors should revise the way they describe children with Crohn disease. The APA 
guidelines should be considered here (children with CD should be used instead of CD 
children or other patterns). The TITLE might be reworded accordi ngly 
 
2. The methods section of the ABSTRACT refers to the number of children: this is a result and 
should be moved  
 
3. Early AZA usage is not defined here  
 
4. The description of the PCDAI scores in the results of the ABSTRACT is unusual and should 
revised  
 
5. The results section of the ABSTRACT mentions multiple data points and then only one p 
value: did all these relationships have the same p value?  
 
6. With reference to the last sentence of the ABSTRACT, one would removing "our" and using 
an impersonal phrase  instead (same comment for later in the manuscript)  
 
7. On page 5 (METHODS AND INTRODUCTION) the word "is" should be "was"  
 
8. The METHODS notes that all patients were also treated with 5 -ASA. One assumes that this 
was directly after diagnosis? What was the indication to commence 5 -ASA? did all children 
continue 5 -ASA through the whole period of the study? this is relevant as it may have 
modified the response to EEN and also contributed to the longer term disease course  
 
9. It is not clear if all patients diag nosed with CD during the period of observation were treated 
with EEN? Or was this just a subset of the total group diagnosed?  
 
10. The details about Modulen should also include the city/country of the company (as per 
standard practice)  
 
11. Although the pati ents with stricturing disease did not enter remission with EEN, did they in 
fact have improved nutrition or inflammatory status regardless? The patients with sticturing 
and penetrating disease evidently did respond to EEN?  
 
12. There have been various repor ts of EEN for penetrating CD and for perianal CD: did the 
patients with perianal disease all respond (the same of those without)?  
 
13. In the section "response to EEN induction" are the values mentioned for all 33 children? (or 
just those who entered remiss ion) 
 
14. The authors report a delta on height of around 2 cms: this is within an 8 week period. Is this 
correct?  
 
15. The second part of this section lists the changes in various inflammatory markers. This data 
would be better presented in Table form (with a summary sentence in the text of the 
manuscript referring to the impressive changes)  
 
16. In page 10, with regards the use of AZA, was the early introduction related to specific 
clinical indications (unstated) or purely due to clinician preference? How lon g after diagnosis 
was AZA commenced in the late group? The mean time after diagnosis (with range) would 
be helpful. Commencement after 8 -9 months may not have had much impact within the 12 
months of observation  
 
17. The maintenance of remission section refe rs to those in remission at 6 and 12 months. Do 
these numbers indicate those who had continuous remission from induction with EEN (with 
no relapses in the intervening time at all), or were these data just the number of children who 
happened to be in remiss ion (regardless of how many relapses in the interim)  
 
18. In line 48 in this section, the authors refer the duration of remission in the early and late 
groups and mention a p value. This sentence should include the mean/SD of each duration for 
direct comparison. Was the difference actually clinically relevant ?? 
 
19. Did any of the children receive maintenance enteral nutrition after the completion of EEN?  
 
20. On page 11 the authors refer to the population of the current study being predominantly SEA 
ethnicity. Earlier it was stated that ALL the children were SE A 
 
21. The discussion could be shortened a little, with enhanced flow  
 
22. There are numerous errors in the references, with some being unrecognizable  
 
23. The titles and legends of all TABLES could be improved. These are currently dependent on 
the text of th e manuscript - revision could make them more independent  
 
24. TABLE 3 includes all 33 children. Should the 3 children who did not respond to EEN be 
considered here? One would favour their exclusion from this analysis  
 
25. The figure used the word "enrolled" which implies that they were recruited prospectively  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work inclu de the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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.  
 
I am able to assess the statistics  
 
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 inter ests, 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 publication 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 currently applying for any patents relating to the c ontent 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.  
 
'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 named report  
including any a ttachments 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 understand that any comment s 
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