Reviewer ’s report  
 
Title: Contributions  of HLA haplotypes, IL8 level and Toxoplasma gondii infection in defining 
new phenotypes in celiac disease  
 
Version: 1 Date: 16 Apr 2018  
 
Reviewer: Ross McManus  
 
Please include al l comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please overwrite this text when adding your comments to the authors.  
This is an interesting observational study of the co -incidence of Toxoplama infection and coeliac 
disease (CD). Of note the authors find that the highest levels of infection in C D patients are 
amongst those exhibiting Marsh III histopathology. They put forward the theory that infections 
such as with Toxoplasma may be important contributors to the severity of symptoms and or 
mucosal damage in CD.   
The main limitation of the study  is that it is small. Given the number of variables examined, the 
question arises as to whether correction for multiple testing should be applied in which case the 
main finding of correlation (p=0.02) between Toxoplasma infection and severity of mucosal 
damage would no longer be statistically significant. In this regard, I note that they find a 
statistically significant difference (p=0.02) in the rate of Toxoplasma positivity in controls (53%) 
vs cases (39%); however in a previous study of CD they found 59%  positivity in cases (it was 
admittedly a very small sample and perhaps different given they were expectant mothers).  
 
Specific comments.  
Is the reason that there is no correlation of IL8 with mucosal damage - lack of power? It is 
somewhat strange that the re is no association of HLA dose, IL8 and Toxoplasma with damage 
since HLA is associated with severity of response, IL8 may be (e.g. Tye -Din et al 
Gastroenterology April 2017 152(5) Suppl 1, pp. S114) and you show a positive association of T. 
gondii here? (The p value seems to be misstated last line of results section p11 line 17). Please 
comment  
It is confusing that you refer to anti T. gondii antibodies as anti -TG - unwary readers might 
misinterpret this as anti Tissue Transglutaminase - e.g abstract and  in discussion under blood 
sample collection P7 line11/12 etc  
Please mention correlations carried out in Methods/Statistical analysis  
Some of the data in the first part of the Results would be clearer if tabulated  
Figure 3 appears unnecessary  
The last 2 sentences of the introduction Paragraph 1 are confusing as was some of the discussion, 
which could be streamlined.  
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 concl usions 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 re view 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  
 
Declarat ion 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 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 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 you r reply is yes to any, please give details below.  
 
I declare 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 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 understand 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: Contributions  of HLA haplotypes, IL8 level and Toxoplasma gondii infection in defining 
new phenotypes in celiac disease  
 
Version: 1 Date: 16 Apr 2018  
 
Reviewer: Ross McManus  
 
Please include al l comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please overwrite this text when adding your comments to the authors.  
This is an interesting observational study of the co -incidence of Toxoplama infection and coeliac 
disease (CD). Of note the authors find that the highest levels of infection in C D patients are 
amongst those exhibiting Marsh III histopathology. They put forward the theory that infections 
such as with Toxoplasma may be important contributors to the severity of symptoms and or 
mucosal damage in CD.   
The main limitation of the study  is that it is small. Given the number of variables examined, the 
question arises as to whether correction for multiple testing should be applied in which case the 
main finding of correlation (p=0.02) between Toxoplasma infection and severity of mucosal 
damage would no longer be statistically significant. In this regard, I note that they find a 
statistically significant difference (p=0.02) in the rate of Toxoplasma positivity in controls (53%) 
vs cases (39%); however in a previous study of CD they found 59%  positivity in cases (it was 
admittedly a very small sample and perhaps different given they were expectant mothers).  
 
Specific comments.  
Is the reason that there is no correlation of IL8 with mucosal damage - lack of power? It is 
somewhat strange that the re is no association of HLA dose, IL8 and Toxoplasma with damage 
since HLA is associated with severity of response, IL8 may be (e.g. Tye -Din et al 
Gastroenterology April 2017 152(5) Suppl 1, pp. S114) and you show a positive association of T. 
gondii here? (The p value seems to be misstated last line of results section p11 line 17). Please 
comment  
It is confusing that you refer to anti T. gondii antibodies as anti -TG - unwary readers might 
misinterpret this as anti Tissue Transglutaminase - e.g abstract and  in discussion under blood 
sample collection P7 line11/12 etc  
Please mention correlations carried out in Methods/Statistical analysis  
Some of the data in the first part of the Results would be clearer if tabulated  
Figure 3 appears unnecessary  
The last 2 sentences of the introduction Paragraph 1 are confusing as was some of the discussion, 
which could be streamlined.  
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 concl usions 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 re view 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  
 
Declarat ion 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 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 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 you r reply is yes to any, please give details below.  
 
I declare 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 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 understand 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: Contributions  of HLA haplotypes, IL8 level and Toxoplasma gondii infection in defining 
new phenotypes in celiac disease  
 
Version: 1 Date: 16 Apr 2018  
 
Reviewer: Ross McManus  
 
Please include al l comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a text format.  
Please overwrite this text when adding your comments to the authors.  
This is an interesting observational study of the co -incidence of Toxoplama infection and coeliac 
disease (CD). Of note the authors find that the highest levels of infection in C D patients are 
amongst those exhibiting Marsh III histopathology. They put forward the theory that infections 
such as with Toxoplasma may be important contributors to the severity of symptoms and or 
mucosal damage in CD.   
The main limitation of the study  is that it is small. Given the number of variables examined, the 
question arises as to whether correction for multiple testing should be applied in which case the 
main finding of correlation (p=0.02) between Toxoplasma infection and severity of mucosal 
damage would no longer be statistically significant. In this regard, I note that they find a 
statistically significant difference (p=0.02) in the rate of Toxoplasma positivity in controls (53%) 
vs cases (39%); however in a previous study of CD they found 59%  positivity in cases (it was 
admittedly a very small sample and perhaps different given they were expectant mothers).  
 
Specific comments.  
Is the reason that there is no correlation of IL8 with mucosal damage - lack of power? It is 
somewhat strange that the re is no association of HLA dose, IL8 and Toxoplasma with damage 
since HLA is associated with severity of response, IL8 may be (e.g. Tye -Din et al 
Gastroenterology April 2017 152(5) Suppl 1, pp. S114) and you show a positive association of T. 
gondii here? (The p value seems to be misstated last line of results section p11 line 17). Please 
comment  
It is confusing that you refer to anti T. gondii antibodies as anti -TG - unwary readers might 
misinterpret this as anti Tissue Transglutaminase - e.g abstract and  in discussion under blood 
sample collection P7 line11/12 etc  
Please mention correlations carried out in Methods/Statistical analysis  
Some of the data in the first part of the Results would be clearer if tabulated  
Figure 3 appears unnecessary  
The last 2 sentences of the introduction Paragraph 1 are confusing as was some of the discussion, 
which could be streamlined.  
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 concl usions 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 re view 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  
 
Declarat ion 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 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 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 you r reply is yes to any, please give details below.  
 
I declare 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 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 understand 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