Reviewer’ s report
Title: IgA, albumin, eosinopenia as early warning indicators for cytomegalovirus infection in
patients with acute ulcerative colitis
Version: 0Date: 27 May 2020
Reviewer: Abhishek Agnihotri
Reviewer's report:
I applaud the authors for highlighting an important problem and often a diagnostic dilemma in
Ulcerative Colitis flares. The most important aspect of any such study is case definition anddiagnostic accuracy. There is some controversy on accurate diagnostic test for CMV colitis whichis more relevant to diagnose in UC patients. Low level peripheral blood PCR positivity may beseen in asymptomatic patients on immunosuppression, hence blood PCR testing may havesensitivity as low as 65% and specificity as low as 40% (Inflammatory Bowel Diseases, Volume22, Issue 12, Pg 2966-2976). Tissue immunohistochemistry along with relevant histology remainsthe gold standard of diagnosis with specificity of 92-100%. 1.The authors define CMV colitis aspositivity of pp65 antigens, CMV IgM antibodies and CMV qPCR. We now know that the antigenassay does not differentiate latent infection from active infection. Also PCR low level positivitymay be seen and most studies have suggested a cut-off of CMV viral load ranging between 4000to 10,000 IU/mL in post-transplant patients. Lastly CMV IgM utility in IBD is fairly low sinceprimary infection is exceedingly unlikely to cause CMV colitis even in immunosuppressed hosts,especially as seroprevalence is so high. Positive IgM may indicate recent infection rather thanacute infection. I would recommend clarifying how many patients were diagnosed based on eachof the above diagnostic test, what was the PCR cut off used for diagnosis and how many had
concurrent tissue diagnosis of CMV colitis, which would be the gold standard of CMV infection,
in absence of effect on any other organ. This at present is a major limitation of the study.2. In firstparagraph of discussion, authors describe difficulty of differentiating UC from CMV colitis andsuggest the results of resent study may aid in that. However, that would not be a valid comparisonas present study is not on CMV colitis specifically.3. The difficulty of a case-control study remainsdifferentiating correlation and causation. The authors have rightly found CMV group to havesignificantly higher use of high dose steroids, eosinopenia, elevated CRP. However, the morelikely explanation remains patients with more severe UC, which are more likely to be on high dosesteroids, which ultimately are the patients with higher seropositivity for CMV. Steroids lead toeosinopenia which is self explanatory. Thus in this study, I woulc argue, we are largely seeingeffects of high dose steroids in a more severe UC patient population instead of direct effects ofCMV infection.4. To further improve the study, I would propose, clarifying diagnostic criteriaused and further description of PCR cut off along with breakdown of patients satisfying differentdiagnostic criterias. It would also be of value to know the proportion of patients with CMV colitisbased on tissue IHC as it is this population that is of great interest and a challenge to differentiatefrom acute UC flare.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
YesAre 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 furtherassessment in your comments to the editors.
I am able to assess the statisticsQuality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, 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 your reply is yes to any, please give details below.
I declare I have no competing interests
Reviewer Publication Consent. 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) if this manu-script is accepted for publication. Any comments that I do not wish to be included in the publishedreport have been included as confidential comments to the editor, which will not be published.Ifyou are not happy for us to publish this report, please contact the editorial office before completingthe review.If you wish, you can include your name in your published report. Please note you mustdecide whether to include your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report.
(default)
Reviewer’ s report
Title: IgA, albumin, eosinopenia as early warning indicators for cytomegalovirus infection in
patients with acute ulcerative colitis
Version: 0Date: 27 May 2020
Reviewer: Abhishek Agnihotri
Reviewer's report:
I applaud the authors for highlighting an important problem and often a diagnostic dilemma in
Ulcerative Colitis flares. The most important aspect of any such study is case definition anddiagnostic accuracy. There is some controversy on accurate diagnostic test for CMV colitis whichis more relevant to diagnose in UC patients. Low level peripheral blood PCR positivity may beseen in asymptomatic patients on immunosuppression, hence blood PCR testing may havesensitivity as low as 65% and specificity as low as 40% (Inflammatory Bowel Diseases, Volume22, Issue 12, Pg 2966-2976). Tissue immunohistochemistry along with relevant histology remainsthe gold standard of diagnosis with specificity of 92-100%. 1.The authors define CMV colitis aspositivity of pp65 antigens, CMV IgM antibodies and CMV qPCR. We now know that the antigenassay does not differentiate latent infection from active infection. Also PCR low level positivitymay be seen and most studies have suggested a cut-off of CMV viral load ranging between 4000to 10,000 IU/mL in post-transplant patients. Lastly CMV IgM utility in IBD is fairly low sinceprimary infection is exceedingly unlikely to cause CMV colitis even in immunosuppressed hosts,especially as seroprevalence is so high. Positive IgM may indicate recent infection rather thanacute infection. I would recommend clarifying how many patients were diagnosed based on eachof the above diagnostic test, what was the PCR cut off used for diagnosis and how many had
concurrent tissue diagnosis of CMV colitis, which would be the gold standard of CMV infection,
in absence of effect on any other organ. This at present is a major limitation of the study.2. In firstparagraph of discussion, authors describe difficulty of differentiating UC from CMV colitis andsuggest the results of resent study may aid in that. However, that would not be a valid comparisonas present study is not on CMV colitis specifically.3. The difficulty of a case-control study remainsdifferentiating correlation and causation. The authors have rightly found CMV group to havesignificantly higher use of high dose steroids, eosinopenia, elevated CRP. However, the morelikely explanation remains patients with more severe UC, which are more likely to be on high dosesteroids, which ultimately are the patients with higher seropositivity for CMV. Steroids lead toeosinopenia which is self explanatory. Thus in this study, I woulc argue, we are largely seeingeffects of high dose steroids in a more severe UC patient population instead of direct effects ofCMV infection.4. To further improve the study, I would propose, clarifying diagnostic criteriaused and further description of PCR cut off along with breakdown of patients satisfying differentdiagnostic criterias. It would also be of value to know the proportion of patients with CMV colitisbased on tissue IHC as it is this population that is of great interest and a challenge to differentiatefrom acute UC flare.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
YesAre 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 furtherassessment in your comments to the editors.
I am able to assess the statisticsQuality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, 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 your reply is yes to any, please give details below.
I declare I have no competing interests
Reviewer Publication Consent. 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) if this manu-script is accepted for publication. Any comments that I do not wish to be included in the publishedreport have been included as confidential comments to the editor, which will not be published.Ifyou are not happy for us to publish this report, please contact the editorial office before completingthe review.If you wish, you can include your name in your published report. Please note you mustdecide whether to include your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report.
(default)
Please review this paper.
user
Reviewer’ s report
Title: IgA, albumin, eosinopenia as early warning indicators for cytomegalovirus infection in
patients with acute ulcerative colitis
Version: 0Date: 27 May 2020
Reviewer: Abhishek Agnihotri
Reviewer's report:
I applaud the authors for highlighting an important problem and often a diagnostic dilemma in
Ulcerative Colitis flares. The most important aspect of any such study is case definition anddiagnostic accuracy. There is some controversy on accurate diagnostic test for CMV colitis whichis more relevant to diagnose in UC patients. Low level peripheral blood PCR positivity may beseen in asymptomatic patients on immunosuppression, hence blood PCR testing may havesensitivity as low as 65% and specificity as low as 40% (Inflammatory Bowel Diseases, Volume22, Issue 12, Pg 2966-2976). Tissue immunohistochemistry along with relevant histology remainsthe gold standard of diagnosis with specificity of 92-100%. 1.The authors define CMV colitis aspositivity of pp65 antigens, CMV IgM antibodies and CMV qPCR. We now know that the antigenassay does not differentiate latent infection from active infection. Also PCR low level positivitymay be seen and most studies have suggested a cut-off of CMV viral load ranging between 4000to 10,000 IU/mL in post-transplant patients. Lastly CMV IgM utility in IBD is fairly low sinceprimary infection is exceedingly unlikely to cause CMV colitis even in immunosuppressed hosts,especially as seroprevalence is so high. Positive IgM may indicate recent infection rather thanacute infection. I would recommend clarifying how many patients were diagnosed based on eachof the above diagnostic test, what was the PCR cut off used for diagnosis and how many had
concurrent tissue diagnosis of CMV colitis, which would be the gold standard of CMV infection,
in absence of effect on any other organ. This at present is a major limitation of the study.2. In firstparagraph of discussion, authors describe difficulty of differentiating UC from CMV colitis andsuggest the results of resent study may aid in that. However, that would not be a valid comparisonas present study is not on CMV colitis specifically.3. The difficulty of a case-control study remainsdifferentiating correlation and causation. The authors have rightly found CMV group to havesignificantly higher use of high dose steroids, eosinopenia, elevated CRP. However, the morelikely explanation remains patients with more severe UC, which are more likely to be on high dosesteroids, which ultimately are the patients with higher seropositivity for CMV. Steroids lead toeosinopenia which is self explanatory. Thus in this study, I woulc argue, we are largely seeingeffects of high dose steroids in a more severe UC patient population instead of direct effects ofCMV infection.4. To further improve the study, I would propose, clarifying diagnostic criteriaused and further description of PCR cut off along with breakdown of patients satisfying differentdiagnostic criterias. It would also be of value to know the proportion of patients with CMV colitisbased on tissue IHC as it is this population that is of great interest and a challenge to differentiatefrom acute UC flare.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
YesAre 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 furtherassessment in your comments to the editors.
I am able to assess the statisticsQuality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, 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 your reply is yes to any, please give details below.
I declare I have no competing interests
Reviewer Publication Consent. 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) if this manu-script is accepted for publication. Any comments that I do not wish to be included in the publishedreport have been included as confidential comments to the editor, which will not be published.Ifyou are not happy for us to publish this report, please contact the editorial office before completingthe review.If you wish, you can include your name in your published report. Please note you mustdecide whether to include your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report.
(default)
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