Title: The Risk for Celiac Disease after Covid-19 Infection
Version: 3 Date: 25 Mar 2023
Reviewer's report:
Many thanks for your submission to BMC Gastroenterology.
your paper’s primary remit was to look at the incidence of celiac disease in relation to COVID-19
infection in the Skane region.
I am aware of other publications regarding the potential of COVID-19 being a trigger and your
report concludes very similarly to those other limited papers
I attach a PubMed search regarding the association. there has been much theorising about
the association and it is reassuring to see that there has not been direct link. as you rightly
discuss there has been much work done in relation to viral triggering of celiac disease including
researchers from your own institute, specifically Dan Agardh and his team, who have also been
key players in the TEDDY study.
https://pubmed.ncbi.nlm.nih.gov/?term=covid%2019%20and%20celiac%20disease
Samasca gives an overview of CD and covid 19.
https://pubmed.ncbi.nlm.nih.gov/34485888/
the trovato paper is of interest as a hypothetical risk…..
https://pubmed.ncbi.nlm.nih.gov/34145702/
and this paper suggests an increase related to covid 19 although the Turkish group report small
numbers in their paper
https://pubmed.ncbi.nlm.nih.gov/34738264/
the crocco paper just published i think will be of direct relevance to your study and data
https://pubmed.ncbi.nlm.nih.gov/36771266/
I have a number of comments and hopefully helpful suggestions that may help make your paper
better and perhaps a little more ‘tight’ with regards age groups and I do wonder whether you
should ask his view on your paper particularly when you are including the under 18 age group.
this is merely a suggestion and do wonder whether it would make your publication much more
publishable.
I am envious of your ability to correlate pathology and patient demographics as part of your
databases in Sweden.
In your abstract it is not clear to me further the population you're looking at is children or adults
and it really should be clearer from the beginning. I struggled even in the text with your patients
and methods on page  to understand whether you were dealing only with biopsy diagnosed
patients or whether you were including a set of children who were also being diagnosed as coeliac
with a no biopsy strategy, or if you are just including patients with positive serology.  The paper
would definitely benefit from you being clearer regarding this. I wonder if you have missed
serology only diagnoses of CD and where you may want to sense check with your paediatric
CD colleagues? I think this may be a gap in your paper but am happy to be proven wrong. If i
am this may be due to the paper just not making it clear to me.
Where I work we have definitely seen an increase in incidence of coeliac disease in children after
the pandemic, and this has been seen across a number of centres. We did see a fall in diagnosis
in 2020 for sure. I wonder whether it would be helpful for you to look at the year 2022 as a
comparator as this I think would be very helpful clinically and if you matched that up with the
incidence rates  of COVID-19 that would be extremely valuable.
I think it would be valuable for you to define what you have taken to be a properly diagnosed
coeliac as I am not clear whether you have included the serology only patients, and possibly
another good reason for collaborating with your paediatric colleagues to sense check their
experiences during the study period.
my experience is very similar to you in that there were a small number of children under the
age of 16 who had definitely been infected by COVID-19 but in whom it could not be blamed
even when we had the omicron variant which appeared in our country to cause more in the way
of gastrointestinal upset.
A few further minor points.
Page 3 - in line 21 you should use ‘proceding’ rather than upcoming.
Page 3 - In your introduction i think the references are very good and give a good overview
of infections and studies looking at these as a trigger. i think you should reference some of the
covid related literature to preface your paper, and include some of the work done in existing
patients, and the other papers that have postulated or looked at the infection as a cause or risk in
CD patients, as this will help the reader get even more context and reference material,. ie 'what
is known' , whilst maybe just making the wording a bit more compact. this is just my view but
hope it may be of help.
I  wonder whether in your patients  and methods section you need to have the biopsy date ie the
date of the scope, as the date of diagnosis rather than the day it arrived in the lab, as there may
have been a delay. This is of course if the biopsies actually made a diagnosis of CD, as some i
guess would not be diagnostic and you should check again to make sure you have not included
patients who had more subtle changes or who have been discarded from your data.
A point regarding IgG based serology, in paediatrics we would not rely on the serology test to
make a CD diagnosis as it is far less reliable than IgA based serology and ESPGHAN 2020
guidance really states that all sIgAd cases are biopsied.
on page 5, you discuss CDA- in the context of first or subsequent tests - i was not clear if this
was to detail a non biopsy group or what ? see line  14 to 15 and 18 to 20.
on page 8, you describe 35 cases of CD after covid, children and adults it would appear and i do
think it woudl help the reader understand what the ages were in this group.
On page 10 in the final line you state that stratification on each was not possible due to the low
numbers of patients. I would think that it would be helpful to have the demographics of those 35
patients detailed as it would be helpful to the reader to know whether they were serology based
diagnosis or biopsy beast and with the limited number of positives I think it might add extra
information to any publication, particularly to detail play ages of those patients diagnosed and
in my particular interest which is obviously in children’s CD.
I was interested to see that there was no time clustering based on your data, from covid to CD
diagnosis which is helpful.
In line 21, i was interested To see your reduction in positive cases of serology tests but I do
wonder what percentage of positive serology tests there were in relation to the total number of
tests performed in the total population. This would give an idea as to whether fewer tests were
done overall as a marker of clinical activity. this may not be possible though and of  course you
have discussed this- i would however think about number of tests from 2016 onwards as a 'rough
marker' of awareness or self presentation.
Again i am keen for you to look at the new diagnosis rate after 2021 and of course you would
have a whole year’s worth of data now to be able to look at.
I note that you have detailed the reduction in cases in Finland 2014 to 2015 but although you
also mention your Swedish studies , this is before your dataset looks at – 2016 to 2021.
You also talk in your discussion about potential coeliac disease. I am not sure that you have
enough evidence to talk to this in detail, again i am not sure about your discussion re CD
autoimmunity and serology based diagnosis – it may be worth relooking at your text  and being
more focused on the covid and CD diagnosis topic.
I think the discussion is overly long and you go into too much  discussion about other infections
that i think divert the reader away too much from the point of your paper which is specifically
covid 19 and CD (you could reference but make it much less wordy). The discussion should
be much more focussed on that, i feel and could be substantially reduced and your message not
lost at all, in fact strengthened,
The paper needs to focus on 'what this study adds'. I do not think your paper is the absolute first
to discuss covid 19 and subsequent coeliac disease (although you will know that most work has
been on the consequences of the infection on all aspects of CD itself , in existing patients , as
detailed in this search on pubmed ) but i totally agree it is an important association to either
prove or refute and i am keen for you to focus on covid 19 and the coeliac question, with relevant
information on the incidence of CD and i am keen for your to focus the paper a bit more if you
are able.
as i stated earlier, I would be including all the relevant literature on covid 19 and coeliac disease
as part of your paper and making that part of the introduction and making your conclusions
tighter re this infection and its association with subsequent CD.
I hope this is helpful and also makes sense ?
Title: The Risk for Celiac Disease after Covid-19 Infection
Version: 3 Date: 25 Mar 2023
Reviewer's report:
Many thanks for your submission to BMC Gastroenterology.
your paper’s primary remit was to look at the incidence of celiac disease in relation to COVID-19
infection in the Skane region.
I am aware of other publications regarding the potential of COVID-19 being a trigger and your
report concludes very similarly to those other limited papers
I attach a PubMed search regarding the association. there has been much theorising about
the association and it is reassuring to see that there has not been direct link. as you rightly
discuss there has been much work done in relation to viral triggering of celiac disease including
researchers from your own institute, specifically Dan Agardh and his team, who have also been
key players in the TEDDY study.
https://pubmed.ncbi.nlm.nih.gov/?term=covid%2019%20and%20celiac%20disease
Samasca gives an overview of CD and covid 19.
https://pubmed.ncbi.nlm.nih.gov/34485888/
the trovato paper is of interest as a hypothetical risk…..
https://pubmed.ncbi.nlm.nih.gov/34145702/
and this paper suggests an increase related to covid 19 although the Turkish group report small
numbers in their paper
https://pubmed.ncbi.nlm.nih.gov/34738264/
the crocco paper just published i think will be of direct relevance to your study and data
https://pubmed.ncbi.nlm.nih.gov/36771266/
I have a number of comments and hopefully helpful suggestions that may help make your paper
better and perhaps a little more ‘tight’ with regards age groups and I do wonder whether you
should ask his view on your paper particularly when you are including the under 18 age group.
this is merely a suggestion and do wonder whether it would make your publication much more
publishable.
I am envious of your ability to correlate pathology and patient demographics as part of your
databases in Sweden.
In your abstract it is not clear to me further the population you're looking at is children or adults
and it really should be clearer from the beginning. I struggled even in the text with your patients
and methods on page  to understand whether you were dealing only with biopsy diagnosed
patients or whether you were including a set of children who were also being diagnosed as coeliac
with a no biopsy strategy, or if you are just including patients with positive serology.  The paper
would definitely benefit from you being clearer regarding this. I wonder if you have missed
serology only diagnoses of CD and where you may want to sense check with your paediatric
CD colleagues? I think this may be a gap in your paper but am happy to be proven wrong. If i
am this may be due to the paper just not making it clear to me.
Where I work we have definitely seen an increase in incidence of coeliac disease in children after
the pandemic, and this has been seen across a number of centres. We did see a fall in diagnosis
in 2020 for sure. I wonder whether it would be helpful for you to look at the year 2022 as a
comparator as this I think would be very helpful clinically and if you matched that up with the
incidence rates  of COVID-19 that would be extremely valuable.
I think it would be valuable for you to define what you have taken to be a properly diagnosed
coeliac as I am not clear whether you have included the serology only patients, and possibly
another good reason for collaborating with your paediatric colleagues to sense check their
experiences during the study period.
my experience is very similar to you in that there were a small number of children under the
age of 16 who had definitely been infected by COVID-19 but in whom it could not be blamed
even when we had the omicron variant which appeared in our country to cause more in the way
of gastrointestinal upset.
A few further minor points.
Page 3 - in line 21 you should use ‘proceding’ rather than upcoming.
Page 3 - In your introduction i think the references are very good and give a good overview
of infections and studies looking at these as a trigger. i think you should reference some of the
covid related literature to preface your paper, and include some of the work done in existing
patients, and the other papers that have postulated or looked at the infection as a cause or risk in
CD patients, as this will help the reader get even more context and reference material,. ie 'what
is known' , whilst maybe just making the wording a bit more compact. this is just my view but
hope it may be of help.
I  wonder whether in your patients  and methods section you need to have the biopsy date ie the
date of the scope, as the date of diagnosis rather than the day it arrived in the lab, as there may
have been a delay. This is of course if the biopsies actually made a diagnosis of CD, as some i
guess would not be diagnostic and you should check again to make sure you have not included
patients who had more subtle changes or who have been discarded from your data.
A point regarding IgG based serology, in paediatrics we would not rely on the serology test to
make a CD diagnosis as it is far less reliable than IgA based serology and ESPGHAN 2020
guidance really states that all sIgAd cases are biopsied.
on page 5, you discuss CDA- in the context of first or subsequent tests - i was not clear if this
was to detail a non biopsy group or what ? see line  14 to 15 and 18 to 20.
on page 8, you describe 35 cases of CD after covid, children and adults it would appear and i do
think it woudl help the reader understand what the ages were in this group.
On page 10 in the final line you state that stratification on each was not possible due to the low
numbers of patients. I would think that it would be helpful to have the demographics of those 35
patients detailed as it would be helpful to the reader to know whether they were serology based
diagnosis or biopsy beast and with the limited number of positives I think it might add extra
information to any publication, particularly to detail play ages of those patients diagnosed and
in my particular interest which is obviously in children’s CD.
I was interested to see that there was no time clustering based on your data, from covid to CD
diagnosis which is helpful.
In line 21, i was interested To see your reduction in positive cases of serology tests but I do
wonder what percentage of positive serology tests there were in relation to the total number of
tests performed in the total population. This would give an idea as to whether fewer tests were
done overall as a marker of clinical activity. this may not be possible though and of  course you
have discussed this- i would however think about number of tests from 2016 onwards as a 'rough
marker' of awareness or self presentation.
Again i am keen for you to look at the new diagnosis rate after 2021 and of course you would
have a whole year’s worth of data now to be able to look at.
I note that you have detailed the reduction in cases in Finland 2014 to 2015 but although you
also mention your Swedish studies , this is before your dataset looks at – 2016 to 2021.
You also talk in your discussion about potential coeliac disease. I am not sure that you have
enough evidence to talk to this in detail, again i am not sure about your discussion re CD
autoimmunity and serology based diagnosis – it may be worth relooking at your text  and being
more focused on the covid and CD diagnosis topic.
I think the discussion is overly long and you go into too much  discussion about other infections
that i think divert the reader away too much from the point of your paper which is specifically
covid 19 and CD (you could reference but make it much less wordy). The discussion should
be much more focussed on that, i feel and could be substantially reduced and your message not
lost at all, in fact strengthened,
The paper needs to focus on 'what this study adds'. I do not think your paper is the absolute first
to discuss covid 19 and subsequent coeliac disease (although you will know that most work has
been on the consequences of the infection on all aspects of CD itself , in existing patients , as
detailed in this search on pubmed ) but i totally agree it is an important association to either
prove or refute and i am keen for you to focus on covid 19 and the coeliac question, with relevant
information on the incidence of CD and i am keen for your to focus the paper a bit more if you
are able.
as i stated earlier, I would be including all the relevant literature on covid 19 and coeliac disease
as part of your paper and making that part of the introduction and making your conclusions
tighter re this infection and its association with subsequent CD.
I hope this is helpful and also makes sense ?
Please review this paper.
user
Title: The Risk for Celiac Disease after Covid-19 Infection
Version: 3 Date: 25 Mar 2023
Reviewer's report:
Many thanks for your submission to BMC Gastroenterology.
your paper’s primary remit was to look at the incidence of celiac disease in relation to COVID-19
infection in the Skane region.
I am aware of other publications regarding the potential of COVID-19 being a trigger and your
report concludes very similarly to those other limited papers
I attach a PubMed search regarding the association. there has been much theorising about
the association and it is reassuring to see that there has not been direct link. as you rightly
discuss there has been much work done in relation to viral triggering of celiac disease including
researchers from your own institute, specifically Dan Agardh and his team, who have also been
key players in the TEDDY study.
https://pubmed.ncbi.nlm.nih.gov/?term=covid%2019%20and%20celiac%20disease
Samasca gives an overview of CD and covid 19.
https://pubmed.ncbi.nlm.nih.gov/34485888/
the trovato paper is of interest as a hypothetical risk…..
https://pubmed.ncbi.nlm.nih.gov/34145702/
and this paper suggests an increase related to covid 19 although the Turkish group report small
numbers in their paper
https://pubmed.ncbi.nlm.nih.gov/34738264/
the crocco paper just published i think will be of direct relevance to your study and data
https://pubmed.ncbi.nlm.nih.gov/36771266/
I have a number of comments and hopefully helpful suggestions that may help make your paper
better and perhaps a little more ‘tight’ with regards age groups and I do wonder whether you
should ask his view on your paper particularly when you are including the under 18 age group.
this is merely a suggestion and do wonder whether it would make your publication much more
publishable.
I am envious of your ability to correlate pathology and patient demographics as part of your
databases in Sweden.
In your abstract it is not clear to me further the population you're looking at is children or adults
and it really should be clearer from the beginning. I struggled even in the text with your patients
and methods on page  to understand whether you were dealing only with biopsy diagnosed
patients or whether you were including a set of children who were also being diagnosed as coeliac
with a no biopsy strategy, or if you are just including patients with positive serology.  The paper
would definitely benefit from you being clearer regarding this. I wonder if you have missed
serology only diagnoses of CD and where you may want to sense check with your paediatric
CD colleagues? I think this may be a gap in your paper but am happy to be proven wrong. If i
am this may be due to the paper just not making it clear to me.
Where I work we have definitely seen an increase in incidence of coeliac disease in children after
the pandemic, and this has been seen across a number of centres. We did see a fall in diagnosis
in 2020 for sure. I wonder whether it would be helpful for you to look at the year 2022 as a
comparator as this I think would be very helpful clinically and if you matched that up with the
incidence rates  of COVID-19 that would be extremely valuable.
I think it would be valuable for you to define what you have taken to be a properly diagnosed
coeliac as I am not clear whether you have included the serology only patients, and possibly
another good reason for collaborating with your paediatric colleagues to sense check their
experiences during the study period.
my experience is very similar to you in that there were a small number of children under the
age of 16 who had definitely been infected by COVID-19 but in whom it could not be blamed
even when we had the omicron variant which appeared in our country to cause more in the way
of gastrointestinal upset.
A few further minor points.
Page 3 - in line 21 you should use ‘proceding’ rather than upcoming.
Page 3 - In your introduction i think the references are very good and give a good overview
of infections and studies looking at these as a trigger. i think you should reference some of the
covid related literature to preface your paper, and include some of the work done in existing
patients, and the other papers that have postulated or looked at the infection as a cause or risk in
CD patients, as this will help the reader get even more context and reference material,. ie 'what
is known' , whilst maybe just making the wording a bit more compact. this is just my view but
hope it may be of help.
I  wonder whether in your patients  and methods section you need to have the biopsy date ie the
date of the scope, as the date of diagnosis rather than the day it arrived in the lab, as there may
have been a delay. This is of course if the biopsies actually made a diagnosis of CD, as some i
guess would not be diagnostic and you should check again to make sure you have not included
patients who had more subtle changes or who have been discarded from your data.
A point regarding IgG based serology, in paediatrics we would not rely on the serology test to
make a CD diagnosis as it is far less reliable than IgA based serology and ESPGHAN 2020
guidance really states that all sIgAd cases are biopsied.
on page 5, you discuss CDA- in the context of first or subsequent tests - i was not clear if this
was to detail a non biopsy group or what ? see line  14 to 15 and 18 to 20.
on page 8, you describe 35 cases of CD after covid, children and adults it would appear and i do
think it woudl help the reader understand what the ages were in this group.
On page 10 in the final line you state that stratification on each was not possible due to the low
numbers of patients. I would think that it would be helpful to have the demographics of those 35
patients detailed as it would be helpful to the reader to know whether they were serology based
diagnosis or biopsy beast and with the limited number of positives I think it might add extra
information to any publication, particularly to detail play ages of those patients diagnosed and
in my particular interest which is obviously in children’s CD.
I was interested to see that there was no time clustering based on your data, from covid to CD
diagnosis which is helpful.
In line 21, i was interested To see your reduction in positive cases of serology tests but I do
wonder what percentage of positive serology tests there were in relation to the total number of
tests performed in the total population. This would give an idea as to whether fewer tests were
done overall as a marker of clinical activity. this may not be possible though and of  course you
have discussed this- i would however think about number of tests from 2016 onwards as a 'rough
marker' of awareness or self presentation.
Again i am keen for you to look at the new diagnosis rate after 2021 and of course you would
have a whole year’s worth of data now to be able to look at.
I note that you have detailed the reduction in cases in Finland 2014 to 2015 but although you
also mention your Swedish studies , this is before your dataset looks at – 2016 to 2021.
You also talk in your discussion about potential coeliac disease. I am not sure that you have
enough evidence to talk to this in detail, again i am not sure about your discussion re CD
autoimmunity and serology based diagnosis – it may be worth relooking at your text  and being
more focused on the covid and CD diagnosis topic.
I think the discussion is overly long and you go into too much  discussion about other infections
that i think divert the reader away too much from the point of your paper which is specifically
covid 19 and CD (you could reference but make it much less wordy). The discussion should
be much more focussed on that, i feel and could be substantially reduced and your message not
lost at all, in fact strengthened,
The paper needs to focus on 'what this study adds'. I do not think your paper is the absolute first
to discuss covid 19 and subsequent coeliac disease (although you will know that most work has
been on the consequences of the infection on all aspects of CD itself , in existing patients , as
detailed in this search on pubmed ) but i totally agree it is an important association to either
prove or refute and i am keen for you to focus on covid 19 and the coeliac question, with relevant
information on the incidence of CD and i am keen for your to focus the paper a bit more if you
are able.
as i stated earlier, I would be including all the relevant literature on covid 19 and coeliac disease
as part of your paper and making that part of the introduction and making your conclusions
tighter re this infection and its association with subsequent CD.
I hope this is helpful and also makes sense ?
assistant