Reviewer’s report
Title: 
Are Gastrointestinal Symptoms Associated with Higher Risk of Mortality
in COVID-19 Patients? A Systematic Review and Meta-Analysis
Version: 
2 
Date: 
02 Sep 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: The authors have provided satisfactory feedback to
the responses. I also commend the authors for updating their Literature searches
and adding more recently published data. There are a few additional comments
that have been raised based on the edits made that are outlined below. The main
comment relates to the age-related analysis that has show significant differences
based on location. This is a very important finding and should not be glossed
over by the authors. Specific comments are follow.
REQUESTED REVISIONS: 
Line 137: Can we add a reference for the Newcastle-Ottawa Scale.
Line 186 - change 'had' to 'have'.
Line 189: Please add back the p value for the I squared statistic).
Lines 212-217: I beleive the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Lines 212-217: I believe the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highlight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Line 217: This is a very important finding. I am not sure I understand the
meaning of the term 'attenuated' here. I suggest replace with another word to
improve clarity of this sentence.
Lines 286-298: Please also refer to note at Line 213. The information here
describing the sub-analysis are very important findings and should be moved to
the findings section. I would suggest adding the tables or figures corresponding
to this finding if these are available. Then the discussion can continue about the
significance of this finding on the respective respective regions and generally. 
Line 297-298: Once again, it is important to underscore that since age is a
significant predictor of COVID-19 outcomes, the differences in mortality for
patients of a certain age is an important finding in this study, that should not be
brushed over. This is a particular value of this meta-analysis. I recommend the
authors add a few more discussion points on this in the context of the reviewed
literature that may be useful for clinicians and public health experts planning for
health care resources to manage older COVID-19 cases exhibiting GI symptoms.
Line 362-364: I do not agree with the authors that the difference in age among
patients in some locations is a limitation. I think this is one of the novel findings
of this meta-analysis and this should be carefully described and discussed in the
paper. The subgroup analysis by age groups should be more carefully reported. 
Table 3: The critical analysis missing from Table 3 is the age related analysis by
sub-region.
ADDITIONAL REQUESTS/SUGGESTIONS: 
I suggest adding the age related sub-analysis by region as this is a critical
finding. In my opinion this IS the major finding of this study and it needs to be
given the prominence it deserves - maybe this can be added to Table 3.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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, 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 your reply is yes to any, please give details below.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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 manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide 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)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Are Gastrointestinal Symptoms Associated with Higher Risk of Mortality
in COVID-19 Patients? A Systematic Review and Meta-Analysis
Version: 
2 
Date: 
02 Sep 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: The authors have provided satisfactory feedback to
the responses. I also commend the authors for updating their Literature searches
and adding more recently published data. There are a few additional comments
that have been raised based on the edits made that are outlined below. The main
comment relates to the age-related analysis that has show significant differences
based on location. This is a very important finding and should not be glossed
over by the authors. Specific comments are follow.
REQUESTED REVISIONS: 
Line 137: Can we add a reference for the Newcastle-Ottawa Scale.
Line 186 - change 'had' to 'have'.
Line 189: Please add back the p value for the I squared statistic).
Lines 212-217: I beleive the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Lines 212-217: I believe the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highlight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Line 217: This is a very important finding. I am not sure I understand the
meaning of the term 'attenuated' here. I suggest replace with another word to
improve clarity of this sentence.
Lines 286-298: Please also refer to note at Line 213. The information here
describing the sub-analysis are very important findings and should be moved to
the findings section. I would suggest adding the tables or figures corresponding
to this finding if these are available. Then the discussion can continue about the
significance of this finding on the respective respective regions and generally. 
Line 297-298: Once again, it is important to underscore that since age is a
significant predictor of COVID-19 outcomes, the differences in mortality for
patients of a certain age is an important finding in this study, that should not be
brushed over. This is a particular value of this meta-analysis. I recommend the
authors add a few more discussion points on this in the context of the reviewed
literature that may be useful for clinicians and public health experts planning for
health care resources to manage older COVID-19 cases exhibiting GI symptoms.
Line 362-364: I do not agree with the authors that the difference in age among
patients in some locations is a limitation. I think this is one of the novel findings
of this meta-analysis and this should be carefully described and discussed in the
paper. The subgroup analysis by age groups should be more carefully reported. 
Table 3: The critical analysis missing from Table 3 is the age related analysis by
sub-region.
ADDITIONAL REQUESTS/SUGGESTIONS: 
I suggest adding the age related sub-analysis by region as this is a critical
finding. In my opinion this IS the major finding of this study and it needs to be
given the prominence it deserves - maybe this can be added to Table 3.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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, 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 your reply is yes to any, please give details below.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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 manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide 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)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Are Gastrointestinal Symptoms Associated with Higher Risk of Mortality
in COVID-19 Patients? A Systematic Review and Meta-Analysis
Version: 
2 
Date: 
02 Sep 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: The authors have provided satisfactory feedback to
the responses. I also commend the authors for updating their Literature searches
and adding more recently published data. There are a few additional comments
that have been raised based on the edits made that are outlined below. The main
comment relates to the age-related analysis that has show significant differences
based on location. This is a very important finding and should not be glossed
over by the authors. Specific comments are follow.
REQUESTED REVISIONS: 
Line 137: Can we add a reference for the Newcastle-Ottawa Scale.
Line 186 - change 'had' to 'have'.
Line 189: Please add back the p value for the I squared statistic).
Lines 212-217: I beleive the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Lines 212-217: I believe the analysis on age related difference is a very
important clinical finding and can be added in the manuscript here. It would be
important to highlight that there is an increased risk among older patients
presenting with GI symptoms compared with younger persons. The authors have
provided a sensible response in the feedback section. this could be added in the
manuscript here.
Line 217: This is a very important finding. I am not sure I understand the
meaning of the term 'attenuated' here. I suggest replace with another word to
improve clarity of this sentence.
Lines 286-298: Please also refer to note at Line 213. The information here
describing the sub-analysis are very important findings and should be moved to
the findings section. I would suggest adding the tables or figures corresponding
to this finding if these are available. Then the discussion can continue about the
significance of this finding on the respective respective regions and generally. 
Line 297-298: Once again, it is important to underscore that since age is a
significant predictor of COVID-19 outcomes, the differences in mortality for
patients of a certain age is an important finding in this study, that should not be
brushed over. This is a particular value of this meta-analysis. I recommend the
authors add a few more discussion points on this in the context of the reviewed
literature that may be useful for clinicians and public health experts planning for
health care resources to manage older COVID-19 cases exhibiting GI symptoms.
Line 362-364: I do not agree with the authors that the difference in age among
patients in some locations is a limitation. I think this is one of the novel findings
of this meta-analysis and this should be carefully described and discussed in the
paper. The subgroup analysis by age groups should be more carefully reported. 
Table 3: The critical analysis missing from Table 3 is the age related analysis by
sub-region.
ADDITIONAL REQUESTS/SUGGESTIONS: 
I suggest adding the age related sub-analysis by region as this is a critical
finding. In my opinion this IS the major finding of this study and it needs to be
given the prominence it deserves - maybe this can be added to Table 3.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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, 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 your reply is yes to any, please give details below.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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 manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide 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)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant