Title: Risk factors of active upper gastrointestinal bleeding in patients with COVID-19 infection
and the effectiveness of PPI prophylaxis
Version: 1 Date: 02 Aug 2022
Reviewer:  Thibault Sixt
Reviewer's report:
The authors have presented a two-part study (retrospective and experimentally) in Thailand
on active gastrointestinal bleeding during COVID-19 and their risk factors. This study brings
new data concerning possible gastrointestinal complication during this disease. The text is well
written and easy to understand. Their main conclusion is that the use of proton pump inhibitors
reduces the risk of active gastrointestinal bleeding and should be prescribed in those patients
once they need hospitalization regardless the severity of COVID-19. This
this conclusion is probably a little hasty because indeed there are several points that need
clarification as well as multiple limitations and sources of bias that needs to be addressed.
1) Abstract
a. Factors associated with UGIB do not correspond to the primary outcome. The primary
outcome is active UGIB and the objective of the study is to find factors associated with this
outcome.
b. The conclusion of the abstract is that PPI prophylaxis should be prescribed once patient needs
hospitalization. However, the conclusion of the manuscript is that PPI should be prescribed when
corticosteroid or anticoagulant are necessary. Please correct, the conclusion to be coherent with
the abstract or vice versa.
2) Introduction
a. Please detail the primary and secondary purposes of the study
3) Methods:
a. What is the external validity of the ICD-10 coding? Is there any risk for misclassification or
missing cases?
b. Is a screening for Helicobacter pylori, which is a major risk of UGIB, was performed during
endoscopy? If yes, you should take into account this element in the logistic regression. If no,
this element should be detailed in the limitations of the study
c. The severity of the disease is reflected only with the requirement of mechanical requirement.
Do you have any score to reflect more precisely the severity of disease (such as SOFA score or
NEWS2 score)? If yes, adjust the logistic regression on it
d. Is there any missing data? If yes, please explain how they were managed.
e. Factors associated with UGIB cannot be a primary outcome. The primary outcome is UGIB
and the objective of the study is to find factors associated with this outcome
f. As previously, cause of UGBI cannot be a secondary outcome. The secondary outcome could
be UGBI (active and non-active).
g. Tabaco and alcohol use are not detailed in the characteristics of the patients but they are known
to be cause of UGBI. Please provide this information.
h. Please detail what is the Glasgow Blatchford score, how is it calculate and its external validity.
4) Statistical analysis
a. Please detailed how the variables for performing the logistic regression were chosen
b. Please detail more precisely the number of subjects needed in the second part with the alpha
and beta risk chosen and the expected difference under PPI
5) Results: Global concern for the results: there is not enough active UGIB to perform a relevant
comparison between active and inactive UGIB
a. Please do not detail all the characteristics of COVID-19 infected patients that are well detailed
in Table 1
b. Please provide a number to treat with PPI to provide in order to highlight the benefit of
treatment with PPI in the general population
c. 23.3% of the patients received anticoagulative agent, is this treatment curative dose or
preventive dose? This must be specified and the analysis must be adjusted to the dose
d. During the second period of the study where all patients had PPI, no information concerning
side effect is reported. Please provide this information to have a correct vison of the risk benefit
of PPI.
e. PPI are known to be risk factors for respiratory and digestive infections. Please provide if lung
or digestive infections have occurred in the second part.
6) Discussion:
a. You recommended the use of PPI prophylaxis for patients hospitalized for COVID 19 having
corticosteroids or anticoagulant. The French national Health Authority already recommends this
attitude. Could you please be more selective regarding the indication during COVID-19?
b. Is there a specific pathophysiology to COVID-19 to explain the bleeding during this infection?
Is there any ACE2 receptor on gastrointestinal cells? Is this only linked to the management of
the disease? Is COVID-19 a risk of bleeding?
c. The main limitation of the study is the small proportion of patients having an active UGIB,
and it can also affect the result of the multivariate regression. This is highlighted by the large
95% CI obtained in the analysis. Please notice this in the discussion and provide perspective.
7) Conclusion
a. Be less assertive in your conclusion due to the many limitations of the study and the possible
side effects of PPI and please offer perspectives to complete your data.
b. You should also mention the interest of the Glasgow Blatchford score
8) Table and figure
a. In figure 2, please provide sensitivity, specificity, PPV and PPN for Glasgow Blatchford score
more than 14
b. In table 1 sample are too small to performed a relevant comparison,
c. In table 3, sample are too small to performed a relevant comparison,
d. In table 4, please defined in the method section the difference between enoxaparin/heparin
use for COVID-19 treatment and anticoagulant use
Title: Risk factors of active upper gastrointestinal bleeding in patients with COVID-19 infection
and the effectiveness of PPI prophylaxis
Version: 1 Date: 02 Aug 2022
Reviewer:  Thibault Sixt
Reviewer's report:
The authors have presented a two-part study (retrospective and experimentally) in Thailand
on active gastrointestinal bleeding during COVID-19 and their risk factors. This study brings
new data concerning possible gastrointestinal complication during this disease. The text is well
written and easy to understand. Their main conclusion is that the use of proton pump inhibitors
reduces the risk of active gastrointestinal bleeding and should be prescribed in those patients
once they need hospitalization regardless the severity of COVID-19. This
this conclusion is probably a little hasty because indeed there are several points that need
clarification as well as multiple limitations and sources of bias that needs to be addressed.
1) Abstract
a. Factors associated with UGIB do not correspond to the primary outcome. The primary
outcome is active UGIB and the objective of the study is to find factors associated with this
outcome.
b. The conclusion of the abstract is that PPI prophylaxis should be prescribed once patient needs
hospitalization. However, the conclusion of the manuscript is that PPI should be prescribed when
corticosteroid or anticoagulant are necessary. Please correct, the conclusion to be coherent with
the abstract or vice versa.
2) Introduction
a. Please detail the primary and secondary purposes of the study
3) Methods:
a. What is the external validity of the ICD-10 coding? Is there any risk for misclassification or
missing cases?
b. Is a screening for Helicobacter pylori, which is a major risk of UGIB, was performed during
endoscopy? If yes, you should take into account this element in the logistic regression. If no,
this element should be detailed in the limitations of the study
c. The severity of the disease is reflected only with the requirement of mechanical requirement.
Do you have any score to reflect more precisely the severity of disease (such as SOFA score or
NEWS2 score)? If yes, adjust the logistic regression on it
d. Is there any missing data? If yes, please explain how they were managed.
e. Factors associated with UGIB cannot be a primary outcome. The primary outcome is UGIB
and the objective of the study is to find factors associated with this outcome
f. As previously, cause of UGBI cannot be a secondary outcome. The secondary outcome could
be UGBI (active and non-active).
g. Tabaco and alcohol use are not detailed in the characteristics of the patients but they are known
to be cause of UGBI. Please provide this information.
h. Please detail what is the Glasgow Blatchford score, how is it calculate and its external validity.
4) Statistical analysis
a. Please detailed how the variables for performing the logistic regression were chosen
b. Please detail more precisely the number of subjects needed in the second part with the alpha
and beta risk chosen and the expected difference under PPI
5) Results: Global concern for the results: there is not enough active UGIB to perform a relevant
comparison between active and inactive UGIB
a. Please do not detail all the characteristics of COVID-19 infected patients that are well detailed
in Table 1
b. Please provide a number to treat with PPI to provide in order to highlight the benefit of
treatment with PPI in the general population
c. 23.3% of the patients received anticoagulative agent, is this treatment curative dose or
preventive dose? This must be specified and the analysis must be adjusted to the dose
d. During the second period of the study where all patients had PPI, no information concerning
side effect is reported. Please provide this information to have a correct vison of the risk benefit
of PPI.
e. PPI are known to be risk factors for respiratory and digestive infections. Please provide if lung
or digestive infections have occurred in the second part.
6) Discussion:
a. You recommended the use of PPI prophylaxis for patients hospitalized for COVID 19 having
corticosteroids or anticoagulant. The French national Health Authority already recommends this
attitude. Could you please be more selective regarding the indication during COVID-19?
b. Is there a specific pathophysiology to COVID-19 to explain the bleeding during this infection?
Is there any ACE2 receptor on gastrointestinal cells? Is this only linked to the management of
the disease? Is COVID-19 a risk of bleeding?
c. The main limitation of the study is the small proportion of patients having an active UGIB,
and it can also affect the result of the multivariate regression. This is highlighted by the large
95% CI obtained in the analysis. Please notice this in the discussion and provide perspective.
7) Conclusion
a. Be less assertive in your conclusion due to the many limitations of the study and the possible
side effects of PPI and please offer perspectives to complete your data.
b. You should also mention the interest of the Glasgow Blatchford score
8) Table and figure
a. In figure 2, please provide sensitivity, specificity, PPV and PPN for Glasgow Blatchford score
more than 14
b. In table 1 sample are too small to performed a relevant comparison,
c. In table 3, sample are too small to performed a relevant comparison,
d. In table 4, please defined in the method section the difference between enoxaparin/heparin
use for COVID-19 treatment and anticoagulant use
Please review this paper.
user
Title: Risk factors of active upper gastrointestinal bleeding in patients with COVID-19 infection
and the effectiveness of PPI prophylaxis
Version: 1 Date: 02 Aug 2022
Reviewer:  Thibault Sixt
Reviewer's report:
The authors have presented a two-part study (retrospective and experimentally) in Thailand
on active gastrointestinal bleeding during COVID-19 and their risk factors. This study brings
new data concerning possible gastrointestinal complication during this disease. The text is well
written and easy to understand. Their main conclusion is that the use of proton pump inhibitors
reduces the risk of active gastrointestinal bleeding and should be prescribed in those patients
once they need hospitalization regardless the severity of COVID-19. This
this conclusion is probably a little hasty because indeed there are several points that need
clarification as well as multiple limitations and sources of bias that needs to be addressed.
1) Abstract
a. Factors associated with UGIB do not correspond to the primary outcome. The primary
outcome is active UGIB and the objective of the study is to find factors associated with this
outcome.
b. The conclusion of the abstract is that PPI prophylaxis should be prescribed once patient needs
hospitalization. However, the conclusion of the manuscript is that PPI should be prescribed when
corticosteroid or anticoagulant are necessary. Please correct, the conclusion to be coherent with
the abstract or vice versa.
2) Introduction
a. Please detail the primary and secondary purposes of the study
3) Methods:
a. What is the external validity of the ICD-10 coding? Is there any risk for misclassification or
missing cases?
b. Is a screening for Helicobacter pylori, which is a major risk of UGIB, was performed during
endoscopy? If yes, you should take into account this element in the logistic regression. If no,
this element should be detailed in the limitations of the study
c. The severity of the disease is reflected only with the requirement of mechanical requirement.
Do you have any score to reflect more precisely the severity of disease (such as SOFA score or
NEWS2 score)? If yes, adjust the logistic regression on it
d. Is there any missing data? If yes, please explain how they were managed.
e. Factors associated with UGIB cannot be a primary outcome. The primary outcome is UGIB
and the objective of the study is to find factors associated with this outcome
f. As previously, cause of UGBI cannot be a secondary outcome. The secondary outcome could
be UGBI (active and non-active).
g. Tabaco and alcohol use are not detailed in the characteristics of the patients but they are known
to be cause of UGBI. Please provide this information.
h. Please detail what is the Glasgow Blatchford score, how is it calculate and its external validity.
4) Statistical analysis
a. Please detailed how the variables for performing the logistic regression were chosen
b. Please detail more precisely the number of subjects needed in the second part with the alpha
and beta risk chosen and the expected difference under PPI
5) Results: Global concern for the results: there is not enough active UGIB to perform a relevant
comparison between active and inactive UGIB
a. Please do not detail all the characteristics of COVID-19 infected patients that are well detailed
in Table 1
b. Please provide a number to treat with PPI to provide in order to highlight the benefit of
treatment with PPI in the general population
c. 23.3% of the patients received anticoagulative agent, is this treatment curative dose or
preventive dose? This must be specified and the analysis must be adjusted to the dose
d. During the second period of the study where all patients had PPI, no information concerning
side effect is reported. Please provide this information to have a correct vison of the risk benefit
of PPI.
e. PPI are known to be risk factors for respiratory and digestive infections. Please provide if lung
or digestive infections have occurred in the second part.
6) Discussion:
a. You recommended the use of PPI prophylaxis for patients hospitalized for COVID 19 having
corticosteroids or anticoagulant. The French national Health Authority already recommends this
attitude. Could you please be more selective regarding the indication during COVID-19?
b. Is there a specific pathophysiology to COVID-19 to explain the bleeding during this infection?
Is there any ACE2 receptor on gastrointestinal cells? Is this only linked to the management of
the disease? Is COVID-19 a risk of bleeding?
c. The main limitation of the study is the small proportion of patients having an active UGIB,
and it can also affect the result of the multivariate regression. This is highlighted by the large
95% CI obtained in the analysis. Please notice this in the discussion and provide perspective.
7) Conclusion
a. Be less assertive in your conclusion due to the many limitations of the study and the possible
side effects of PPI and please offer perspectives to complete your data.
b. You should also mention the interest of the Glasgow Blatchford score
8) Table and figure
a. In figure 2, please provide sensitivity, specificity, PPV and PPN for Glasgow Blatchford score
more than 14
b. In table 1 sample are too small to performed a relevant comparison,
c. In table 3, sample are too small to performed a relevant comparison,
d. In table 4, please defined in the method section the difference between enoxaparin/heparin
use for COVID-19 treatment and anticoagulant use
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