Title: Multicenter epidemiological survey of pneumatosis intestinalis in Japan
Version: 1 Date: 24 Nov 2021
Reviewer's report:
Major comments
The clinical manifestation of pneumatosis intestinalis (PI) ranges from asymptomatic to a life-
threatening condition. Thus, defining the poor prognostic factors is essential to managing this
condition. In the current study, the authors demonstrated that a small bowel-involved type of PI
is associated with complications; moreover, mortality in patients accompanied by complications
was higher than those without it.
Although the current study provides evidence associated with small bowel-involved PI and poor
prognostic factors for PI, there are several limitations. First, The study participants may not
represent the target population since the current study enrolled a relatively small number of
participants (32% of response rate) and included only 15.6% cases of complications and 4.6%
cases of surgery. Second, the laboratory and image findings that potentially affect the risks of
PI were not collected and analyzed. Third, several study results were not consistent with the
previous reports. However, the authors did not suggest evidence supporting this.
Specific comments
Introduction
The background and clinical importance of this study are not suggested concisely.  There are
only lists of related factors of complications and mortality.
Method
1. Line 135-137: The author mentioned that adynamic ileus was regarded as a complication
by definition. However, adynamic ileus is not on the list of complications in Table 1 (Survey
parameters).  The diagnostic methods and definition of complications were unclear. Even though
it was a survey study, the definition of some medical conditions is required.
1) Did bowel obstruction mean adynamic ileus?
2) What was the definition of massive GI bleeding?
2. Line 159-160: Provide more information on the multivariate analysis. Which variables
were used for multivariate analysis to access the risk factors of small bowel involved type,
complicating PI, treatment, outcomes of PI, and death other than categorical items with P-values
less than 0.10 in the univariate analysis?
Result:
3. Line 164-168: It would be more informative to provide data about the level of health care
which patients recruited. Report the proportion of primary, secondary, or tertiary centers in this
study.
4. Consider providing Table 1 as a supplementary table.
5. There is too much information not directly associated with PI and not categorized in Table
2 and Table 3. It reduces readability.
6. Total number of PI with 'right-sided colon only' was 84 in table 3. However, It is 83 in
supplementary table 2. Furthermore, the data about 'left-sided colon only' is different between
table 3 and suppl Table 2. Correct this error.
7. Line 181-189: In supplementary table 2, symptoms were presented most of the patients with
complications (96.2%), and the crude OR was high (23.96, P<0.0001).
1) Although statistically significant, the symptoms are not mentioned in the manuscript. Please
describe this.
2) Are the symptoms included in the multivariate analysis?
3) Consider including the symptoms in the complicating PI in Table 4.
8. Line 185: It is challenging to consist causal inferences in this type of study.
9. Line 191-200: Could you describe the result of each treatment, such as success rate,
exacerbation, or death if possible.
Discussion:
10. Line 239-240: The effect size for the risk of complicating PI in patients taking allopurinol/
benzbromarone is quite high. What is the postulated mechanism or evidence for this?
11. Line 241-247: Provide more postulated evidence supporting CKD as a risk factor for small
bowel PI or PI if possible.
12. Line 256: Please, clearly define the "positive intraoperative findings."
13.  Line 257: Correct the lactic academia to lactic acidemia
14. What is postulated reasons that small bowel-involved PI is associated with complications.
15. Importantly, what is the strength of this study compared to other previous studies.
Conclusion
16. Line: 277-278: Although small-bowel involved type is associated with the risk of
complication, there was no evidence supporting a direct causal relationship between the small
bowel involved type and poor prognoses in the current study.
Title: Multicenter epidemiological survey of pneumatosis intestinalis in Japan
Version: 1 Date: 24 Nov 2021
Reviewer's report:
Major comments
The clinical manifestation of pneumatosis intestinalis (PI) ranges from asymptomatic to a life-
threatening condition. Thus, defining the poor prognostic factors is essential to managing this
condition. In the current study, the authors demonstrated that a small bowel-involved type of PI
is associated with complications; moreover, mortality in patients accompanied by complications
was higher than those without it.
Although the current study provides evidence associated with small bowel-involved PI and poor
prognostic factors for PI, there are several limitations. First, The study participants may not
represent the target population since the current study enrolled a relatively small number of
participants (32% of response rate) and included only 15.6% cases of complications and 4.6%
cases of surgery. Second, the laboratory and image findings that potentially affect the risks of
PI were not collected and analyzed. Third, several study results were not consistent with the
previous reports. However, the authors did not suggest evidence supporting this.
Specific comments
Introduction
The background and clinical importance of this study are not suggested concisely.  There are
only lists of related factors of complications and mortality.
Method
1. Line 135-137: The author mentioned that adynamic ileus was regarded as a complication
by definition. However, adynamic ileus is not on the list of complications in Table 1 (Survey
parameters).  The diagnostic methods and definition of complications were unclear. Even though
it was a survey study, the definition of some medical conditions is required.
1) Did bowel obstruction mean adynamic ileus?
2) What was the definition of massive GI bleeding?
2. Line 159-160: Provide more information on the multivariate analysis. Which variables
were used for multivariate analysis to access the risk factors of small bowel involved type,
complicating PI, treatment, outcomes of PI, and death other than categorical items with P-values
less than 0.10 in the univariate analysis?
Result:
3. Line 164-168: It would be more informative to provide data about the level of health care
which patients recruited. Report the proportion of primary, secondary, or tertiary centers in this
study.
4. Consider providing Table 1 as a supplementary table.
5. There is too much information not directly associated with PI and not categorized in Table
2 and Table 3. It reduces readability.
6. Total number of PI with 'right-sided colon only' was 84 in table 3. However, It is 83 in
supplementary table 2. Furthermore, the data about 'left-sided colon only' is different between
table 3 and suppl Table 2. Correct this error.
7. Line 181-189: In supplementary table 2, symptoms were presented most of the patients with
complications (96.2%), and the crude OR was high (23.96, P<0.0001).
1) Although statistically significant, the symptoms are not mentioned in the manuscript. Please
describe this.
2) Are the symptoms included in the multivariate analysis?
3) Consider including the symptoms in the complicating PI in Table 4.
8. Line 185: It is challenging to consist causal inferences in this type of study.
9. Line 191-200: Could you describe the result of each treatment, such as success rate,
exacerbation, or death if possible.
Discussion:
10. Line 239-240: The effect size for the risk of complicating PI in patients taking allopurinol/
benzbromarone is quite high. What is the postulated mechanism or evidence for this?
11. Line 241-247: Provide more postulated evidence supporting CKD as a risk factor for small
bowel PI or PI if possible.
12. Line 256: Please, clearly define the "positive intraoperative findings."
13.  Line 257: Correct the lactic academia to lactic acidemia
14. What is postulated reasons that small bowel-involved PI is associated with complications.
15. Importantly, what is the strength of this study compared to other previous studies.
Conclusion
16. Line: 277-278: Although small-bowel involved type is associated with the risk of
complication, there was no evidence supporting a direct causal relationship between the small
bowel involved type and poor prognoses in the current study.
Please review this paper.
user
Title: Multicenter epidemiological survey of pneumatosis intestinalis in Japan
Version: 1 Date: 24 Nov 2021
Reviewer's report:
Major comments
The clinical manifestation of pneumatosis intestinalis (PI) ranges from asymptomatic to a life-
threatening condition. Thus, defining the poor prognostic factors is essential to managing this
condition. In the current study, the authors demonstrated that a small bowel-involved type of PI
is associated with complications; moreover, mortality in patients accompanied by complications
was higher than those without it.
Although the current study provides evidence associated with small bowel-involved PI and poor
prognostic factors for PI, there are several limitations. First, The study participants may not
represent the target population since the current study enrolled a relatively small number of
participants (32% of response rate) and included only 15.6% cases of complications and 4.6%
cases of surgery. Second, the laboratory and image findings that potentially affect the risks of
PI were not collected and analyzed. Third, several study results were not consistent with the
previous reports. However, the authors did not suggest evidence supporting this.
Specific comments
Introduction
The background and clinical importance of this study are not suggested concisely.  There are
only lists of related factors of complications and mortality.
Method
1. Line 135-137: The author mentioned that adynamic ileus was regarded as a complication
by definition. However, adynamic ileus is not on the list of complications in Table 1 (Survey
parameters).  The diagnostic methods and definition of complications were unclear. Even though
it was a survey study, the definition of some medical conditions is required.
1) Did bowel obstruction mean adynamic ileus?
2) What was the definition of massive GI bleeding?
2. Line 159-160: Provide more information on the multivariate analysis. Which variables
were used for multivariate analysis to access the risk factors of small bowel involved type,
complicating PI, treatment, outcomes of PI, and death other than categorical items with P-values
less than 0.10 in the univariate analysis?
Result:
3. Line 164-168: It would be more informative to provide data about the level of health care
which patients recruited. Report the proportion of primary, secondary, or tertiary centers in this
study.
4. Consider providing Table 1 as a supplementary table.
5. There is too much information not directly associated with PI and not categorized in Table
2 and Table 3. It reduces readability.
6. Total number of PI with 'right-sided colon only' was 84 in table 3. However, It is 83 in
supplementary table 2. Furthermore, the data about 'left-sided colon only' is different between
table 3 and suppl Table 2. Correct this error.
7. Line 181-189: In supplementary table 2, symptoms were presented most of the patients with
complications (96.2%), and the crude OR was high (23.96, P<0.0001).
1) Although statistically significant, the symptoms are not mentioned in the manuscript. Please
describe this.
2) Are the symptoms included in the multivariate analysis?
3) Consider including the symptoms in the complicating PI in Table 4.
8. Line 185: It is challenging to consist causal inferences in this type of study.
9. Line 191-200: Could you describe the result of each treatment, such as success rate,
exacerbation, or death if possible.
Discussion:
10. Line 239-240: The effect size for the risk of complicating PI in patients taking allopurinol/
benzbromarone is quite high. What is the postulated mechanism or evidence for this?
11. Line 241-247: Provide more postulated evidence supporting CKD as a risk factor for small
bowel PI or PI if possible.
12. Line 256: Please, clearly define the "positive intraoperative findings."
13.  Line 257: Correct the lactic academia to lactic acidemia
14. What is postulated reasons that small bowel-involved PI is associated with complications.
15. Importantly, what is the strength of this study compared to other previous studies.
Conclusion
16. Line: 277-278: Although small-bowel involved type is associated with the risk of
complication, there was no evidence supporting a direct causal relationship between the small
bowel involved type and poor prognoses in the current study.
assistant