Diabetic Ketoacidosis Was Associated with High Morbidity and Mortality in Hospitalized Patients with COVID-19 in the NYC Public Health System
, Natalia Chamorro-Pareja 1,2, Amrin Kharawala 1,2, Kenneth H Hupart 1,3,4, Joan Curcio 1,5,6, Christina Coyle 1,2, Daniel Buchnea 1,7, Dimitris Karamanis 8, Robert Faillace 1,2, Leonidas Palaiodimos 1,2 and Preeti Kishore 1,2,*
Round 1
Reviewer 1 Report
Diabetic Ketoacidosis was associated with High Morbidity and Mortality in hospitalized patients with COVID-19 in the NYC public health system
Dear Authors,
Congratulations on writing such an interesting study. This manuscript aims to reveal the impact of DKA on the in-hospital outcomes of patients with COVID-19 of different sexes, age groups, and racial/ethnic backgrounds.
The following are my comments and suggestions:
Abstract and Introduction:
1. My most of comments are on the presentation of information. The manuscript needs to be edited for pictorial presentation. For example, kindly provide the diagrams for about study flow and condition establishment and how results were drawn.
2. DKA relationship with type 2 and type 1 diabetes. What’s the distinct feature in diabetes 2 and 1 in respect to DKA involvement?
3. Kindly provide what happens with DKA in in case of prolong Covid-19 infection in brief?
4. What will happen in case of hyperosmolar hyperglycemic state? Any changes induced by hyperosmolar hyperglycemic state?
Methods:
1. Kindly describe the pathological characteristic of control group in the detail.
2. What was the concentration of serum ketone bodies in control and in other groups? Ketone bodies will be present in serum because of extensive exercise or starvation.?
3. Statistical analysis - did author find any correlation among all pathological parameters? Interesting observation?
Results:
1. All tables are presented very well. Consistency, punctuation, and font size as well. However, the p-value should be written in italic format. In the table description, kindly mention the statical analysis applied and p-value considered significance. .
2. More preciously, few and the most important results can be presented in scatter bar graph form and the significant p-values should be highlighted in the graphs so that readers can understand the outcomes of data analysis easily and proficiently. Instead of using the numbers in the tables, please put few graphs and diagrams to make manuscript more enjoyable to read.
3. Table 7 – what does it mean of **/* in the table? Please explain it in the table description.
Discussion:
It will be great to read about the role of IFN-gamma in the death of a beta-cell in the presence of SARS-CoV-2. Kindly provide brief details about action of mechanism of IFN-gamma in case of SARS-CoV-2 infection in Diabetic patients. Kindly explain the case of vaccinated diabetic patient who get infected with Covid-19 and developed DKA. Any interesting observations that author noticed?
Comments for author File: 
Comments.pdf
Author Response
Response to Reviewers’ comments
Dear Editor,
We would like to thank you for the opportunity you gave us to improve our manuscript through this robust review process. In addition, we are grateful to our Reviewers for their constructive and thoughtful feedback. We have addressed the comments to the best of our ability and responded in a point-wise manner below.
Reviewer #1:
Congratulations on writing such an interesting study. This manuscript aims to reveal the impact of DKA on the in-hospital outcomes of patients with COVID-19 of different sexes, age groups, and racial/ethnic backgrounds.
Response: We would like to thank our Reviewer for this kind comment.
Abstract and Introduction:
- My most of comments are on the presentation of information. The manuscript needs to be edited for pictorial presentation. For example, kindly provide the diagrams for about study flow and condition establishment and how results were drawn.
Response: We would like to thank our Reviewer for this constructive comment and do realize that a pictorial presentation could be very helpful for the reader. A flowchart of the analysis was added in the revised manuscript as Figure 1.
- DKA relationship with type 2 and type 1 diabetes. What’s the distinct feature in diabetes 2 and 1 in respect to DKA involvement?
Response: We would like to thank our Reviewer for this excellent feedback. We have included these features in the introduction.
- Kindly provide what happens with DKA in in case of prolong Covid-19 infection in brief?
Response: Thanks for your suggestion. After a review we found did not find an association of DKA with long-COVID. We have added the following line to the discussion: “The effects of long-COVID on rates or mortality of DKA are unknown”.
- What will happen in case of hyperosmolar hyperglycemic state? Any changes induced by hyperosmolar hyperglycemic state?
Response: Our analysis only included patients that met criteria for DKA. Some case reports have described course of hyperosmolar hyperglycemic state with DKA. We have added this to the discussion.
Methods:
1. Kindly describe the pathological characteristic of control group in the detail.
Response: Baseline characteristics of the control group are presented in Table 1
What was the concentration of serum ketone bodies in control and in other groups? Ketone bodies will be present in serum because of extensive exercise or starvation.?
Response: Thank you for your comment. We agree that ketone bodies may be positive in cases of exercise or starvation. Ketone bodies would not be tested routinely in patients with diabetes admitted for other reasons unless ketosis was suspected. We were careful in assuring DKA patients in our data set met all criteria for DKA such as an elevated glucose. We believe this will minimize any errors associated with other types of ketosis in our data analysis.
Statistical analysis - did author find any correlation among all pathological parameters? Interesting observation?
Response: Thank you for this useful comment. We have added two tables of correlation matrices in the supplementary material and present the Cramér's V correlation indexes which is a measure of association between two nominal variables. The Table S1 refers to correlation indexes in the cohort of the matching (N=22,694), while Table S2 refers to correlation indexes in the subgroup of DKA patients (N=422). No special relationship was observed.
Results:
1. All tables are presented very well. Consistency, punctuation, and font size as well. However, the p-value should be written in italic format. In the table description, kindly mention the statical analysis applied and p-value considered significance. .
Response: Thanks for this helpful comment. We have modified manuscript as suggested.
2. More preciously, few and the most important results can be presented in scatter bar graph form and the significant p-values should be highlighted in the graphs so that readers can understand the outcomes of data analysis easily and proficiently. Instead of using the numbers in the tables, please put few graphs and diagrams to make manuscript more enjoyable to read.
Response: Thank you for the comment. In the revised manuscript extra graphs were added containing all the important information for the reader (number of patients and p-values). Now both tables of outcomes (Tables 3 and 4) are also presented in graphical form and a total number of 12 statistical comparisons are presented in Figures 2 & 3 helping the reader easily to understand the main outcomes of the study. As the comparisons are between nominal variables, we were not able to use scatter bar plots which are suitable for comparisons between nominal vs continuous variables.
In total, now, our revised manuscript along with the revised supplementary material contains 5 graphs, demonstrating the flow of our analysis, the significant outcomes along with statistical comparisons, and graphs concerning the quality of the matching technique used.
- Table 7 – what does it mean of **/* in the table? Please explain it in the table description.
Response: Thanks for your comment. We have added in the notes of tables 5,6, and 7 that stars in the regressions indicate significances at different levels ** p<0.01, * p<0.05. We hope that this will help the reader clearly understand the level of significant associations in the tables.
Discussion:
It will be great to read about the role of IFN-gamma in the death of a beta-cell in the presence of SARS-CoV-2. Kindly provide brief details about action of mechanism of IFN-gamma in case of SARS-CoV-2 infection in Diabetic patients. Kindly explain the case of vaccinated diabetic patient who get infected with Covid-19 and developed DKA. Any interesting observations that author noticed?
Response: We thank the reviewer for this excellent suggestion. We have added a sentence which explains the role of IFN-gamma in patients with COVID-19 and have also highlighted the cases of DKA post vaccination.
Author Response File: 
Author Response.docx
Reviewer 2 Report
This is observational retrospective cohort study aimed to explore the in-hospital outcomes of patients who presented with COVID-19 and diabetic ketoacidosis /DKA/. The authors conducted the propensity score-matched observational retrospective cohort study in hospitalized patients with COVID-19 in the public health care system of New York City from March 1st, 2020 to October 31st, 2020. The data was obtained from 11 acute care hospitals of the New York City Health + Hospitals (NYC H+H) system and included more than 83000 pts. The authors concluded that DKA was associated with significantly higher in-hospital mortality in hospitalized patients with COVID-19. There are some minor issues to be clarified.
1. Line 41: worse COVID-19 infection… please redefine this sentence..
2. Line 83….death, please define cause…. From renal reasons, cardiovascular death, all cause death ….
3. Table 1. Row Coexisting disorder is with no data, please correct
4. Line 270 ….please use term antihyperglycemic and not anti diabetes medication …
Author Response
Response to Reviewers’ comments
Dear Editor,
We would like to thank you for the opportunity you gave us to improve our manuscript through this robust review process. In addition, we are grateful to our Reviewers for their constructive and thoughtful feedback. We have addressed the comments to the best of our ability and responded in a point-wise manner below.
Reviewer #2
This is observational retrospective cohort study aimed to explore the in-hospital outcomes of patients who presented with COVID-19 and diabetic ketoacidosis /DKA/. The authors conducted the propensity score-matched observational retrospective cohort study in hospitalized patients with COVID-19 in the public health care system of New York City from March 1st, 2020 to October 31st, 2020. The data was obtained from 11 acute care hospitals of the New York City Health + Hospitals (NYC H+H) system and included more than 83000 pts. The authors concluded that DKA was associated with significantly higher in-hospital mortality in hospitalized patients with COVID-19. There are some minor issues to be clarified.
We thank the reviewer for the precise summary and their comments.
- Line 41: worse COVID-19 infection… please redefine this sentence..
Response: We thank the reviewer for this constructive comment. We have modified the wording of the sentence to make it more easily understandable.
- Line 83….death, please define cause…. From renal reasons, cardiovascular death, all cause death ….
Response: We thank the reviewer for this thoughtful comment. This is death from all causes. We have made this change in the manuscript.
- Table 1. Row Coexisting disorder is with no data, please correct
Response: We thank the reviewer for this comment. The field of ‘co-existing disorders’ is a sub-heading and the data is presented below it where the percentage of each of these comorbidities is listed out.
- Line 270 ….please use term antihyperglycemic and not anti diabetes medication …
Response: We thank the reviewer for this thoughtful comment. We have made the correction as suggested.
Author Response File: Author Response.docx
