Hyperlipidemia and Obesity’s Role in Immune Dysregulation Underlying the Severity of COVID-19 Infection

Round 1

Reviewer 1 Report

Dear Author,

The review was drafted very well with updated references. I have provided a few comments and suggestions to improve reviews understandability. Please look at the attached file for your correspondence. 

I would like to see if the author can present and give references to clinical studies where their hypothesis can be fit. So far, no clinical studies have mentioned where Vit-D and GSH were effective against COVID infection. All claim seems like indirect relation and no clear path to prevent Covid infection. 

 

Comments for author File: Comments.pdf

Author Response

Reviewer #1’s comments:

 

“I would like to see if the author can present and give references to clinical studies where their hypothesis can be fit. So far, no clinical studies have mentioned where Vit-D and GSH were effective against COVID infection. All claim seems like indirect relation and no clear path to prevent Covid infection.”

GSH and COVID-19 section: We have added the reasons in how GSH plays an important role in the availability of ACE2 receptor, and how high ferritin level, as found in obesity, can lead to increased probability of patient developing ARDS. We have also added a couple case reports and a clinical trial that demonstrate effectiveness of GSH in relieving respiratory symptoms in patients with SAR-CoV-2 infection. ( Lines 268-295)

Vitamin D and COVID-19 section: Added proposed mechanism of Vitamin D action as well as a clear statement that there is no potent clinical evidence that shows Vitamin D alone can effectively treat COVID-19. (Lines 235 - 258)

Author Response File: Author Response.docx

Reviewer 2 Report

The topic of this paper is that the inflammatory response in obese and dyslipidemic patients may aggravate the severity of COVID-19. Especially It is an important subject for this moment, and well reported for the endogenous mechanisms of inflammation. However, it would be better to make the point clearer and to make the structure of each subhead consistent with the whole topic. Below are the recommendations.

It would be better to show the search engines or the search terms at least, as a review paper.

This paper said that the virus alters the lipid profile. How? Lipid cells make it easier for the virus to enter, then obese people are more vulnerable to COVID-19? Or does the virus alter the lipid profile to allow the viral entry easier and to cause lipid cell accumulation?

As an adjuvant therapy, the use if vit. D or GSH may help the inflammatory response. However, those researches cannot support that using those supplements can help the immune response among the COVID-19 population. Readers may want the solid logic and reasons.

Author Response

Dear Reviewer,

We truly appreciate your comprehensive and thorough review of our paper. We have taken each comment to heart and to the best of our ability, made revisions to improve upon our original paper. We thank you for the feedback.

 

Reviewer #2’s comments:

“It would be better to show the search engines or the search terms at least, as a review paper.”

A methods section has been added after the introduction section (lines 61-72) denoting the search process and criteria.

“This paper said that the virus alters the lipid profile. How? Lipid cells make it easier for the virus to enter, then obese people are more vulnerable to COVID-19? Or does the virus alter the lipid profile to allow the viral entry easier and to cause lipid cell accumulation?”

(Lines 121-126 and 134-148): Included explanation of difference in COVID-19-infected individual’s lipid profile in comparison to uninfected individual’s lipid profile.

Whether SARS-CoV-2 causes lipid alterations requires further investigation. While unsure whether SARS-CoV-2 causes lipid alterations directly, SARS-CoV-2 can utilize pre-existing altered lipid profiles, from diseases like obesity, for its own survival, replication, and infectivity purposes. Thus, individuals with such comorbid conditions are more likely to develop severe pathogenesis of SARS-CoV-2 that may include the cytokine storm. This is because the virus exacerbates inflammatory processes which create environments of oxidative stress that target non-homeostatic lipids, causing surplus amounts of inflammatory cytokine release. This cytokine storm leads to end-organ damage, which is seen among SARS-CoV-2, so patients with altered lipid profiles show higher rates of infection, hospitalization and death when compared to healthy patients.

 

“As an adjuvant therapy, the use if vit. D or GSH may help the inflammatory response. However, those researches cannot support that using those supplements can help the immune response among the COVID-19 population. Readers may want the solid logic and reasons.”

GSH and COVID-19 section: We have added the reasons on how GSH plays an important role in the availability of ACE2 receptor, and how high ferritin level, as found in obesity, can lead to increased probability of patient developing ARDS. We have also added a couple case reports and a clinical trial that demonstrate effectiveness of GSH in relieving respiratory symptoms in patients with SAR-CoV-2 infection.( Lines 268-295)

Vitamin D and COVID-19 section: Added proposed mechanism of Vitamin D action as well as a clear statement that there is no potent clinical evidence that shows Vitamin D alone can effectively treat COVID-19. (Lines 235 - 258)

 

Other modifications:

(Lines 89-95): Included explanation of increased COVID-19 infectivity

(lines 50-51): Included evidence of obesity as a risk factor for COVID-19

(Line 37): Added the word “chronic” for clarification of inflammatory state of COVID

(Line 82, Figure 1 of lines 309-310, and Figure legend of lines 316-322 ): Included a figure to depict SARS-CoV-2 mechanism of entry into host cells

(Line 232): Included Vitamin D dose used

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Dear Authors,

It was my pleasure to read your review about Covid-19 and obesity. Indeed Obesity leads to the severity of Covid-19 infection.

I have given few comments, which will synchronise the flow of review writing as few paragraphs lack inter- connection during reading. 

You need to explain some keywords that appearing repeatedly. eg. cytokines storm. 

 

 

Comments for author File: Comments.pdf

Author Response

Dear Reviewer:

Thanks for the constructive feedback. We have revised our manuscript to incorporate all your recommendations. We look forward to publishing this work.

 

Reviewer #1 Comments

 

“Explain certain cancer examples.”

 

Obesity and SARS-CoV-2 Section: I have added examples of certain cancers, such as endometrial and esophageal adenocarcinomas, that have been indicated to be further progressed by obesity (Line 194)

 

 

“High fat diet-induced obesity and Mediterranean diet reverse obesity.”

 

Obesity and SARS-CoV-2 Section: The reviewer makes a valid argument that simply stating diet-induced obesity does not indicate which type of diet, as some diets are indicated to increase obesity, and others decrease it. For that reason, I have added a specific indication as to the type of diet that was intended of mention from the source (high-fat) (Line 199)

 

 

“Please explain endothelial dysfunction in brief.”

 

Obesity and SARS-CoV-2 Section: I have added a brief description of endothelial dysfunction, as it defines the imbalance between vasodilatory and vasoconstricting agents in the vascular endothelium (Lines 223-224)

 

“This two paragraphs are not looking well connected. Please merge them and explain about chronic inflammatory event progression.”

 

The two paragraphs were rearranged and chronic inflammatory event progression was further elaborated on. (lines 44-46 and 49-59)

 

“Does BMI play similar role as it increase severity of co-morbidity increase?”

 

Added the following sentence to address this question: “A clinical study of hospitalized patients with SARS-CoV-2 showed a significant association between patients with BMI >24 and disease exacerbation, pneumonia, and ICU admission [46].” (Lines 147-149)

 

“You need to explain some keywords that appearing repeatedly. eg. cytokines storm.”

 

Cytokine storm was elaborated under the subsection ‘Cholesterol’s role in COVID pathogenesis’ on lines 166-168

 

“How much HDL was lower in Covid-19 infected person compare to non-infected person?”

 

HDL concentrations included in COVID-19 patients and controls (lines 181-182)

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

Please provide the details of selection criteria. As a review paper, it requires the review procedure, such as flow diagram, the number of materials. You can find more information elsewhere. (http://www.prisma-statement.org/)

Author Response

Dear Reviewer:

Thanks for the constructive feedback. We have revised our manuscript to incorporate all your recommendations. We look forward to publishing this work.

 

Reviewer #2’s Comments:

 

“Please provide the details of selection criteria. As a review paper, it requires the review procedure, such as flow diagram, the number of materials. You can find more information elsewhere. (http://www.prisma-statement.org/)”

 

Included a flow chart in the figures section (line 315-316) and in-text reference to the figure (lines 76-77) to clarify selection process

Author Response File: Author Response.docx