Serum Level of Ceruloplasmin, Angiotensin-Converting Enzyme and Transferrin as Markers of Severity in SARS-CoV-2 Infection in Patients with Type 2 Diabetes

Round 1

Reviewer 1 Report

The manuscript by Restea et al tried to introduce a new finding on the maker of SARS-CoV-2 severity. My major concerns are as follows:

1. It seems that the several essential study groups were missing in the present study, including SARS-CoV-2 group, and T2DM group. Without these groups, we could not determine to what extent the major findings of the present study were affected by the status of T2DM.

2. How was the sample size determined?

3. Age distributions of the T2DM & SARS-CoV-2 group and the healthy control group were significantly differed. Could this difference contribute to the differential profiling of IL-6, serum iron, ACE, ceruloplasmin, or transferrin?

4. The R2 value in the fitting curves from Figure 1 to Figure 4 are too small to support the relationship between COVID-19 severity and the other parameters.

5. The authors should provide the genotyping results of the enrolled SARS-CoV-2, which could essentially contribute to COVID-19 severity.

6. For population-based analysis, the adjusted p value should be applied for adjusting of the possile interfering factors.

A native English speaker should be employed to improve the language quality.

Author Response

Our response is attached.

Author Response File: Author Response.docx

Reviewer 2 Report

This is an interesting study evaluating three serum markers- ceruloplasmin, transferin and ACE- as potential markers of SARS-CoV-2 disease severity. However, there are several points to be addressed:

(a) The authors use as a control group healthy subjects whereas the disease group include patients with type 2 diabetes melitus infected with COVID-19. The design of the study in that way is problematic since the control group should be diabetic type 2 patients not infected with SARS-CoV-2. How the authors can exclude the possibility that T2D increase the levels of ceruloplasmin and other acute phase proteins? (for reference see: https://pubmed.ncbi.nlm.nih.gov/34222081/).

(b) The authors should compare their results also with other classic serum indicators for COVID-19 infection such as ferritin, d-dimers, troponin levels. 

(c) How is COVID-19 severity is defined? Please mention this definition in the material and methods section. 

English are fine.

Author Response

Our response is attached.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Most of my concerns have not been fitted.

1. I cannot accepted the explanations provided by the authors for the missing group of the present study. There are too much differences between SARS-CoV-2/T2DM and the healthy control. And most of the analysis in the present study are limited to association analysis. Thus, detatil grouping is essential to interpret the results.

2. The authors did not answer how the sample size was determined, but provide an answer to the include/exclude criteria.

3. The authors did not make it clear if the significant age distribution between the study group and the control group could make a difference to the observed results.

4. It seems the reply is reasonable. Please make a clear presentation on this topic to avoid mis-interpretation.

5.  I cannot agree with the authors reply that "Our research area does not include viral genotype analysis". Because the genotypes of the virus is an essential factors influencing the results of the present study.

6. I do not think the authors have answered my question. 

The language of the manuscript should be improved.

 

Author Response

Our response is attached.

Author Response File: Author Response.pdf

Reviewer 2 Report

All my comments have been succesfully addressed. 

I have no comments 

Author Response

Our response is attached.

Author Response File: Author Response.pdf