The Impact of Serum Albumin Levels on COVID-19 Mortality

Round 1

Reviewer 1 Report

The work by Bella et. al., correlates  human serum albumin (HSA) content/concentration with COVID-19 patatin's mortality. They try to pinpoint the role of HSA in COVID-19  pneumonia patients. Nowadays the COVID-19 virus is our strongest enemy. Thus I recommend that the article can be published after a major revision. 1. The overall articleis very scattered. Sometimes it totally deviates from the main topics. 2. Please rewrite the 'Discussion' part. 3. That would be great if you are able to propose a plausible mechanism  that correlates HSA and COVID-19 relationship. 4. The article becomes more attractive if you are able to propose a diagram that brings all of your concepts in a single figure. 5. Some important references are missing. Please rewrite the portion. -Thank you.

Author Response

We thank the reviewer for her/his comment. We have arranged the Discussion, adding other relevant references and reinforcing the section in which pathophysiological considerations are present. We realized a graphical abstract which brings all the concepts in a single figure.

Author Response File: Author Response.docx

Reviewer 2 Report

The aim of the study was to identify, through a cohort prospective observational study, SA thresholds to predict the need for invasive mechanical ventilation (IMV), the risk of longer hospital stay, and the risk of death in hospitalized adult patients with COVID- 72 19 pneumonia.

The study has a high quality of presentation but it hasn't  novelty.

Author Response

We agree with the reviewer. We declared at the beginning of the Discussion that our work confirms previous literature data. However, we think that our work supports some interesting novelties. After premising that a universal cut off for hypoalbuminemia is lacking, our work was aimed at identifying specific serum albumin thresholds for both the risk of severe respiratory failure (3.17 g/dL) and 90-day mortality (3.23 g/dL) with very high negative predictive values (96% and 90%, respectively). Moreover, these thresholds appeared as independent risk factors for the risk of invasive mechanical ventilation and 90-day mortality, respectively, in multivariate Cox regression analysis. We think that these findings are substantially novel and could help clinicians to better identify -since hospital admission- COVID-19 patients at higher risk for poor outcomes.

Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript by Zerbato et al., was a relatively comprehensive research article on the potential roles of serum proteins in the injury response and recovery in the patients with COVID-19 disease. The authors seemed to focus on albumin and tested the hypoalbuminemia. Overall scope was not innovative as research on albumin as a prognosis for critically ill patients had been already known regarding the pathophysiology similar. There were also some moderate concerns:

• The antibody level and immune responses were unknown in the study.
• Missing follow-updetails in Materials and Methods 
• The logistic regression analysis seemed not to includeall factors (such as for Table 2) and the multiple linear regression not to include all factors (such as for Table 3).
• Other suggestion to use data analysis violin plotsin Figure 1.

Author Response

• The antibody level and immune responses were unknown in the study.

We thank the reviewer for her/his comment. Unfortunately we were not able to assess antibody levels in our cohort. Our Laboratory started doing routine serologic tests only in June 2020, when our study was already approved and started.

• Missing follow-up details in Materials and Methods

Follow up details were reported in the Study outcomes section. Now further details about follow up have been added.

• The logistic regression analysis seemed not to include all factors (such as for Table 2) and the multiple linear regression not to include all factors (such as for Table 3).

We are not sure to have perfectly understood the reviewer’s remark. As stated in the Data analysis section, in the multivariable models albumin was controlled for patient’s age, sex and relevant comorbid conditions (i.e., obesity, diabetes, hypertension, heart disease, metastatic cancer). Consistently with the adopted forward stepwise selection method, only covariates showing a statistically significant association with the respective dependent variable in the final model were reported in the table, while the variables excluded from the final model were reported in the tables’ footnotes.

• Other suggestion to use data analysis violin plots in Figure 1.”

Unfortunately, the adopted statistics software does not support this feature.

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

The manuscript by Zerbato et al., was a relatively comprehensive research article on the potential roles of high-flow nasal cannula and related oxygen therapy in the treatment of COVID-19 disease. The authors tested the potential mechanisms of blood biochemistry and focused on the long-term outcome of the diseases among the patients. The article was given careful revision. However, there were still some concerns:

• More high-flow nasal cannula study papers should be cited.
• Previous concerns addressed but not included in revised manuscript.
• Table 3 and related data can be compared with published non-COVID results for high-flow nasal cannula (DOI: 10.3389/fnhum.2021.801918).

Author Response

Dear reviewer, thank you for your comment. We respectfully disagree since, in our opinion, a comparison with high-flow nasal cannula results in non COVID-19 patients, will not add quality to the manuscript. We would prefer to leave the manuscript as it is. Thank you in advance for your patience.