Cytokine Dynamics in Severe COVID-19 vs. Influenza A Elderly Patients: A Prospective Comparative Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript refers to the analysis of cytokines in patients with COVID versus influenza A. Even tough the cohort is very small, the rationale of the article is adequate. The methodology used is standard as well as the statistical analysis. The Tables are informativve althoguh the discussion should focus on different aspects of cytokine response and possible importance of combiened infections in severe patients. Also, a more detailed analysis of MCP-1 alues should be carried out in comparison to IL-6 and vascular events. The limitations of the study should be included at the end of the text 

Author Response

Please see the attachment. Thank you!

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The research question is timely, the study design is appropriate, and the findings contribute to understanding immunopathological differences in this vulnerable population. The description of statistical significance in Section 2.3 is confusing. The text states that only IL-6 was significantly different at Day 1, but Table 4 seems to imply otherwise. Please clarify the statistical testing used (e.g., Mann-Whitney U test between groups at each time point) and report exact p-values consistently.

In Section 2.4, the rationale for using ROC-derived thresholds solely for dichotomization in regression models, despite their modest AUCs, should be briefly justified in the Methods or Results section.

The introduction adequately covers general concepts but could be more focused. Please sharpen the rationale by explicitly stating the knowledge gap this study addresses: the lack of paired, longitudinal cytokine data comparing Omicron-era COVID-19 to FluA specifically in the elderly population, and the prognostic value of such dynamics.

Reference the known attenuated severity of Omicron compared to earlier variants earlier in the introduction to better frame the study's context.

The discussion on MCP-1 is interesting but speculative. While the immunosenescence hypothesis is plausible, consider toning down the certainty. Phrases like "we argue that the explanation resides in..." could be softened to "we hypothesize that this may be explained by...".

The paragraph comparing NIV frequency between groups (Page 9) is excellent. Consider integrating the point about parenchymal vs. systemic injury more explicitly into the overall interpretation of the cytokine data

Section 4.1: Clarify if all patients were tested with all listed diagnostic assays or if this is a list of potential tests used.

Section 4.3: Specify the lower limits of detection (LLOD) for each cytokine in the Luminex assay, as this is critical for interpreting the non-detection of IL-1β and IL-34.

Table 1: The p-value for "Hemiplegia" is 0.02, indicating a significant difference. This should be mentioned in the text.

Table 3: The title and content mention "complications," but only acute renal failure is discussed. Briefly mention the others or adjust the table title.

Author Response

Please see the attachment. Thank you!

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript was improved. I have no further comments

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed my comments and concerns. The revised manuscript is improved in clarity, rigor, and presentation. The study provides valuable comparative longitudinal cytokine data in a relevant elderly cohort during the Omicron era. I recommend accepting the manuscript for publication