Review Reports

Round 1

Reviewer 1 Report

Review of the article

Increased kynurenine indicates a fatal course of COVID-19 2

Harald Mangge1*, Florian Prüller1, Markus Herrmann1, Andreas Meinitzer1, Sabine Pailer1, Pero Curcic1, Zdenka 3 Sloup1 and Magdalena Holter2

The present study seeks for biomarkers that indicate a fatal outcome of COVID-19 in the early phases of the infection when clinical symptoms are starting. The authors analyzed the levels of kynurenine (KYN), Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterward due to COVID-19, had significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Cox regression analysis, KYN had the highest hazard ratio (1.209, CI: 1.068-1.368) followed by age. KYN values above the cut-off limit of 4.82 nmol/l (as specified by the Youden index) had a sensitivity of 82% and a specificity of 72% to predict COVID-19 related death within 90 days of observation time. The authors conclude that kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons. The patients who recovered from COVID-19 had significantly lower plasma levels of KYN, CRP, IL-6, ferritin, NTproBNP, cTnT, and creatinine. This may explain also the worse clinical courses of COVID-19 seen in patients with cancer and cardiovascular diseases where KYN concentrations are already high before the infection with SARS-CoV-2.

The article is of high quality, written in nice and understandable English, didactically and scientifically at a high level. The obtained results are original, statistically well processed, and demonstrated in figures and tables. The article will have a high impact on readers and I recommend accepting it in the present form.  

Author Response

Dear Reviewer:

Great thanks for the fine feedback.

Harald

Reviewer 2 Report

This is a review of the initial submission of "Increased kynurenine indicates a fatal course of COVID-19" to the MDPI journal, Antioxidants.

This article reports quantification of several biomolecules from COVID-19 patients upon first hospital visit. Kynurenine levels were found to be correlated with mortality in SARS-CoV-2 infection. As such, kynurenine may be considered as a biomarker for serious cases.  This is a timely, convincing pilot study that employs proper statistical methods and would be of interest to the medical community. As such, it should be published after a minor revision to address the comments below.

Figures should use a sans serif font and may be easier to read if a thicker line width were used.

Line 40: TPO should be TDO.

Line 52: Most tryptophan degraded by the kynurenine pathway is fully oxidized to CO2 (10.1016/S0021-9258(17)45237-9), with NAD being a relatively minor side product.

Line 84 states that LC-MS/MS, however the methods describe LC-UV/Fluorometric detection.

Line 108: "250 mol/L" is likely meant to be "mmol/L"

Author Response

Figures should use a sans serif font and may be easier to read if a thicker line width were used.

Re.: Done.

Line 40: TPO should be TDO.

Re.: Corrected.

Line 52: Most tryptophan degraded by the kynurenine pathway is fully oxidized to CO2 (10.1016/S0021-9258(17)45237-9), with NAD being a relatively minor side product.

Re.: We add this text and cite this reference in the suggested context.

Line 84 states that LC-MS/MS, however the methods describe LC-UV/Fluorometric detection.

Re.: Thank for this important correction. This is stated accordingly in the manuscript.

Line 108: "250 mol/L" is likely meant to be "mmol/L"

Re.: Corrected.

 

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.