Increased Kynurenine Indicates a Fatal Course of COVID-19

Abstract

(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods: We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised 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. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results: At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a 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 Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071–1.319) followed by age (1.041, 95% CI: 1.011–1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66–95%) and a specificity of 72% (95% CI: 65–82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions: 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.

Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19

“…Within the identified significantly different molecules in plasma (Figure 3A heatmap and Online Supplementary Table S2) tryptophan metabolites deserve consideration. As previously described (31), tryptophan metabolism is altered in COVID-19 plasma, resulting in decreased anthranilate and indole acetaldehyde and increased kynurenine in patients, which is associated with a higher mortality risk (31, 32) (Figure 3C). Compared to control conditions (CinC), plasma kynurenine significantly increases upon exposure of patient RBCs in control plasma (PinC).…”

Kynurenine pathway in Coronavirus disease (COVID‐19): Potential role in prognosis

“…While Mangge et al suggested KYN level as a potential marker in determining the fatality of COVID‐19 patients, fatality was not evaluated in our study. 27 Danlos et al, 28 on the contrary, suggested an inhibitory effect of KYN or anthranilic acid on IDO and TPO, having an immunosuppressive effect. Particularly, according to the results of correlation analysis in patient and total groups, KYN pathway metabolites (especially KYN:TRP ratio, PA, and QA) may be markers of the inflammatory response.…”

“…5 In this study, significant correlations were found between N:L ratio, procalcitonin, CRP, IL-6, and ferritin and some KYN pathway metabolites, especially in the total and COVID-19 patient groups, but no significant correlations were found in the healthy group ( determining the fatality of COVID-19 patients, fatality was not evaluated in our study. 27 Danlos et al, 28 on the contrary, suggested an inhibitory effect of KYN or anthranilic acid on IDO and TPO, having an immunosuppressive effect. Particularly, according to the results of correlation analysis in patient and total groups, KYN pathway metabolites (especially KYN:TRP ratio, PA, and QA) may be markers of the inflammatory response.…”

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

“…Nineteen full-text papers were eligible for the systematic review after 11 records were removed from the initial number of articles. Finally, the meta-analysis involved 14 articles as 5 papers were excluded for reasons listed in ESF, Table 3 (Blasco, Bessy et al 2020, Fraser, Slessarev et al 2020, Kimhofer, Lodge et al 2020, Robertson, Gostner et al 2020, Thomas, Stefanoni et al 2020, Ansone, Briviba et al 2021, D’Amora, Silva et al 2021, Herrera-Van Oostdam, Castaneda-Delgado et al 2021, Lawler, Gray et al 2021, Lionetto, Ulivieri et al 2021, Mangge, Herrmann et al 2021, Marin-Corral, Rodriguez-Morato et al 2021, Michaelis, Zelzer et al 2021, Xiao, Nie et al 2021).…”