https://doi.org/10.1007/s00392-025-02625-4
1Uniklinik RWTH Aachen Med. Klinik I - Kardiologie, Angiologie und Internistische Intensivmedizin Aachen, Deutschland; 2Uniklinik RWTH Aachen Med. Klinik V - Klinik für Pneumologie und Internistische Intensivmedizin Aachen, Deutschland; 3UZ Leuven Department of Nephrology Leuven, Belgien; 4Uniklinik RWTH Aachen Med. Klinik III - Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin Aachen, Deutschland; 5Uniklinik RWTH Aachen RWTH cBMB am Institut für Pathologie Aachen, Deutschland
Introduction:
Tryptophan (Trp) metabolism plays a crucial role in the regulation of immune responses and inflammation. The kynurenine pathway, a major route of Trp catabolism, is involved in inflammatory conditions. SARS-CoV-2 exploits ACE2 for cellular entry, a protein essential for intestinal Trp uptake. This study investigated Trp metabolism in COVID-19 compared to other pulmonary infections.
Methods:
A targeted serum analysis of Trp metabolites by HPLC was performed in COVID-19 patients (n=116; ARDS=45, Non-ARDS n=71), patients with pulmonary infection but with exclusion of COVID-19 (n=67, ARDS n=25, Non-ARDS n=42), uninfected individuals (n=114) and in an independent heart failure (HF) cohort with no current infection (n=108). Patients were matched for age, sex and eGFR. Echocardiographic examinations were performed in 32 patients of the COVID-19 cohort and in the HF cohort.
Results:
We found tryptophan metabolism to be significantly altered in patients with SARS-CoV2 infection compared to uninfected individuals especially in patients with ARDS (p=<0.0001, Figure 1a). Compared to matched patients with non-COVID-19 pulmonary infection, no differences in kynurenine levels were neither present in ARDS patients (p=0.47) nor in patients without ARDS (p>0.99; Figure 1b). Therefore, kynurenine exaggeration by pulmonary infection seems to be independent of SARS-CoV2. We next evaluated kynurenine as a potential biomarker for mortality and disease severity in COVID-19. Within 60 days deceased patients had higher levels of kynurenine at baseline compared to survivors. Kaplan Meier curve revealed the highest mortality in individuals with the upper kynurenine tertile (p=0.002, figure 1c). In multiple logistic regression, kynurenine remained an independent predictor for mortality after correction for age, sex, BMI, eGFR and SOFA Score (p=<0.001, Figure 1d). In addition, kynurenine correlated with markers of disease severity e.g. hospitalization days, intensive care days, oxygen days (all p<0.05).
To unveil underlying mechanisms, we investigated the relationship between kynurenine and organ failure markers. We found a significant correlation between kynurenine and cardiac biomarker NT-proBNP (r=0.38, p<0.0001) in COVID-19. Echocardiographic investigations in these patients confirmed an association between elevated kynurenine and cardiac dysfunction (left ventricular ejection fraction (LV-EF): r=-0.48, p=0.02; global longitudinal strain (GLS): r=0.55, p=0.02, Figure 1e). To evaluate the impact of kynurenine on cardiac function in absence of inflammation, we analyzed Trp metabolism in an independent HF cohort. Here, we also discovered significant correlations between kynurenine and NT-proBNP, LV-EF and GLS (Figure 1f).
Conclusion:
Trp metabolite kynurenine is elevated in pulmonary infection and could serve as biomarker for disease severity and mortality. The association between kynurenine and cardiac dysfunction markers provides insights into underlying mechanisms that may also be relevant in uninfected individuals, particularly in HF.
Figure 1: a: Trp metabolism in COVID-19, b: in patients matched for age, sex, eGFR. c: Kaplan-Meier-Curve comparing kynurenine tertiles. d: Multiple logistic regression for mortality. e: Correlation of kynurenine to NT-proBNP and echocardiographic parameters in COVID-19 patients; f: and in a HF cohort. *p=<0.05, **p=<0.01, ***p=<0.001, ***p=<0.0001.