Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics

Abstract

Introduction: In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples.

Material and methods: The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels.

Results: Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range.

Conclusion: Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.

Keywords: COVID-19 monitoring; Long-COVID biomarkers; inflammation diagnostics; innate immunity; kynurenine reference values.

Figure 1

Overview of the different study populations and the respective experimental biomarkers. Group NC (normal controls) consisted of healthy blood donors (30, 31) where kynurenine concentrations were measured and taken as reference values for the Sars-CoV-2 infected individuals (Group A and Group B). ICU = Intensive Care Unit; CRP = C-Reactive Protein; IL-6 = Interleukin 6.

Figure 2

Kynurenine in normal controls (n=302) vs. COVID-19 patients in the early acute clinical state (n=85). The difference was significant (p< 0.001). We left out two results (58 and 43 µM) with an extreme hyperinflammatory syndrome in the COVID-19 positive group A.

Figure 3

Comparison of kynurenine values between normal controls (n=302) and previously positive COVID-19 patients (Group B, n=66) with an existing Long-COVID syndrome (p<0.001). Patients with the LCS were currently under therapeutic management.

Figure 4

Measurement of Kynurenine in serum and in saliva in normal controls (n=302) and in patients with COVID-19 infection (Group B, n=11). Serum and saliva values in the previously COVID-19 positive patients were significantly higher compared to normal controls (p<0.001).

Figure 5

(A) Follow up of C–Reactive Protein and Kynurenine–measurement in patients either cured (n=11) or with a Long-COVID-syndrome (n=11) from a subset of Group B CRP was in a normal range after month 2 post infection (verified by a positive PCR-Test). (B) Kynurenine was still significantly increased.

Figure 6

Kynurenine (Serum) in the 3rd month after positive PCR-testing: either cured or with a Long-COVID syndrome for 3 months or Post-COVID syndrome more than 5 months in a subset of Group B Kynurenine is still significantly increased, whereas the values of the cured patients are in a normal range.