OBJECTIVES: Currently, no biomarker or scoring system could clearly identify patients at risk of progression to a severe coronavirus disease (COVID)-19. Even in patients with known risk factors, the fulminant course cannot be predicted with certainty. Analysis of commonly determined clinical parameters (frailty score, age, or body mass index) together with routine biomarkers of host response (C-reactive protein and viral nucleocapsid protein) in combination with new biomarkers neopterin, kynurenine, and tryptophan, could aid in predicting the patient outcome. METHODS: In 2021 and 2022, urine and serum samples were prospectively collected on 1st to 4th day after hospital admission in 108 consecutive COVID-19 patients hospitalized at the University Hospital Hradec Králové, Czech Republic. Delta and omicron virus variants were studied. Neopterin, kynurenine and tryptophan were determined by liquid chromatography. RESULTS: A significant correlation was observed between urinary and serum biomarker concentrations. Urinary and serum neopterin, kynurenine and kynurenine/tryptophan ratio were significantly (p≤0.05) higher in patients who subsequently needed oxygen therapy vs. patients without oxygen therapy. These parameters were also significantly increased in patients who died during the hospitalization compared to survivors. Complex equations have been derived using the investigated biomarkers and other clinical or laboratory parameters to predict the risk of subsequent oxygen therapy or death during hospitalization. CONCLUSIONS: Present data demonstrate that neopterin, kynurenine and kynurenine/tryptophan ratio in the serum or in the urine represent promising biomarkers in the management of COVID-19 that may help to guide important therapeutic decisions.

Deparment of Infectious Diseases University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Analytical Chemistry Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic

Department of Clinical Biochemistry and Diagnostics University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Oncology Faculty of Medicine and Dentistry Palacký University Olomouc Czech Republic

Pulmonary Department University Hospital in Hradec Králové Hradec Králové Czech Republic

Zobrazit více v PubMed

Hamming, I, Timens, W, Bulthuis, MLC, Lely, AT, Navis, GJ, van Goor, H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS phatogenesis. J Pathol 2004;203:631–7. https://doi.org/10.1002/path.1570 . DOI

Al-Kuraishy, HM, Al-Gareeb, AL, Alzahrani, KJ, Cruz-Martins, N, Batiha, GES. The potential role of neopterin in Covid-19: a new perspective. Mol Cell Biochem 2021;476:4161–6. https://doi.org/10.1007/s11010-021-04232-z . DOI

Henry, BM, Oliveira, MHS, Benoit, S, Plebani, M, Lippi, G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med 2020;58:1021–8. https://doi.org/10.1515/cclm-2020-0369 . DOI

Bonetti, G, Manelli, F, Patroni, A, Bettinardi, A, Borrelli, G, Fiordalisi, G, et al.. Laboratory predictors of death from coronavirus disease 2019 (COVID-19) in the area of Valcamonica, Italy. Clin Chem Lab Med 2020;58:1100–5. https://doi.org/10.1515/cclm-2020-0459 . DOI

Fuchs, D, Gisslen, M. Laboratory diagnostic value of neopterin measurements in patients with COVID-19 infection. Pteridines 2021;32:1–4. https://doi.org/10.1515/pteridines-2021-0001 . DOI

Zheng, B, Cao, KY, Chan, CPY, Choi, JWY, Leung, W, Leung, M, et al.. Serum neopterin for early assessmentof severity of severe acute respiratory syndrome. Clin Immunol 2005;116:18–26. https://doi.org/10.1016/j.clim.2005.03.009 . DOI

Rasmi, Y, Heidari, N, Kırboğa, KK, Hatamkhani, S, Tekin, B, Alipour, S, et al.. The importance of neopterin in COVID-19: the prognostic value and relation with the disease severity. Clin Biochem 2022;104:1–12. https://doi.org/10.1016/j.clinbiochem.2022.03.002 . DOI

Thomas, T, Stefanoni, D, Reisz, JA, Nemkov, T, Bertolone, L, Francis, RO, et al.. COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status. medRxiv 2020;05:20102491. https://doi.org/10.1101/2020.05.14.20102491 . DOI

Hailemichael, W, Kiros, M, Akelew, Y, Getu, S, Andualem, H. Neopterin: a promising candidate biomarker for severe COVID-19. J Inflamm Res 2021;14:245–51. https://doi.org/10.2147/jir.s290264 . DOI

Robertson, J, Gostner, JM, Nilsson, S, Andersson, LM, Fuchs, D, Gisslen, M. Serum neopterin levels in relation to mild and severe COVID-19. BMC Infect Dis 2020;20:942. https://doi.org/10.1186/s12879-020-05671-7 . DOI

Bellmann-Weiler, R, Lanser, L, Burkert, F, Seiwald, S, Fritsche, G, Wildner, S, et al.. Neopterin predicts disease severity in hospitalized patients with COVID-19. Open Forum Infect Dis 2020;8:ofaa521. https://doi.org/10.1093/ofid/ofaa521 . DOI

Ozger, HS, Dizbay, M, Corbacioglu, SK, Aysert, P, Demirbas, Z, Tunccan, OG, et al.. The prognostic role of neopterin in COVID‐19 patients. J Med Virol 2021;93:1520–5. https://doi.org/10.1002/jmv.26472 . DOI

Vernerova, A, Krcmova, LK, Heneberk, O, Radochova, R, Strouhal, O, Kasparovsky, A, et al.. Chromatographic method for the determination of inflammatory biomarkers and uric acid in human saliva. Talanta 2021;233:122598. https://doi.org/10.1016/j.talanta.2021.122598 . DOI

Melichar, B, Krcmova, L, Kalabova, H, Svobodova, I, Dragounova, E, Vesely, P, et al.. Urinary neopterin in patients with ovarian cancer. Pteridines 2006;17:145–53. https://doi.org/10.1515/pteridines.2006.17.4.145 . DOI

Krcmova, LK, Cervinkova, B, Solichova, D, Sobotka, L, Hansmanova, L, Melichar, B, et al.. Fast and sensitive HPLC method for the determination of neopterin, kynurenine and tryptophan in amniotic fluid, malignant effusions and wound exudates. Bioanalysis 2015;7:2751–62. https://doi.org/10.4155/bio.15.175 . DOI

Melichar, B, Spisarova, M, Bartouskova, M, Krcmova, LK, Javorska, L, Studentova, H. Neopterin as a biomarker of immune response in cancer patients. Ann Transl Med 2017;5:280. https://doi.org/10.21037/atm.2017.06.29 . DOI

Krcmova, L, Solichova, D, Melichar, B, Kasparova, M, Plisek, J, Sobotka, L, et al.. Determination of neopterin, kynurenine, tryptophan and creatinine in human serum by high throuput HPLC. Talanta 2011;85:1466–71. https://doi.org/10.1016/j.talanta.2011.06.027 . DOI

Cermanova, M, Melichar, B, Solichova, D, Blaha, M, Blaha, V, Blazek, M, et al.. Urinary neopterin and microalbuminuria in patients treated by low-density lipoprotein apheresis. Pteridines 2005;16:174–83. https://doi.org/10.1515/pteridines.2005.16.4.174 . DOI

Zhang, Y, Ong, CM, Yun, C, Mo, W, Whitman, JD, Lynch, KL, et al.. Diagnostic value of nucleocapsid protein in blood for SARS-CoV-2 infection. Clin Chem 2021;68:240–8. https://doi.org/10.1093/clinchem/hvab148 . DOI

Ahava, MJ, Kurkela, S, Kuivanen, S, Lappalainen, M, Jarva, H, Jääskeläinen, AJ. Detection of SARS-CoV-2 nucleocapsid antigen from serum can aid in timing of COVID-19 infection. J Virol Methods 2022;302:114469. https://doi.org/10.1016/j.jviromet.2022.114469 . DOI

Rottler, M, Ocskay, K, Sipos, Z, Görbe, A, Virág, M, Hegyi, P, et al.. Clinical Frailty Scale (CFS) indicated frailty is associated with increased in-hospital and 30-day mortality in COVID-19 patients: a systematic review and meta-analysis. Ann Intensive Care 2022;12:17. https://doi.org/10.1186/s13613-021-00977-4 . DOI

Rencher, AC. Methods of multivariate analysis , 2nd ed. New York: Interscience; 2002:361–6 pp.

Neopterin . Neopterin – English . http://www.neopterin.net/neopterin_e.pdf [Accessed 12 Apr 2023].

Oh, JS, Seo, HS, Kim, KH, Pyo, H, Chung, BC, Lee, J. Urinary profiling of tryptophan and its related metabolites in patients with metabolic syndrome by liquid chromatography-electrospray ionization/mass spectrometry. Anal Bioanal Chem 2017;409:5501–12. https://doi.org/10.1007/s00216-017-0486-4 . DOI

Sousa, A, Ribeiro, C, Gonçalves, VMF, Barbosa, J, Peixoto, B, Andrade, A, et al.. Development and validation of a liquid chromatography method using UV/fluorescence detection for the quantitative determination of metabolites of the kynurenine pathway in human urine: application to patients with heart failure. J Pharm Biomed Anal 2021;198:113997. https://doi.org/10.1016/j.jpba.2021.113997 . DOI

Sakurai, M, Yamamoto, Y, Kanayama, N, Hasegawa, M, Mouri, A, Takemura, M, et al.. Serum metabolic profiles of the tryptophan-kynurenine pathway in the high risk subjects of major depressive disorder. Sci Rep 2020;10:1–13. https://doi.org/10.1038/s41598-020-58806-w . DOI

Lippi, G, Plebani, M. The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. Clin Chem Lab Med 2020;58:1063–9. https://doi.org/10.1515/cclm-2020-0240 . DOI

Geisler, S, Lytton, SD, LinhToan, N, HuuNghia, T, MinhNam, N, VuHung, H, et al.. Neopterin levels and Kyn/Trp ratios were significantly increased in dengue virus patients and subsequently decreased after recovery. Int J Infect Dis 2020;91:162–8. https://doi.org/10.1016/j.ijid.2019.12.005 . DOI

Lippi, G, Henry, BM, Plebani, M. Optimizing effectiveness of COVID-19 vaccination: will laboratory stewartship play a rol? Clin Chem Lab Med 2021;59:1885–8. https://doi.org/10.1515/cclm-2021-0972 . DOI

Pizzini, A, Kurz, K, Santifaller, J, Tschurtschenthaler, C, Theurl, I, Fuchs, D, et al.. Assessment of neopterin and indoleamine 2,3‐dioxygenase activity in patients with seasonal influenza: a pilot study. Influenza Other Respir Viruses . 2019;13:603–9, https://doi.org/10.1111/irv.12677 . DOI

Eisenhut, M. Neopterin in diagnosis and monitoring of infectious diseases. J. Biomark 2013:1–10. https://doi.org/10.1155/2013/196432 . DOI

Urinary kynurenine,tryptophan, and neopterin concentrations during physiological pregnancy