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

BACKGROUND: Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP. METHODS: This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls. RESULTS: The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = - 1.002, 95%CI: - 1.738; - 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = - 0.909, 95% CI: - 1.569; - 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls. CONCLUSIONS: Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.