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

Abstract

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.

Is SARS-CoV-2 a Risk Factor of Bipolar Disorder?—A Narrative Review

“…Slightly different results have been observed by Almulla et al (2022). Similar to other researchers, they noticed an increase in the KYN/TRP ratio but it was not accompanied by a significant increase in KYNA [ 178 ]. All the above-described changes are indicative of activation of the kynurenine pathway among COVID-19 patients and appear to shift towards Th1 mediated activation of microglial IDO.…”

“…These disorders are so specific that the level of TRP below 105 μM and KYN above 5.3 μM has 95% of AUC in the differentiating of the COVID (−) and COVID (+) groups [ 176 ]. Many studies have also shown increase in the KYN/TRP ratio and its positive correlation with the severity of COVID-19 [ 177 , 178 , 179 , 180 ]. Other metabolites of kynurenic acid which are elevated in SARS-CoV-2-infected patients include 3-HK, PA, AA and 3-HAA [ 177 , 179 , 180 ].…”

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways

“…Men have more severe acute respiratory syndrome and critical COVID-19 during acute COVID-19 infection, whereas women have more sickness symptoms and fatigue [ 20 ]. Such differences may be explained by the effects of different neuro-immune pathways, with males having a more activated NLRP3 inflammasome, which leads to severe acute respiratory syndrome [ 20 ], and females having increased cytokine-induced activation of indoleamine-2,3-dioxygenase, which is associated with acute COVID-19, depression, anxiety, and chronic fatigue [ 57 , 58 ].…”

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: A systematic review and meta-analysis

“…Nonetheless, our negative results concerning TRYCAT and IDO levels do not support the theory that activation of IDO/TDO is involved in MDD/BD ( Maes, 2015 ). While the TRYCAT pathway is activated during severe IRS responses, such as acute COVID-19 infection ( Almulla et al, 2022b ) and IFN-α therapy ( Bonaccorso et al, 2002 ), no such changes may be observed in conditions of mild chronic inflammation, such as MDD/BD (this study) and Alzheimer's disease ( Almulla et al, 2022a ). Since plasma/serum TRP concentrations are around 50 μmol/L while KYN concentrations are around 3 μmol/L, TRP is abundantly available as a substrate for KYN formation.…”

“…Quality paper controls consists of two scoring scales, namely the quality and redpoints scales, which are detailed in ESF, Table 2 . These rating scales were largely used ( Almulla et al, 2022a , 2022b , 2022c ) to evaluate the methodological quality of the publications that assessed the levels of TRYCATs in individuals with affective disorders. The score on the quality scale varied from 0 to 10, representing lower to better quality, and it focused largely on sample size, control of confounders, and sampling duration.…”