Accelerated Tryptophan Degradation Predicts Poor Survival in Trauma and Sepsis Patients

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients

Interferon-alpha–induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment

Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-α therapy. Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-α treatment and continuing for the first 12 weeks of IFN-α therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-α treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-α therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients. The results suggest that reduced TRP availability plays a role in IFN-α–induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-α, attenuates the behavioral consequences of IFN-α–mediated TRP depletion

Early Increase of Plasma Homocysteine in Sepsis Patients with Poor Outcome

Moderate hyperhomocysteinemia is a well-established coronary risk factor that develops when dietary supply with folate and/or vitamin B12 is inadequate. Recently, stimulated peripheral blood mononuclear cells were shown to produce homocysteine. Thus, the stimulated immune system may contribute to moderate hyperhomocysteinemia during certain diseases. Because multiple trauma and sepsis are accompanied by often strong inflammatory responses, we investigated whether hyperhomocysteinemia may develop in patients. Total homocysteine and cysteine concentrations were measured in 83 plasma specimens from 18 patients (14 men, 4 women; 15 posttrauma with sepsis and 3 with sepsis alone) every third day of follow-up. Finally results were compared with concentrations of cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, the immune activation marker neopterin and the extent of tryptophan degradation as indicated by the kynurenine-to-tryptophan ratio (kyn/trp). Compared with baseline, average total homocysteine (P < 0.05, d 4–d 10) and cysteine (P < 0.05, d 7–d 13) concentrations increased during follow-up of patients. However, only the increase of homocysteine was related to the survival status: total homocysteine was significantly higher in nonsurvivors (P < 0.05, d 4 and d 10) than in survivors, whereas cysteine concentrations increased in both subgroups. Homocysteine correlated with kyn/trp but not with neopterin concentrations. Increase of total homocysteine is common in patients after trauma with unfavorable outcome. Because all patients received standardized enteral nutrition after the end of hypodynamic shock, inconsistent vitamin supply is unlikely to be the reason for hyperhomocysteinemia in some of the patients; rather, it is associated with a stronger proinflammatory response. Certainly, the number of patients in our study is still small and results can only be regarded as preliminary