Neopterin and kynurenine in serum and urine as prognostic biomarkers in hospitalized patients with delta and omicron variant SARS-CoV-2 infection.

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.

Olfactory Performance in Post Mild-to-Moderate Acute Covid-19 across 2 Years

Background: Previous longitudinal studies (n=6) of objective olfaction performance post-acute COVID-19 have a maximum follow-up of 6-month and do not often test biomarkers. Although olfactory dysfunction appears to improve within two months of symptom onset, 4/6 longitudinal studies show persistent olfactory impairment. Method(s): PCR-confirmed COVID-19 patients in the prospective ADAPT cohort (Sydney, Australia) were assessed across 18 acute symptoms and hospitalization status: 40% mild, 50% moderate, 10% severe/hospitalised - none deceased). Blood samples were taken 2 (N=179), 4 (N=148) and 12-month (N=118) post-diagnosis. The NIH Odor Identification Test (OIT) and the Cogstate brief cognitive battery were performed. 58 also had an olfaction test at 24-month. The OIT raw data were transformed into demographically-corrected T-scores. OIT's attrition was completely random and only initial age (40+/-15 versus 47+/-15) differed between patients lost to follow-up and those in the study at 24-month. We tested peripheral neurobiomarkers (NFL, GFAP, S100B, GM-CSF) and immune markers (Interleukin-IL panel: 1-beta, 1Ralpha, 4, 5, 6, 8, 10, 12p40, 12p70, 13, and MCP-1, TNF-alpha and INF-gamma), analyzed as Log transformed and elevated/normal range using published references. Our previous analyses had shown no relationship with the kynurenine pathway, but an association of impaired olfaction and impaired cognition at 2-month only. Linear mixed effect regressions with time effect (months) tested olfaction trajectories (random subject effect) and their association with the biomarkers (main and time interaction). Result(s): At 2 months post-diagnosis 30% had impaired olfaction and those who had acute severe disease were more likely to be impaired (54% versus 26%, p=.009). 21%, 31% and 37% had impaired olfaction at 4, 12 and 24-months. Olfactory performance declined over time (p< .0001), which was dependent on the initial performance (Fig 1). Neurobiomarkers were within the normal range. IFN-gamma, IL-1Ralpha, IL-13 and TNF-alpha increased across time, p< .03-p< .0005. TNF-alpha and IFN-gamma showed a time covariance with poorer olfaction performance. Conclusion(s): Post-acute mild to moderate COVID-19 is associated with a declining olfactory performance up to 2-yr post-diagnosis, especially when initially impaired with the provisio of attrition although random. Olfactory performance decline may be mediated by upregulated immune parameters which are distinct from those driving cognitive changes. (Figure Presented).

7th Turkey in vitro Diagnostics (IVD) Symposium

The proceedings contain 75 papers. The topics discussed include: development of different product groups in the cleaning industry with synthesized nanosilver;investigation of the antimetastatic potential of thymbra spicata in human breast adenocarcinoma cells combined with standard chemotherapy;the effect of toll-interancing protein on inflammatory status of hepatocellular carcinoma cell line;surgery and inflammation: surgical inflammation;biochemistry of inflammation;its mediators and activities;pathophysiology of inflammation;classic and new biomarkers of inflammation;thymol reduces the lipopolysaccharide-induced acute kidney inflammation by modulating lysosomal stress;metabolic shift of the kynurenine pathway in inflammatory conditions;and evaluation of HBA1C level in patients with COVID-19.

Inflammation and severity of depressive symptoms in physically active individuals after COVID-19 - An exploratory immunopsychological study investigating the effect of inflammation on depressive symptom severity.

Background: SARS-CoV-2 infection is a risk factor for the development of depressive symptoms such as lack of energy, loss of interest, and depressed mood. Inflammatory processes might underline this association. The aim of this study was to investigate the association between inflammatory markers and the severity of depression after SARS-CoV-2 infection and the predictive effect of inflammatory markers on the severity of depressive symptoms. Lifestyle factors and lifestyle-related diseases can influence inflammation and depressive symptoms. As these lifestyle factors and lifestyle-related diseases are less common in physically active individuals, they are a suitable population for investigating this research question. Methods: We investigated 61 at least moderate physically active individuals on average ∼6 months (SD = 4.22, range = 0.5-19 months) after SARS-CoV-2 infection (t0) and performed a follow-up after 3 months (t1). Depressive symptoms and biomarkers of inflammation (interleukin [IL]-1ß, IL-8, IL-10, Ferritin, Lipopolysaccharide-binding-protein [LBP], neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR]) and kynurenine [KYN] were measured at both time points. Concentrations of inflammatory markers at t0 were used to predict the severity of depressive symptoms at t0 and t1. Results: Concentrations of KYN were negatively related to the severity of depressive symptoms at t0. Concentrations of LMR predicted higher depressive symptoms at t0 as well as at t1. Furthermore, individuals with lower concentrations of LBP at t0 showed a higher severity of depressive symptoms at t1. No correlation was found between severity of depressive symptoms and IL-1ß, IL-8, IL-10, ferritin, NLR, and PLR at both time points. Conclusions: KYN, LBP and LMR might be useful as a predictive factor of depressive symptoms in physically active individuals after SARS-CoV-2 infection. While the results for KYN confirm the current scientific evidence, our results highlight the importance of the innovative inflammatory markers LMR and LBP. LMR and LBP might be interesting targets for predicting the development of depressive symptoms in SARS-CoV-2 infected populations and should be further investigated in future studies.

Long COVID: Is there a kidney link?

Metabolic causes such as altered bioenergetics and amino acid metabolism may play a major role in Long COVID. Renal-metabolic regulation is an integral part of these pathways but has not been systematically or routinely investigated in Long COVID. Here we discuss the biochemistry of renal tubular injury as it may contribute to Long COVID symptoms. We propose three potential mechanisms that could be involved in Long COVID namely creatine phosphate metabolism, un-reclaimed glomerular filtrate and COVID specific proximal tubule cells (PTC) injury-a tryptophan paradigm. This approach is intended to allow for improved diagnostics and therapy for the long-haul sufferers.

Alterations in the Kynurenine-Tryptophan Pathway and Lipid Dysregulation Are Preserved Features of COVID-19 in Hemodialysis.

Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in end-stage kidney disease (CKD G5), we analyzed the plasma metabolites in different COVID-19 stages in patients with or without HD. We recruited 18 and 9 asymptomatic and mild, 11 and 11 moderate, 2 and 13 severely affected, and 10 and 6 uninfected HD and non-HD patients, respectively. Plasma samples were taken at the time of diagnosis and/or upon admission to the hospital and analyzed by targeted metabolomics and cytokine/chemokine profiling. Targeted metabolomics confirmed stage-dependent alterations of the metabolome in non-HD patients with COVID-19, which were less pronounced in HD patients. Elevated kynurenine levels and lipid dysregulation, shown by an increase in circulating free fatty acids and a decrease in lysophospholipids, could distinguish patients with moderate COVID-19 from non-infected individuals in both groups. Kynurenine and lipid alterations were also associated with ICAM-1 and IL-15 levels in HD and non-HD patients. Our findings support the kynurenine pathway and plasma lipids as universal biomarkers of moderate and severe COVID-19 independent of kidney function.

Alteration of the kynurenine pathway is inversely associated with the humoral immune response in patients with SARS-CoV-2.

BACKGROUND: The scale and the course of antibody production in patients with SARS-CoV-2 is highly variable. Factors involved in the immune regulation during the infection may play a major role in the antibody response. We investigated the relationship between the inflammatory markers of the kynurenine pathway and the concentration of antibodies against SARS-CoV-2 in infected patients 8 - 11 days after admission. METHODS: The study included 72 SARS-CoV-2 - positive inpatients hospitalized between August 2020 and April 2021. The plasma concentrations of tryptophan, kynurenine, anti-SARS-CoV-2 antibodies and the leucocyte count were measured 8 - 11 days after admission. The kynurenine/tryptophan ratio (KYN/TRP ratio) was calculated. Tertiles based on the values for tryptophan, kynurenine, KYN/TRP ratio and the leucocytes were generated. RESULTS: Statistically significant correlations were observed between anti-SARS-CoV-2 antibodies and tryptophan, kynurenine, KYN/TRP ratio and the leucocytes (p-values < 0.001-0.007). The high kynurenine and KYN/TRP ratio tertiles showed significantly lower antibody titers compared to the low tertiles (p-values 0.017 and < 0.001). The low tryptophan and leucocytes tertiles showed significantly lower antibody titers compared to the high tertiles (p-values 0.001 and 0.008). CONCLUSION: Patients with higher activation levels of the kynurenine pathway tended to develop lower anti-SARS-CoV-2 antibody titers.

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

For 2.5 years we have been facing the coronavirus disease (COVID-19) and its health, social and economic effects. One of its known consequences is the development of neuropsychiatric diseases such as anxiety and depression. However, reports of manic episodes related to COVID-19 have emerged. Mania is an integral part of the debilitating illness-bipolar disorder (BD). Due to its devastating effects, it is therefore important to establish whether SARS-CoV-2 infection is a causative agent of this severe mental disorder. In this narrative review, we discuss the similarities between the disorders caused by SARS-CoV-2 and those found in patients with BD, and we also try to answer the question of whether SARS-CoV-2 infection may be a risk factor for the development of this affective disorder. Our observation shows that disorders in COVID-19 showing the greatest similarity to those in BD are cytokine disorders, tryptophan metabolism, sleep disorders and structural changes in the central nervous system (CNS). These changes, especially intensified in severe infections, may be a trigger for the development of BD in particularly vulnerable people, e.g., with family history, or cause an acute episode in patients with a pre-existing BD.

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

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.

2021 CDDW Abstracts

The proceedings contain 243 papers. The topics discussed include: KRT15+ tumor cells as putative cancer stem cells in esophageal cancer;the circadian timing of inflammatory bowel disease;GM-CSF autoantibodies: predictors of Crohn's disease development and a novel therapeutic approach;an INULIN-type Fructan enriched exclusive enteral nutrition formula modulates the gut microbiome and promotes expansion of anti-inflammatory T cell subsets to suppress colitis;dietary tryptophan modulates kynurenine and indole production in healthy individuals;dorsal root ganglia neuronal responses and substance p production are higher in male mice;food antigen-stress interaction leads to increase pain signaling in ileum and colon via STAT6 in an IBS model;risk perception and knowledge of COVID-19 in patients with celiac disease;pre-treatment HLADQA1-hladrb1 testing for the prevention of azathioprine-induced pancreatitis in inflammatory bowel disease: a prospective cohort study;and a high salt diet synergizes with UC microbiota to induce a proinflammatory immune tone in immunocompetent gnotobiotic mice.

Metabolomic Biomarkers Measured at Patient Discharge Predict Long- Term Physical Function in Survivors of Acute Respiratory Failure

RATIONALE: Long-term quality of life is a significant concern for survivors of sepsis and acute respiratory failure (ARF). Financial burdens await as many patients never return to work. Notably, the duration of the ICU stay significantly correlates with the severity of physical impairment and up to 25% of skeletal muscle is lost within one week in the ICU. The recent pandemic due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) is likely to exacerbate these issues. We have previously reported that metabolites related to mitochondrial bioenergetics status can predict acute patient outcomes. Here, we propose that these same metabolomic and mitochondrial biomarkers of mortality also predict physical function in survivors. METHODS: To test this hypothesis, we performed a retrospective analysis of metabolomic changes in ARF survivors using ultrahigh performance liquid chromatography mass spectrometry. Six months after ICU admission, physical function was determined by the short physical performance battery (SPPB), an objective physical function measurement assessing gait speed, balance and lower extremity strength. A total of 70 consecutively enrolled patients were selected, of which 35 had good physical function (SPPB ≥ 7) and 35 had poor physical function (SPPB ≤6). The patients were matched for age, race and sex. Metabolomic analysis of patient's serum was measured at ICU admittance (n=70), 5d-post admittance (n=20) and discharge (n=20). RESULTS: More than 1250 named compounds were identified. There were only 19 metabolites that were significantly different at admittance (ANOVA;p < 0.05), of which seven were bile acids. However at discharge, despite less patient samples tested, 151 metabolites were significantly different (ANOVA;p < 0.05). Specifically, we found that 10 lysophospholipids, eight bile acids, three TCA cycle metabolites, eight kynurenine-related metabolites and nine urea cycle metabolites were significantly different. Many of these pathways have previously been shown to be altered in nonsurvivors of sepsis and ARF. CONCLUSIONS: Findings suggest that bioenergetic abnormalities arising during the acute phase of recovery may be persistent and predict longer-term decrements of physical function in survivors of ARF. Larger retrospective and prospective studies are needed to confirm these preliminary findings;however, predicting poor physical function in survivors as well as identifying the affected metabolic pathways may lead to improved therapies and long-term patient outcomes.

Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress.

Coronavirus disease 2019 (COVID-19) has resulted in long-term psychiatric symptoms because of the immunologic response to the virus itself as well as fundamental life changes related to the pandemic. This immune response leads to altered tryptophan (TRP)-kynurenine (KYN) pathway (TKP) metabolism, which plays an essential role in the pathophysiology of mental illnesses. We aimed to define TKP changes as a potential underlying mechanism of psychiatric disorders in post-COVID-19 patients. We measured plasma levels of several TKP markers, including KYN, TRP, kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), as well as the TRP/KYN, KYNA/3-HK, and KYNA/QUIN ratios, in 90 post-COVID-19 patients (on the first day of hospitalization) and 59 healthy controls (on the first admission to the Check-Up Center). An online questionnaire that included the Depression, Anxiety and Stress Scale-21 (DASS-21) was used 6 months after the initial assessment in both groups. A total of 32.2% of participants with COVID-19 showed depressive symptoms, 21.1% exhibited anxiety, and 33.3% had signs of stress at follow-up, while 6.6% of healthy controls exhibited depressive and anxiety symptoms and 18.6% had signs of stress. TRP and 3-HK were negative predictors of anxiety and stress, but KYN positively predicted anxiety and stress. Moreover, TRP negatively predicted depression, while KYNA/3-HK was a negative predictor of anxiety. The correlation between depression, anxiety, and stress and TKP activation in COVID-19 could provide prospective biomarkers, especially the reduction in TRP and 3HK levels and the increase in KYN. Our results suggest that the alteration of TKP is not only a potential biomarker of viral infection-related long-term psychiatric disorders but also that the therapy targets future viral infections related to depression and anxiety.

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia.

Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome's evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.

QUINOLINIC ACID IS A BIOMARKER of COVID-19-ASSOCIATED COGNITIVE IMPAIRMENT

Background: COVID-19 infection-associated cognitive and olfaction impairments have an unclear pathogenesis, possibly related to systemic disease severity, hypoxia, or illness-associated anxiety and depression. A biomarker for these neurocognitive changes is lacking. The kynurenine pathway (KP) is an interferon stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity and vascular injury, that is dysregulated in COVID-19. We hypothesized that neurocognitive impairments were associated with an activated KP. Methods: The current analysis includes COVID-19 patients as part of the ADAPT study, a prospective cohort (St Vincent's Hospital Sydney, Australia). Disease severity was assessed with 18 acute symptoms and hospitalization status. Blood samples were taken 2 months (N=136) and 4 months (N=121) post diagnosis along with cognitive (Cogstate Computerized Battery, CBB;NIH toolbox Odor Identification Test, OIT) and mental health screenings (DMI-10;IESR, SPHERE-34 Psychological subscale grouped into a composite score). KP metabolites (PIC, QUIN, 3HK, 3HAA, AA, KYN, TRP, log for analyses except for TRP) were measured by GC-MS and uHPLC. The CBB and OIT data were demographically-corrected. CBB follow-up data was also corrected for practice effect. Linear mixed effect regression models with time effect (days post diagnosis) tested whether cognition, and olfaction were associated the KP (main and time interaction);while correcting for disease severity, mental health and comorbidities. Results: 136 patients: mean age=46±15;40% females;90% English speaking background;disease severity: 40% mild, 50% moderate, 10% severe/hospitalised;34% treated comorbidities. At 2 months post diagnosis, 16% had cognitive impairment, and 25% had impaired olfaction. Cognitive impairment was more common in those with anosmia (p=.05). At 4 months, 23% had cognition impairment and 20% had impaired olfaction. QUIN (p=.001), 3HAA (p<.0001) increased over the study period, while TRP decreased (p=.02). QUIN level associated with poorer cognitive scores (p=.0007;QUIN (nM) between 800-1000 was most predictive). There was no time∗QUIN interaction. QUIN association to cognition persisted when severe cases were excluded (p<.005). Conclusion: COVID-19 is associated with KP activation, and the latter with cognitive impairment. QUIN was the only biomarker associated with cognitive impairment, and may be useful in monitoring and elucidating COVID-19 neuropathogenesis and treatment.

Role of the Microbiome in the Pathogenesis of COVID-19.

The ongoing pandemic coronavirus disease COVID-19 is caused by the highly contagious single-stranded RNA virus, SARS-coronavirus 2 (SARS-CoV-2), which has a high rate of evolution like other RNA viruses. The first genome sequences of SARS-CoV-2 were available in early 2020. Subsequent whole-genome sequencing revealed that the virus had accumulated several mutations in genes associated with viral replication and pathogenesis. These variants showed enhanced transmissibility and infectivity. Soon after the first outbreak due to the wild-type strain in December 2019, a genetic variant D614G emerged in late January to early February 2020 and became the dominant genotype worldwide. Thereafter, several variants emerged, which were found to harbor mutations in essential viral genes encoding proteins that could act as drug and vaccine targets. Numerous vaccines have been successfully developed to assuage the burden of COVID-19. These have different rates of efficacy, including, although rarely, a number of vaccinated individuals exhibiting side effects like thrombosis. However, the recent emergence of the Britain strain with 70% more transmissibility and South African variants with higher resistance to vaccines at a time when several countries have approved these for mass immunization has raised tremendous concern regarding the long-lasting impact of currently available prophylaxis. Apart from studies addressing the pathophysiology, pathogenesis, and therapeutic targets of SARS-CoV-2, analysis of the gut, oral, nasopharyngeal, and lung microbiome dysbiosis has also been undertaken to find a link between the microbiome and the pathogenesis of COVID-19. Therefore, in the current scenario of skepticism regarding vaccine efficacy and challenges over the direct effects of currently available drugs looming large, investigation of alternative therapeutic avenues based on the microbiome can be a rewarding finding. This review presents the currently available understanding of microbiome dysbiosis and its association with cause and consequence of COVID-19. Taking cues from other inflammatory diseases, we propose a hypothesis of how the microbiome may be influencing homeostasis, pro-inflammatory condition, and the onset of inflammation. This accentuates the importance of a healthy microbiome as a protective element to prevent the onset of COVID-19. Finally, the review attempts to identify areas where the application of microbiome research can help in reducing the burden of the disease.

Glutamate Receptor and Kynurenine Pathway Functioning in the Pathobiology of Gulf War Illness

This project has 2 aims: (i) examine the involvement in veterans with Gulf War Illness of a neural excitatory state as a consequence of impaired brain immune, neuron and glia functioning using biomarkers obtained from cerebrospinal fluid (CSF) in 1990-1991 Gulf War veterans with (n=46) and without (n=23) GWI, and (ii) examine involvement in veterans with GWI of a neural excitatory state defined as increased glutamatergic receptor functioning by testing the effect of a single infusion of 0.5 mg/kg of N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine on gamma band EEG (for NMDAR target engagement), other EEG markers, and on symptoms of Gulf War Illness in 19 cases. Outcomes will provide evidence of an expected neural excitatory and pro-inflammatory state in cases that could predispose to neuronal damage via NMDAR hyperactivation through kynurenine pathway activation, and will provide evidence in humans of possible effects of temporarily blocking NMDARs with a subanesthetic dose (0.5 mg/kg) of ketamine.

Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19.

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.

Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-2-Related Inflammation.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19's inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease.

Kynurenine pathway in Coronavirus disease (COVID-19): Potential role in prognosis.

BACKGROUND: It is known that inflammatory responses play an important role in the pathophysiology of COVID-19. AIMS: In this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID-19 disease AQ5. MATERIALS & METHODS: Seventy COVID-19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry. RESULTS: TRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID-19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID-19 patients was statistically higher than that of mild-moderate COVID-19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL-6, ferritin, and procalcitonin were only found in COVID-19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID-19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1-1.87, p = 0.008) and 1.06 (1.02-1.11, p = 0.006), respectively. DISCUSSION & CONCLUSION: According to the results of this study, KYN metabolites play a role in the pathophysiology of COVID-19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID-19 cases.

Assessment of tryptophan and kynurenine as prognostic markers in patients with SARS-CoV-2.

BACKGROUND: Immune dysregulation and inflammation in patients with SARS-CoV-2 is associated with a poor clinical outcome. We investigated the value of the inflammatory markers tryptophan and kynurenine in predicting the survival outcome of patients with SARS-CoV-2. METHODS: The study included 252 inpatients with a SARS-CoV-2 infection hospitalized between August 2020 and April 2021. Two groups were generated based on disease survival (survival group: n = 199; deceased group: n = 53). Plasma concentrations of tryptophan, kynurenine and interleukin-6 (IL-6) were measured on admission. In a subset of patients (n = 105; 81 survivors and 24 deceased) concentrations of tryptophan and kynurenine were checked 7 days after admission. The kynurenine/tryptophan ratio (TRP/KYN ratio) was calculated. RESULTS: On admission, the deceased group showed significantly higher concentrations of kynurenine and a significantly higher KYN/TRP ratio compared to the survival group (p-values < 0.001). Kynurenine and the KYN/TRP ratio significantly correlated with IL-6 (ρ = 0.441 and 0.448, p-values < 0.001). In the survival group, kynurenine and the KYN/TRPratio were significantly lower after seven days (p-values < 0.001). In the deceased group, no significant differences were found between the measurements. CONCLUSION: Kynurenine and the KYN/TRP ratio are potentially useful parameters in predicting the survival outcome in SARS-CoV-2 positive patients.