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Background Long COVID, defined as the presence of coronavirus disease 2019 (COVID-19) symptoms ≥28 days after clinical onset, is an emerging challenge to healthcare systems. The objective of the current study was to explore recovery phenotypes in nonhospitalized individuals with COVID-19. Methods A dual cohort, online survey study was conducted between September 2020 and July 2021 in the neighboring European regions Tyrol (TY; Austria, n = 1157) and South Tyrol (STY; Italy, n = 893). Data were collected on demographics, comorbid conditions, COVID-19 symptoms, and recovery in adult outpatients. Phenotypes of acute COVID-19, postacute sequelae, and risk of protracted recovery were explored using semi-supervised clustering and multiparameter least absolute shrinkage and selection operator (LASSO) modeling. Results Participants in the study cohorts were predominantly working age (median age [interquartile range], 43 [31–53] years] for TY and 45 [35–55] years] for STY) and female (65.1% in TY and 68.3% in STY). Nearly half (47.6% in TY and 49.3% in STY) reported symptom persistence beyond 28 days. Two acute COVID-19 phenotypes were discerned: the nonspecific infection phenotype and the multiorgan phenotype (MOP). Acute MOP symptoms encompassing multiple neurological, cardiopulmonary, gastrointestinal, and dermatological symptoms were linked to elevated risk of protracted recovery. The major subset of individuals with long COVID (49.3% in TY; 55.6% in STY) displayed no persistent hyposmia or hypogeusia but high counts of postacute MOP symptoms and poor self-reported physical recovery. Conclusions The results of our 2-cohort analysis delineated phenotypic diversity of acute and postacute COVID-19 manifestations in home-isolated patients, which must be considered in predicting protracted convalescence and allocating medical resources.

The naturally occurring stilbenoid oxyresveratrol was shown to influence inflammatory and metabolic processes. During cellular immune activation, tryptophan breakdown and neopterin formation via the enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and GTP-cyclohydrolase, respectively, are induced. Neopterin and the kynurenine to tryptophan ratio are reliable and pertinent biomarkers of Th1-type immune response and are also used in vitro to monitor effects of active plant ingredients on peripheral blood mononuclear cells (PBMCs). We investigated the effects of oxyresveratrol on the activity of the above-mentioned pathways in mitogen-stimulated human PBMC and in the myelomonocytic cell line THP-1. Oxyresveratrol exerted suppressive effects on tryptophan breakdown in both stimulated cell models. Of note, in PBMC, tryptophan breakdown was induced at lower concentrations (5–20 µM) and suppressed at higher treatment concentrations only. Neopterin formation was decreased dose-dependently in stimulated PBMC. In unstimulated PBMC similar, albeit lesser effects were observed. Data indicate that oxyresveratrol exerts distinct and concentration-dependent effects on different immune cell types. IDO-1 is targeted by oxyresveratrol and its activity can be modulated in both directions. Detailed investigations of the interactions would be interesting to fully explore the activity of this phytocompound.

BackgroundSequelae of Coronavirus disease 2019 (COVID-19) were investigated by both patient-initiated and academic initiatives. Patient’s subjective illness perceptions might differ from physician’s clinical assessment results. Herein, we explored factors influencing patient’s perception during COVID-19 recovery.MethodsParticipants of the prospective observation CovILD study with persistent somatic symptoms or cardiopulmonary findings at the clinical follow-up one year after COVID-19 were analyzed (n = 74). Explanatory variables included baseline demographic and comorbidity data, COVID-19 course and one-year follow-up data of persistent somatic symptoms, physical performance, lung function testing (LFT), chest computed tomography (CT) and trans-thoracic echocardiography (TTE). Factors affecting illness perception (Brief Illness Perception Questionnaire, BIPQ) were identified by penalized multi-parameter regression and unsupervised clustering.ResultsIn modeling, 47% of overall illness perception variance at one year after COVID-19 was attributed to fatigue intensity, reduced physical performance, hair loss and baseline respiratory comorbidity. Overall illness perception was independent of LFT results, pulmonary lesions in CT or heart abnormality in TTE. As identified by clustering, persistent somatic symptom count, fatigue, diminished physical performance, dyspnea, hair loss and sleep problems at the one-year follow-up and severe acute COVID-19 were associated with the BIPQ domains of concern, emotional representation, complaints, disease timeline and consequences.ConclusionPersistent somatic symptoms rather than clinical assessment results, revealing lung and heart abnormalities, impact on severity and quality of illness perception at one year after COVID-19 and may foster unhelpful coping mechanisms. Besides COVID-19 severity, individual illness perception should be taken into account when allocating rehabilitation and psychological therapy resources.Study registrationClinicalTrials.gov: NCT04416100.

Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression offers an alternative therapy, since more than every third patient is not responding to adequate antidepressive treatment. In this interventional study safety, symptom development and changes of serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain-derived neurotrophic factor (BDNF), nitrite as well as of salivary amylase were measured before and after a frontal polar cortex stimulation using rTMS as add-on treatment in 38 patients with treatment-resistant depression. Out of these, 17 patients received sham stimulation as a control. Treatment was well tolerated: with the exception of one patient of the verum group, who described discomfort during the second treatment, no serious adverse effects were observed. Improvement of depression with a significant decrease in the HAMD-7 scale (p = 0.001) was found in patients treated with rTMS, but not in sham-treated patients. Furthermore, serum phenylalanine and tyrosine dropped significantly (p = 0.03 and p = 0.027, respectively) in rTMS-treated patients. The kynurenine to tryptophan ratio (Kyn/Trp) tended to decrease under rTMS (p = 0.07). In addition, associations between concentrations of BDNF and neopterin as well as serum nitrite levels were found in patients after rTMS treatment, which indicates an influence of immune regulatory circuits on BDNF levels. In the sham-treated patients, no changes of biomarker concentrations were observed. Results show that rTMS is effective in the treatment of resistant depression. rTMS appears to influence the enzyme phenylalanine hydroxylase, which plays a central role in the biosynthesis of neurotransmitter precursors tyrosine and dihydroxyphenylalanine (DOPA).

BackgroundOlfactory dysfunction (OD) often accompanies acute coronavirus disease 2019 (COVID-19) and its sequelae. Herein, we investigated OD during COVID-19 recovery in the context of other symptoms, quality of life, physical and mental health.MethodsSymptom recovery patterns were analyzed in a bi-national, ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and a multi-center observational cross-sectional cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up) with multi-dimensional scaling, association rule mining and partitioning around medoids clustering.ResultsBoth in the ambulatory collective (72%, n = 655/906) and the cross-sectional ambulatory and hospitalized cohort (41%, n = 44/108) self-reported OD was frequent during acute COVID-19, displayed a slow recovery pace (ambulatory: 28 days, cross-sectional: 90 days median recovery time) and commonly co-occurred with taste disorders. In the ambulatory collective, a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorder (>90 days) was identified. This post-acute smell and taste disorder phenotype was characterized by a low frequency of other leading post-acute symptoms including fatigue, respiratory and neurocognitive complaints. Despite a protracted smell and taste dysfunction, this subset had high ratings of physical performance, mental health, and quality of life.ConclusionOur results underline the clinical heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype may represent a distinct COVID-19 recovery pathway characterized by a good recovery of other COVID-19 related symptoms.Study registrationClinicalTrials.gov: NCT04661462 (ambulatory collective), NCT04416100 (cross-sectional cohort).

Aims Anaemia and iron deficiency (ID) are frequently found in patients with chronic heart failure (CHF) and associated with adverse outcome. However, it is unclear whether absolute [transferrin saturation (TSAT) 100 μg/L) with and without anaemia had similar or different consequences for such patients. Methods and results Within this retrospective cohort study, 2223 patients (1601 men and 622 women) with CHF, referred to our department, between 2000 and 2018, were followed for a median time of 84 months. Anaemia was found in 393 patients and was an independent predictor for an adverse outcome [HR 2.164 (95% CI 1.865–2.512), P

Aims: Immune activation and disturbances of vitamin D metabolism are frequently encountered in patients with heart failure. Elevated fibroblast growth factor 23 (FGF23) levels as well as immune activation have been associated with a worse outcome in patients with heart failure. We evaluated the relationship of vitamin D metabolism and FGF23 levels with immune activation and its association with cardiac function and outcome in patients with heart failure. Methods and Results: In 149 patients with heart failure caused by nonischaemic cardiomyopathy, parameters of vitamin D metabolism (vitamin D, parathormone, phosphate, C-terminal FGF23, calcium), inflammation (hsCRP, neopterin) and cardiac function were investigated. Patients with elevated inflammatory parameters had significantly higher Ct-FGF23 levels (37.33 RU/mL vs. 17.60 RU/mL, p < 0.001). The highest Ct-FGF23 and phosphate levels were found in patients with elevated neopterin and hsCRP levels as well as in in patients with progressive heart failure. Patients with high Ct-FGF23 and neopterin levels (Ct-FGF23 > 22.60 RU/mL, neopterin > 6.90 nmol/L) had a significantly higher risk for adverse events compared to patients with low Ct-FGF23 and neopterin levels (HR 7.386, [95%CI 2.543 – 21.447], p < 0.001). Conclusions: Our study indicates a strong relationship of vitamin D metabolism, especially FGF23, with Th1 immune activation in patients with heart failure. Elevated Ct-FGF23 and neopterin levels are additive predictors for adverse cardiovascular events in patients with heart failure.

Background: Currently available medication for Alzheimer’s disease (AD) may slows cognitive decline only transitory, but has failed to bring about long term positive effects. For this slowly progressive neurodegenerative disease so far no disease modifying therapy exists. Objective: To find out if non-pharmacologic non-ivasive neuromodulatory repetitive transcranial magnetic stimulation (rTMS) may offer a new alternative or an add on therapeutic strategy against loss of cognitive functions. Methods: In this exploratory intervention study safety and symptom development before and after frontopolar cortex stimulation (FPC) using intermittent theta burst stimulation (iTBS) at 10 subsequent working days was monitored as add-on treatment in 28 consecutive patients with AD. Out of these, 10 randomly selected patients received sham stimulation as a control. In addition, Serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain derived neurotrophic factor (BDNF) as well as of nitrite were measured. Results: Treatment was well tolerated, no serious adverse effects were observed. Improvement of cognition was detected by an increase of Mini Mental State Examination score (MMSE; p#60;0.01, paired rank test) and also by an increase in a modified repeat address phrase test, part of the 6-item cognitive impapairment test (p #60;0.01). A trend to an increase in the clock drawing test (CDT; p = 0.08) was also found in the verum treated group. Furtheron, in 10 of the AD patients with additional symptoms of depression treated with iTBS, a significant decrease in the HAMD-7 scale (p Conclusion: Our preliminary results may indicate that iTBS is effective in the treatment of AD. Also a slight influence of iTBS on the metabolism of phenylalanine was found after 10 iTBS sessions. An impact of iTBS to influence the enzyme phenylalanine hydroxylase (PAH), as found in previous series of treatment resistant depression, could not be seen in this our first observational trial in 10 AD patients with comorbidity of depression. Longer treatment periods for several weeks in a higher number of AD patients with depression could cause more intense and disease modifying effects visible in different neurotransmitter concentrations important in the pathogenesis of AD.

Background:The optimal procedures to prevent, identify, monitor, and treat long-term pulmonary sequelae of COVID-19 are elusive. Here, we characterized the kinetics of respiratory and symptom recovery following COVID-19.Methods:We conducted a longitudinal, multicenter observational study in ambulatory and hospitalized COVID-19 patients recruited in early 2020 (n = 145). Pulmonary computed tomography (CT) and lung function (LF) readouts, symptom prevalence, and clinical and laboratory parameters were collected during acute COVID-19 and at 60, 100, and 180 days follow-up visits. Recovery kinetics and risk factors were investigated by logistic regression. Classification of clinical features and participants was accomplished by unsupervised and semi-supervised multiparameter clustering and machine learning.Results:At the 6-month follow-up, 49% of participants reported persistent symptoms. The frequency of structural lung CT abnormalities ranged from 18% in the mild outpatient cases to 76% in the intensive care unit (ICU) convalescents. Prevalence of impaired LF ranged from 14% in the mild outpatient cases to 50% in the ICU survivors. Incomplete radiological lung recovery was associated with increased anti-S1/S2 antibody titer, IL-6, and CRP levels at the early follow-up. We demonstrated that the risk of perturbed pulmonary recovery could be robustly estimated at early follow-up by clustering and machine learning classifiers employing solely non-CT and non-LF parameters.Conclusions:The severity of acute COVID-19 and protracted systemic inflammation is strongly linked to persistent structural and functional lung abnormality. Automated screening of multiparameter health record data may assist in the prediction of incomplete pulmonary recovery and optimize COVID-19 follow-up management.Funding:The State of Tyrol (GZ 71934), Boehringer Ingelheim/Investigator initiated study (IIS 1199-0424).Clinical trial number:ClinicalTrials.gov: NCT04416100

BACKGROUNDLong COVID, defined as presence of COVID-19 related symptoms 28 days or more after the onset of acute SARS-CoV-2 infection, is an emerging challenge to healthcare systems. The objective of this study was to phenotype recovery trajectories of non-hospitalized COVID-19 individuals.METHODSWe performed an international, multi-center, exploratory online survey study on demographics, comorbidities, COVID-19 symptoms and recovery status of non-hospitalized SARS-CoV-2 infected adults (Austria: n=1157), and Italy: n= 893).RESULTSWorking age subjects (Austria median: 43 yrs (IQR: 31 – 53), Italy: 45 yrs (IQR: 35 – 55)) and females (65.1% and 68.3%) predominated the study cohorts. Course of acute COVID-19 was characterized by a high symptom burden (median 13 (IQR: 9 – 18) and 13 (7 – 18) out of 44 features queried), a 47.6 – 49.3% rate of symptom persistence beyond 28 days and 20.9 – 31.9% relapse rate. By cluster analysis, two acute symptom phenotypes could be discerned: the non-specific infection phenotype and the multi-organ phenotype (MOP), the latter encompassing multiple neurological, cardiopulmonary, gastrointestinal and dermatological features. Clustering of long COVID subjects yielded three distinct subgroups, with a subset of 48.7 – 55 % long COVID individuals particularly affected by post-acute MOP symptoms. The number and presence of specific acute MOP symptoms and pre-existing multi-morbidity was linked to elevated risk of long COVID.CONCLUSIONThe consistent findings of two independent cohorts further delineate patterns of acute and post-acute COVID-19 and emphasize the importance of symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources.Key PointsQuestionWhich acute symptom patterns of acute COVID-19 are associated with prolonged symptom persistence, symptom relapse or physical performance impairment?FindingsIn this multicenter international comparative survey study on non-hospitalized SARS- CoV-2 infected adults (Austria: n = 1157, Italy: n = 893) we identified distinct and reproducible phenotypes of acute and persistent features. Acute multi-organ symptoms including neurological and cardiopulmonary manifestations are linked to elevated risk of long COVID.MeaningThese findings suggest to employ symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources.

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism. Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence. Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated. Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

BackgroundCOVID-19 convalescents are at risk of developing a de novo mental health disorder or of worsening of a pre-existing one. The objectives of our study was to phenotype individuals at highest risk of mental health disorders among COVID-19 outpatients.MethodsWe conducted a binational online survey study with adult non-hospitalized COVID-19 convalescents (Austria/AT: n=1157, Italy/IT: n= 893). Primary endpoints were positive screening for depression and anxiety (PHQ-4, Patient Health Questionnaire) and self-perceived overall mental health and quality of life rated with 4 point Likert scales. Psychosocial stress was surveyed with a modified PHQ stress module. Associations of the mental health with socio-demographic variables, COVID-19 course and recovery data were assessed by multi-parameter random forest and serial univariable modeling. Mental disorder risk subsets were defined by self-organizing map and hierarchical clustering algorithms. The survey analyses are publicly available (https://im2-ibk.shinyapps.io/mental_health_dashboard/).ResultsIn the study cohorts, 4.6 (IT)/6% (AT) of participants reported depression and/or anxiety before to infection. At a median of 79 days (AT)/96 days (IT) post COVID-19 onset, 12.4 (AT)/19.3% (IT) of subjects were screened positive for anxiety and 17.3 (AT)/23.2% (IT) for depression. Over one-fifth of the respondents rated their overall mental health (AT: 21.8%, IT: 24.1%) or quality of life (AT: 20.3%, IT: 25.9%) as fair or poor. In both study collectives, psychosocial stress, high numbers of acute and persistent COVID-19 complaints and the presence of acute neurocognitive symptoms (impaired concentration, confusion, forgetfulness) were the strongest correlates of deteriorating mental health and poor quality of life. In clustering analysis, these variables defined a ‘high risk’ subset with particularly high propensity of post-COVID-19 mental health impairment and decreased quality of life. Pre-existing depression or anxiety was associated with an increased symptom burden during acute COVID-19 and recovery.ConclusionOur study revealed a bidirectional relationship between COVID-19 symptoms and mental health. We put forward specific acute symptoms of the disease as ‘red flags’ of mental health deterioration which should prompt general practitioners to identify COVID-19 patients who may benefit from early psychological and psychiatric intervention.Trial registrationClinicalTrials.gov: NCT04661462.

Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.

Immune activation coincides with disturbances in iron and vitamin D metabolism in patients with cardiomyopathy. In this study, we investigated whether there are differences regarding immune activation, iron and vitamin D metabolism between the different cardiomyopathy aetiologies. Patients and methods: Parameters of iron metabolism (haemoglobin, iron, transferrin, transferrin saturation, ferritin, hepcidin), vitamin D metabolism (Ct-FGF23, parathormone, phosphate, vitamin D) and immune activation (C-reactive protein and neopterin) were determined in 149 patients (98 men, 51 women) with non-ischaemic cardiomyopathy. Results: Patients with amyloid cardiomyopathy presented with higher neopterin, ferritin and hepcidin levels than other cardiomyopathy aetiologies. Furthermore, they showed the highest rate of cardiovascular events. C-reactive protein levels were significantly higher in patients with inflammatory cardiomyopathy. Patients with virus positive cardiomyopathy presented with significantly higher ferritin and Ct-FGF23 levels compared to patients with virus negative inflammatory cardiomyopathy. Conclusion: This study indicates that there are some differences regarding the extent of immune activation and inflammation as well as alterations in iron metabolism disorders between different cardiomyopathy aetiologies. Further studies with larger patient cohorts are needed to investigate these findings more precisely.

Background Seasonal influenza is an important cause of morbidity and mortality worldwide. Immune activation after stimulation with interferon‐gamma leads to increased production of neopterin but also results in increased tryptophan catabolism through indoleamine 2,3‐dioxygenase (IDO). Our pilot study determined neopterin serum levels and IDO activity in patients with influenza infection and investigated whether neopterin is linked to clinical outcome parameters (mortality ≤30 days, acute cardiac events (ACE) length of hospitalization, ICU admission). Methods Neopterin concentrations were analyzed in serum samples of 40 patients with a confirmed diagnosis of influenza infection and in‐hospital treatment for >24 hours. Data were compared to values of 100 healthy blood donors and 48 age‐matched pneumonia patients. In a subgroup of 14 patients, tryptophan and kynurenine concentrations, as well as kynurenine‐to‐tryptophan ratio, were analyzed. Results In all influenza patients, neopterin concentrations were increased and significantly higher compared to those determined in patients with pneumonia and healthy controls. Positive correlations between the duration of hospitalization and neopterin were found. Significantly higher levels of kynurenine, kynurenine‐to‐tryptophan ratio, and lower levels of tryptophan were seen in influenza patients compared to healthy controls. Conclusions Neopterin seems to be related to the course of the disease and could be a valuable biomarker to identify patients at an elevated risk of a worsened outcome; however, further prospective validation studies are needed to support the here presented preliminary results.

Bacteremia is a major clinical challenge requiring early treatment. Metabolic alterations occur during bacteremia, and accordingly plasma concentrations of lipoproteins LDL-C and HDL-C are substantially changed. We questioned whether bacteremia with Gram-negative versus Gram-positive bacteria causes contrasting changes of lipoprotein levels in order to differentiate between the 2-g stain types and if there is a relation with outcome parameters namely ICU-admission, 30-day mortality, duration of hospitalization. This is a retrospective dual-center cross-sectional study, including 258 patients with bacteremia. Plasma lipid levels were analyzed within 48 h to positive blood culture. Upon admission, HDL-C, LDL-C, and total cholesterol (p = 0.99) in plasma did not significantly differ between patients with Gram-negative and Gram-positive bacteremia, while significantly higher triglyceride concentrations were found in Gram-negative bacteremia (p

Objective:Anemia is often found in patients with coronary artery disease (CAD) or acute coronary syndrome (ACS) and related to disease severity. Our study investigated the relationship between anemia, iron homeostasis and inflammation in CAD and examined their influence on the outcome of patients.Patients and Methods:Markers of immune activation (neopterin, interleukin [IL]-12, IL-6, high sensitive C-reactive protein (hsCRP), fibrinogen, serum amyloid A [SAA]) and iron metabolism (ferritin, transferrin saturation, hemoglobin) were determined in 2,082 patients (68.7 % men, median age 63 years) from the Ludwigshafen Risk and cardiovascular Health (LURIC) cohort. Patients were followed-up for a median of 9.81 years.Results:960 patients (46.1 %) presented with chronic CAD, 645 patients (31.0 %) had an ACS, and 477 patients (22.9 %) presented with no CAD in coronary angiography (CAG). Anemia (n= 357, 17.1 %) was associated with disease severity (reflected by more progressed stenosis in CAG, CCS, and NYHA classes, and a lower LV-EF), a higher cardio-cerebrovascular event rate and higher levels of inflammatory markers. Interestingly, anemia was only predictive for an adverse outcome in patients with elevated inflammatory markers. Accordingly, anemia of chronic disease (ACD) was associated with a higher cardio-cerebrovascular event-rate in the subsequent 2 years as compared to patients with other types of anemia or without anemia (14.3 vs. 6.1 vs. 4.0%,p< 0.001).Conclusions:This study confirms that anemia and immune activation are strongly related to cardiovascular disease progression and an adverse outcome. Our data suggest that the association of anemia with disease severity and outcome might mainly be due to underlying inflammation.

The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO-1) has gained major attention due the immunoregulatory nature of this pathway. Both depletion of tryptophan concentrations as well as the accumulation of downstream metabolites are relevant for the mediation of the manifold consequences of increased tryptophan metabolism. Increased tryptophan catabolism is indicative for several chronic inflammatory disorders such as infections, autoimmune diseases or cancer. Low tryptophan availability is likely to be involved in the manifestation of a variety of comorbidities such as anemia, cachexia, depression and neurocognitive disturbances.Several nutrient sensing kinases are implicated in the downstream effects of dysregulated tryptophan metabolism. These include mechanisms that were conserved during evolution but have gained special features in multicellular eukaryotes, such as pathways regulated by eukaryotic translation initiation factor 2 (eIF-2)-alpha kinase (GCN2, also named general control nonderepressible 2 kinase), 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) and target of rapamycin (TOR).The interplay between IDO-1 and above-mentioned pathway seems to be highly context dependent. A better understanding of the crosstalk is necessary to support the search for druggable targets for the treatment of inflammatory and autoimmune disorders.

Background Metabolic profiling in non-small cell lung cancer (NSCLC) may identify key metabolic vulnerabilities and shows enormous discovery potential. Preclinical studies showed that metabolic rewiring in cancer plays an essential role in modulation of immunotherapy response. However, this situation is understudied in the clinical setting. Therefore, we aimed to evaluate the plasma metabolic profile of immune checkpoint inhibitor (CI) responding versus non-responding NSCLC patients. The aim of this project is to identify potential predictive biomarkers for CI response. Methods Plasma samples from CI treated NSCLC patients were analysed at baseline and at the first follow up scan by using a broad targeted metabolomics mass spectrometry panel, and were compared to healthy controls. For further validation of identified key alterations high-performance liquid chromatography (HPLC) for tryptophan (Trp) and kynurenine (Kyn) as indicator of IDO-activity was performed. Results Sixty-seven metabolites were significantly altered in NSCLC patients compared to healthy controls. The metabolic profile of patients with primary CI resistance showed an increase in indoleamine-2,3-dioxygenase (IDO) and a decrease in branched-chain amino acids (BCAA) compared to baseline concentrations. Deregulated IDO activity was validated by additional HPLC measurements, which revealed that baseline Trp levels were predictive for CI response. According to receiver operating characteristic (ROC)-analysis baseline Trp levels ≥49.3 µmol/L predicted disease control at the first follow up scan with a sensitivity of 89% and a specificity of 71%. Conclusions We showed that NSCLC patients are characterized by a distinct metabolic profile compared to healthy controls. Moreover, metabolic changes during CI therapy were observed. Of those IDO metabolism seemed to play an important role in primary CI resistance. Trp as a surrogate parameter of IDO activity is a promising biomarker in patients undergoing treatment with CIs and might be a future marker in trials investigating IDO inhibitors.

The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO-1) has gained major attention due the immunoregulatory nature of this pathway. Both depletion of tryptophan concentrations as well as the accumulation of downstream metabolites are relevant for the mediation of the manifold consequences of increased tryptophan metabolism. Increased tryptophan catabolism is indicative for several chronic inflammatory disorders such as infections, autoimmune diseases or cancer. Low tryptophan availability is likely to be involved in the manifestation of a variety of comorbidities such as anemia, cachexia, depression and neurocognitive disturbances.Several nutrient sensing kinases are implicated in the downstream effects of dysregulated tryptophan metabolism. These include mechanisms that were conserved during evolution but have gained special features in multicellular eukaryotes, such as pathways regulated by eukaryotic translation initiation factor 2 (eIF-2)-alpha kinase (GCN2, also named general control nonderepressible 2 kinase), 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) and target of rapamycin (TOR).The interplay between IDO-1 and above-mentioned pathway seems to be highly context dependent. A better understanding of the crosstalk is necessary to support the search for druggable targets for the treatment of inflammatory and autoimmune disorders.

The microbiota–gut–brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer’s disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of “pro-inflammatory” gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.

This study evaluates the predictive value of circulating inflammatory markers, especially neopterin, in patients with coronavirus disease 2019 (COVID-19). Within this retrospective analysis of 115 hospitalized COVID-19 patients, elevated neopterin levels upon admission were significantly associated with disease severity, risk for intensive care unit admission, need for mechanical ventilation, and death. Therefore, neopterin is a reliable predictive marker in patients with COVID-19 and may help to improve the clinical management of patients.

Background Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. Methods We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. Results We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. Discussion Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. Trial registration ClinicalTrials.gov number: NCT04416100.

The novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a global health concern. Vitamin D (VITD) deficiency has been suggested to alter SARS-CoV-2 susceptibility and the course of disease. Thus, we aimed to investigate associations of VITD status to disease presentation within the CovILD registry. This prospective, multicenter, observational study on long-term sequelae includes patients with COVID-19 after hospitalization or outpatients with persistent symptoms. Eight weeks after PCR confirmed diagnosis, a detailed questionnaire, a clinical examination, and laboratory testing, including VITD status, were evaluated. Furthermore, available laboratory specimens close to hospital admission were used to retrospectively analyze 25-hydroxyvitamin D levels at disease onset. A total of 109 patients were included in the analysis (60% males, 40% females), aged 58 &plusmn, 14 years. Eight weeks after the onset of COVID-19, a high proportion of patients presented with impaired VITD metabolism and elevated parathyroid hormone (PTH) levels. PTH concentrations were increased in patients who needed intensive care unit (ICU) treatment, while VITD levels were not significantly different between disease severity groups. Low VITD levels at disease onset or at eight-week follow-up were not related to persistent symptom burden, lung function impairment, ongoing inflammation, or more severe CT abnormalities. VITD deficiency is frequent among COVID-19 patients but not associated with disease outcomes. However, individuals with severe disease display a disturbed parathyroid-vitamin-D axis within their recovery phase. The proposed significance of VITD supplementation in the clinical management of COVID-19 remains elusive.

Background: Interferon-γ (IFN- γ) regulates the degradation of tryptophan to kynurenine via induction of indoleamine- 2,3-dioxygenase (IDO). Local tryptophan depletion and accumulation of toxic metabolites might impair the proliferative capacity of lymphocytes. The aim of this study was to assess the actual status of immune system activation of patients with bacterial infection in the acute phase and during convalescence in vivo and in vitro. Parameters of systemic immune system activation were evaluated for associations with proliferative responsiveness of immune cells, and compared with healthy controls. Methods: 24 patients with various acute bacterial infections were included in the group of acutely ill patients. Sixteen patients participated in a follow-up examination after convalescence. The control group consisted of 6 healthy people. To assess the status of immune system activation in vivo, inflammation parameters C-reactive protein and differential blood counts were determined. Neopterin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Tryptophan and kynurenine measurements were performed with high pressure liquid chromatography (HPLC). Peripheral blood mononuclear cells (PBMCs) were isolated from the patients’ blood and stimulated with concanavalin A (Con A), phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in vitro proliferation rates were evaluated by ³H-thymidine incorporation and neopterin production and tryptophan degradation were determined in supernatants of mitogen stimulated PBMCs. Results: Patients with acute bacterial infections showed reduced tryptophan and elevated neopterin concentrations, which did not normalize after convalescence period. Higher plasma neopterin values and increased IDO-activity were associated with reduced proliferative responses in vitro after stimulation with PHA. Associations were observed during acute infection as well as convalescence. Conclusions: Results of this study show that increased immune system activation in vivo is associated with impaired proliferative responsiveness of immune cells in vitro in acute bacterial infections as well as during convalescence.

Acute exacerbations and community-acquired pneumonia (CAP) are severe complications in patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed inflammatory parameters in serum including C-reactive protein (CRP), procalcitonin (PCT), and serum neopterin (NPT) to determine their potential to differentiate between patients with CAP+COPD and with acute exacerbations of COPD (AECOPD) without pneumonia. 102 (39 women and 63 men) patients were included in this retrospective study, of whom 48 presented with CAP without underlying COPD, 20 with CAP+COPD and 34 with AECOPD. CRP, PCT, and blood counts were determined by routine automated tests, and NPT concentrations were determined by ELISA. The ratios of CRP to NPT levels were calculated. Upon patient admission, CRP, PCT, and NPT levels were significantly higher in patients with CAP compared to those in AECOPD patients. CRP/NPT ratio was lower in AECOPD compared to CAP (+/-COPD) patients. Positive correlations were found between duration of hospitalization and CRP levels and the CRP/NPT ratio at study entry. Patients who were readmitted within 30 days tended to have higher NPT levels at initial presentation. Patients under ongoing corticosteroid treatment presented with lower inflammatory parameters. The CRP/NPT-ratio was suited well to discriminate between AECOPD and CAP on the basis of COPD, a CRP/NPT cutoff of 0.346 provided a sensitivity of 65% and a specificity of 79%. The combinatory use of inflammatory patterns might help to differentiate patients with AECOPD from those with CAP on the basis of COPD.

Background After the 2002/2003 SARS outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking. Methods In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100 days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography, and thoracic low-dose computed tomography (CT). Results Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100 days after COVID-19 onset, with dyspnea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of both, symptoms and CT abnormalities over time. Conclusion A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with pulmonary abnormalities more than 100 days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time., 100 days after COVID-19 onset, a high portion of patients exhibit persisting symptoms and cardiopulmonary impairment. Still, a marked improvement of symptoms, pulmonary function, and CT pathologies was found at follow-up.

Anemia often coincides with depression and impaired quality of life (QoL) in cancer patients. Sustained immune activation can lead to the development of anemia. Furthermore, it also may go along with changes in tryptophan and phenylalanine metabolism. The aim of our pilot study was to study the relationship between anemia, immune-mediated changes in amino acid metabolism, and the QoL and mood of cancer patients. Questionnaires to measure QoL and depression were completed by 152 patients with solid tumors. Hemoglobin, parameters of immune activation as well as tryptophan and phenylalanine metabolism were determined in the patients&rsquo, sera. Anemic patients (51.7%) presented with higher inflammatory markers, and a higher tryptophan breakdown with lower tryptophan concentrations. They reported an impaired QoL and had higher depression scores. Patients with an impaired QoL (65.8%) also suffered from more fatigue and impaired physical, emotional, and social functioning. They, furthermore, presented with higher concentrations of inflammatory markers (C-reactive protein (CRP) and neopterin) as well as higher tryptophan degradation (in men) and higher phenylalanine concentrations (in women). Sixty-one patients (40.1%) had (mostly mild) depression. In these patients, a higher degree of Th1 immune activation was found. The results of our study suggest that cancer-related anemia goes along with an impaired QoL, which is also associated with immune-mediated disturbances of tryptophan and phenylalanine metabolism.

ObjectivesNeutralisation of tumour necrosis factor (TNF) is widely used as a therapy for rheumatoid arthritis (RA). However, this therapy is only effective in less than a half of patients and is associated with several side effects. We hypothesised that TNF may possess non-redundant protective and immunomodulatory functions in vivo that cannot be blocked without a cost. The present work aimed to identify cellular sources of protective and pathogenic TNF, and its molecular forms during autoimmune arthritis.MethodsMice lacking TNF expression by distinct cell types, such as myeloid cells and T or B lymphocytes, were subjected to collagen-induced arthritis (CIA) and collagen antibody-induced arthritis. Mice lacking soluble TNF production were also employed. The severity and incidence of the disease, as well as humoral and cellular responses were assessed.ResultsMyeloid cell-derived TNF contributes to both induction and pathogenesis of autoimmune arthritis. Conversely, T cell-derived TNF is protective during the induction phase of arthritis via limiting of interleukin-12 production by dendritic cells and by subsequent control of autoreactive memory T cell development, but is dispensable during the effector phase of arthritis. B cell-derived TNF mediates severity of CIA via control of pathogenic autoantibody production.ConclusionsDistinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell types may be superior to pan-anti-TNF therapy.

Intramuscular cystic echinococcosis is a very rare occurrence. Herein we report a case of a 37-year-old patient who presented with progressive swelling of his left thigh. Ultrasound evaluation showed a multicystic, encapsulated lesion (16 × 3.5 × 8.5 cm) in the M. vastus lateralis, and serology confirmed the diagnosis of Echinococcus granulosus s.l. infection. No additional cysts were detected upon total body CT scan. The patient was treated with albendazole pre-operatively; surgical resection of the mass was then successfully performed. The patient feels well and no signs of residual infestation were seen after 2 years of follow-up.

Inflammation and immune activation play an important role in the pathogenesis of cardiac remodelling in patients with heart failure. The aim of this study was to assess whether biomarkers of inflammation and immune activation are linked to disease severity and the prognosis of heart failure patients. In 149 patients (65.8% men, median age 49.7 years) with heart failure from nonischaemic cardiomyopathy, the biomarkers neopterin and C-reactive protein were tested at the time of diagnosis. Patients were followed-up for a median of 58 months. During follow-up, nineteen patients died, five had a heart transplantation, two needed a ventricular assistance device, and twenty-one patients had to be hospitalised because of heart failure decompensation. Neopterin concentrations correlated with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations (rs = 0.399, p < 0.001) and rose with higher New York Heart Association (NYHA) class (I: 5.60 nmol/L, II: 6.90 nmol/L, III/IV: 7.80 nmol/L, p = 0.033). Higher neopterin levels were predictive for an adverse outcome (death or hospitalisation due to HF decompensation), independently of age and sex and of established predictors in heart failure such as NYHA class, NT-proBNP, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LV-EF) (HR 2.770; 95% CI 1.419–5.407; p = 0.003). Patients with a neopterin/eGFR ratio ≥ 0.133 (as a combined marker for immune activation and kidney function) had a more than eightfold increased risk of reaching an endpoint compared to patients with a neopterin/eGFR ratio ≤0.065 (HR 8.380; 95% CI 2.889–24.308; p < 0.001). Neopterin is associated with disease severity and is an independent predictor of prognosis in patients with heart failure.