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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.

Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

Anemia and disturbances of iron metabolism are frequently encountered in patients with COVID-19 and associated with an adverse clinical course. We retrospectively analyzed 645 consecutive COVID-19 patients hospitalized at the Innsbruck University Hospital. Pre-existing anemia was associated with increased risk for in-hospital death. We further found that the decline in hemoglobin levels during hospital stay is more pronounced in patients with signs of hyperinflammation upon admission, the latter being associated with a nearly two-fold higher risk for new onset anemia within one week. Anemia prevalence increased from 44.3% upon admission to 87.8% in patients who were still hospitalized after two weeks. A more distinct decrease in hemoglobin levels was observed in subjects with severe disease, and new-onset anemia was associated with a higher risk for ICU admission. Transferrin levels decreased within the first week of hospitalization in all patients, however, a continuous decline was observed in subjects who died. Hemoglobin, ferritin, and transferrin levels normalized in a median of 122 days after discharge from hospital. This study uncovers pre-existing anemia as well as low transferrin concentrations as risk factors for mortality in hospitalized COVID-19 patients, whereas new-onset anemia during hospitalization is a risk factor for ICU admission. Anemia and iron disturbances are mainly driven by COVID-19 associated inflammation, and cure from infection results in resolution of anemia and normalization of dysregulated iron homeostasis.

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) <20%, ferritin <100 μg/L] or inflammation‐driven functional ID (TSAT <20%, ferritin >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 < 0.001]. In 674 patients with available parameters of iron metabolism, ID was present in 228 patients and was associated with an unfavourable outcome [HR 1.499 (95% CI 1.158–1.940), P = 0.002]. ID was best predicting an adverse outcome in men ≤59 years, with heart failure with reduced ejection fraction, preserved kidney function, no inflammation, and a body mass index (BMI) ≥25.5 kg/m2. Functional ID in women and absolute ID in men were associated with poor prognosis. Of note, TSAT <20% but not low ferritin levels were predictive for an adverse outcome. Anaemic patients with high ferritin levels, advanced inflammation, older age, low BMI, male gender, and reduced glomerular filtration rate had the worst prognosis. Conclusions Anaemia and low tissue iron availability as reflected by TSAT <20% are negative predictors of outcome in patients with CHF. Systemic inflammation, renal function, BMI, age, and gender are important contributors for the clinical course.

Coronavirus Disease 2019 causes significant morbidity, and different variants of concern (VOCs) can impact organ systems differently. We conducted a single-center retrospective cohort analysis comparing biomarkers and clinical outcomes in hospitalized patients infected with the wild-type or Alpha (wt/Alpha) VOC against patients infected with the Omicron VOC. We included 428 patients infected with the wt/Alpha VOC and 117 patients infected with the Omicron VOC. The Omicron cohort had higher maximal median high-sensitivity Troponin-T (hs-TnT) levels (wt/Alpha: 12.8 ng/L, IQR 6.6–29.5 vs. Omicron: 27.8 ng/L, IQR 13.7–54.0; p < 0.001) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (wt/Alpha: 256 ng/L, IQR 74.5–913.5 vs. Omicron: 825 ng/L, IQR 168–2759; p < 0.001) levels. This remained true for patients under 65 years of age and without pre-existing cardiovascular disease (hs-TnT (wt/Alpha: 6.1 ng/L, IQR 2.5–10.25 vs. Omicron: 8.6 ng/L, IQR 6.2–15.7; p = 0.007) and NT-proBNP (wt/Alpha: 63 ng/L, IQR 25–223.75 vs. Omicron: 158 ng/L, IQR 75.5–299.5; p = 0.006)). In-hospital mortality was similar between the two groups (wt/Alpha: 53 or 12.7% vs. Omicron: 9 or 7.7%; p = 0.132) and more patients infected with wt/Alpha VOC required intensive care admission (wt/Alpha: 93 or 22.2% vs. Omicron: 14 or 12%; p = 0.014). Increased cardiac biomarkers were correlated with a higher risk of mortality and ICU admission in both groups. Herein, we detected higher levels of cardiac biomarkers in hospitalized patients infected with the Omicron VOC when compared to wt/Alpha, being indicative of higher cardiac involvement. Although hs-TnT and NT-proBNP levels were higher in the Omicron cohort and both markers were linked to in hospital mortality in both groups, the mortality rates were similar.

Introduction: Influenza and the coronavirus disease 2019 (COVID-19) are two potentially severe viral infections causing significant morbidity and mortality. The causative viruses, influenza A/B and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) can cause both pulmonary and extra-pulmonary disease, including cardiovascular involvement. The objective of this study was to determine the levels of cardiac biomarkers in hospitalized patients infected with influenza or COVID-19 and their correlation with secondary outcomes. Methods: We performed a retrospective comparative analysis of cardiac biomarkers in patients hospitalized at our department with influenza or COVID-19 by measuring high-sensitivity troponin-T (hs-TnT) and creatinine kinase (CK) in plasma. Secondary outcomes were intensive care unit (ICU) admission and all-cause in-hospital mortality. Results: We analyzed the data of 250 influenza patients and 366 COVID-19 patients. 58.6% of patients with influenza and 46.2% of patients with COVID-19 presented with increased hs-TnT levels. Patients of both groups with increased hs-TnT levels were significantly more likely to require ICU treatment or to die during their hospital stay. Compared with COVID-19, cardiac biomarkers were significantly higher in patients affected by influenza of all age groups, regardless of pre-existing cardiovascular disease. In patients aged under 65 years, no significant difference in ICU admission and mortality was detected between influenza and COVID-19, whereas significantly more COVID-19 patients 65 years or older died or required intensive care treatment. Conclusions: Our study shows that increased cardiac biomarkers are associated with higher mortality and ICU admission in both, influenza and SARS-CoV-2-infected patients. Cardiac biomarkers are higher in the influenza cohort; however, this does not translate into worse outcomes when compared with the COVID-19 cohort.

Aims Iron is essential to maintain cellular energy metabolism in the myocardium. Impaired cellular iron availability negatively affects myocardial physiology and can aggravate heart failure (HF). Iron deficiency (ID) is frequently found in patients with acute and chronic HF (AHF, CHF) and associated with clinical outcome. The aim of this analysis was to assess the true ID prevalence in HF patients on the basis of different ID definitions. Methods We performed a retrospective analysis of 329 AHF and 613 CHF patients, recruited between 02/2021 and 05/2022 at the Innsbruck Medical University (47%/32% female, median age 81/64 years). ID was defined according to a general definition, gastroenterology and cardiology guidelines as ferritin <30 or <45 ng/mL or <100/ng/mL (absolute ID), ferritin 30–100 or 45–150 or 100–299 ng/mL plus TSAT <20% (combined ID), and ferritin >100 or >150 or ≥300 ng/mL plus TSAT <20% (functional ID). Results ID prevalence was significantly higher in AHF compared with CHF patients: general definition (74.8% vs. 32.6%, P < 0.001), gastroenterology guidelines (75.7% vs. 34.7%, P < 0.001), cardiology guidelines (79.9% vs. 47.3%, P < 0.001). We found distinctive differences in prevalence of ID types between the three definitions. Absolute ID prevalence was highest when applying cardiology compared with gastroenterology guidelines and general definition (AHF: 44.7% vs. 20.4% vs. 7.0%; CHF: 34.1% vs. 13.4% vs. 7.2%), while frequency of combined ID was almost equally distributed. Functional ID prevalence was highest when applying general definition compared with gastroenterology and cardiology guidelines (AHF: 34.7% vs. 23.4% vs. 11.6%; CHF: 13.1% vs. 9.0% vs. 3.4%). Out of 494 patients classified as having absolute or combined ID according to the cardiology guidelines, only 252 patients received the same classification while 107 and 135 patients were classified having no and functional ID when applying the general definition. Conclusions We show that ID prevalence is higher in AHF versus CHF patients in a continuous cohort of HF patients managed at the same institution over the same period of time. There were distinctive differences in detection of ID and the type of ID when applying several recommended definitions thus affecting sensitivity and specificity for absolute and functional ID detection. This may result in exclusion of patients, which may benefit from iron supplementation and inclusion of those who may not respond or even anticipate site effects. Our study calls for the urgent need of prospective trials for redefinition of ID and identification of biomarkers associated with therapeutic response to optimize patient outcomes.

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.

ObjectivesThe identification of the SARS-CoV-2 Omicron variants BA.1 and BA.2 immediately raised concerns about the efficacy of currently used monoclonal antibody therapies. Here, we analyzed the activity of Sotrovimab and Regdanvimab, which are used in clinics for treatment of moderate to severe SARS-CoV-2 infections, and Cilgavimab/Tixagevimab, which are approved for prophylactic use, against BA.1 and BA.2 in a 3D model of primary human bronchial epithelial cells.MethodsPrimary human airway epithelia (HAE) cells in a 3D tissue model were infected with clinical isolates of SARS-CoV-2 Delta, BA.1 or BA.2. To mimic the therapeutic use of mAbs, we added Regdanvimab, Sotrovimab or Cilgavimab/Tixagevimab 6 h after infection. In order to mirror the prophylactic use of Cilgavimab/Tixagevimab, we added this compound 6 h prior to infection to the fully differentiated, pseudostratified epithelia cultured in air-liquid interphase (ALI).ResultsWe observed that Sotrovimab, but not Regdanvimab, is active against BA.1; however, both antibodies lose their efficacy against BA.2. In contrast, we found that BA.2 was sensitive to neutralization by the approved prophylactic administration and the therapeutic use, which is not yet permitted, of Cilgavimab/Tixagevimab.ConclusionImportantly, while the use of Tixagevimab/Cilgavimab is effective in controlling BA.2 but not BA.1 infection, monoclonal antibodies (mAbs) with efficacy against BA.1 are ineffective to reduce BA.2 virus replication in a human lung model. Our data may have implications on the variant specific clinical use of monoclonal antibodies.