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In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2–5 and 7–10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79–0.80, p  < 0.05). During hospitalization the decline was most significant for IP-10 ( p  < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.

Evidence from both experimental and clinical trials indicates that inflammatory mediators are of importance in the pathogenesis of chronic heart failure (HF) contributing to cardiac remodeling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1β and IL-6 in HF patients in plasma and circulating leukocytes, as well as in the failing myocardium itself. There is strong evidence that these mediators are involved in processes leading to cardiac remodeling such as hypertrophy, fibrosis and apoptosis. Some of these cytokines can also give useful prognostic information as reliable biomarkers in this disorder. In general, immunomodulating treatments have, with a few exceptions, been neutral or even harmful. However, the negative results of anti-TNF studies, for instance, do not necessarily argue against the ‘cytokine hypothesis’. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients and result in beneficial net effects. Future studies should identify the crucial actors and their mechanisms of action in the immunopathogenesis of chronic HF and, in particular, clarify the balance between adaptive and maladaptive effects of these molecules. Such studies are a prerequisite for the development of new treatment strategies that target inflammatory and immunopathogenic mechanisms in HF. In this review article, these issues are thoroughly discussed, and we also argue for the possibility of future therapeutic targets such as mediators in innate immunity, chemokines and mediators in matrix remodeling.

Background Gut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce. Methods Rectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n  = 123) and three-month post-admission ( n  = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality. Results Gut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO 2 /FiO 2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p  < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00–8.6], p  < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p  = 0.007). Conclusions Although our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted. Trial registration NCT04381819 . Retrospectively registered May 11, 2020.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21–0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52–7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08–3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11–2.50, p = 0.014, OR 1.86, 95% CI 1.25–2.77, p = 0.002, OR 0.32, 95% CI 0.15–0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22–2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.

BackgroundHigher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population.MethodsIn an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival.ResultsMean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity.ConclusionsThe present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF.Graphic abstractCategories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF).

The overuse of compression ultrasound procedures on patients with suspected deep vein thrombosis compromise the cost-effectiveness of deep vein thrombosis management and emphasize room for improvement of the current diagnostic algorithm. As the complement system and hemostasis are comprehensively intertwined, we aimed to investigate complement activation products as diagnostic tests for acute deep vein thrombosis alone or together with D-dimer. We performed a cross-sectional study using consecutive sampling of outpatients referred to the emergency department with suspected first-time deep vein thrombosis of the lower limbs, to investigate the diagnostic utility of the index tests C3bc and C5b-C9 terminal complex (TCC) with compression ultrasound as reference standard. For comparison of receiver operating characteristics, analyses were also performed for D-dimer and C-reactive protein in addition to analyses for the index tests on a D-dimer positive patient subgroup. Of the 366 included patients, 103 had deep vein thrombosis. The calculated effect sizes of differences between groups (Cohen's d) with 95% confidence intervals (95%CI) were 0.25 (95%CI 0.03-0.48) for C3bc, 0.33 (95%CI 0.09-0.57) for C5b-C9 terminal complex (TCC), 0.88 (95%CI 0.61-1.15) for C-reactive protein, and 1.64 (95%CI 1.37-1.91) for D-dimer. The areas under the curves derived from comparison receiver operating characteristics analyses with corresponding 95%CIs for C3bc, C5b-C9 terminal complex (TCC), C-reactive protein and D-dimer were 0.56 (95%CI 0.50-0.63), 0.64 (95%CI 0.58-0.69), 0.73 (95%CI 0.67-0.79) and 0.92 (95%CI 0.89-0.95), respectively. The plasma levels of the complement activation products C3bc and C5b-C9 terminal complex (TCC) were elevated in patients with acute deep vein thrombosis but displayed low diagnostic performance for deep vein thrombosis alone or together with D-dimer.

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI. Men develop larger myocardial infarction (MI) sizes than women. Here, the authors show that male sex and testosterone, via bone marrow stroma, exacerbates MI-induced neutrophilia and cardiac injury and that response to anti-inflammatory treatment in MI is greater in men than women

Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra ( P  = 0.01) and IL-18 ( P  = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 ( P  = 0.02) and PRS of anxiety and IL-18 ( P  = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R ( P  = 0.02) and PRS of educational attainment and sIL-2R ( P  = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P  = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P  = 0.02) and sTNFR-1 (IE, P  = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

BackgroundImmunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs.MethodsWe included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference.ResultsAP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) (β = 0.094, p = 0.8E-4), AD use with higher serum levels of CRP (β = 0.072, p = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) (β = 0.063, p = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels (β = 0.045, p = 2.3E-4), AD dose with CRP levels (β = 0.039, p = 0.001), MS dose with sIL-2R levels (β = 0.048, p = 0.001), and serum concentration of AD was nominally positively associated with CRP (β = 0.072, p = 0.002).ConclusionsThe findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.