Cluster analysis of volatile organic compounds - A pilot study in patients with severe acute decompensated heart failure.

INTRODUCTION: Acute decompensated heart failure (ADHF) is a global health problem and early detection of high-risk patients for effective treatment is important. Exhaled breath analysis and measurement of volatile organic compounds (VOCs) may be a fast and cost-effective non-invasive diagnostic and screening tool complementing measurement of cardiac biomarkers. Another technique to detect and characterize VOCs is the ion mobility spectrometry (IMS) not requiring vacuum or sample pretreatment. METHODS: This prospective controlled proof-of-concept study prospectively enrolled adult patients with severe ADHF at the University Hospital Heart Centre Brandenburg. Severe ADHF was defined as patients presenting with symptomatic acute decompensation and NTproBNP >7000 pg/dL. Cardiac patients with NT-proBNP 220 pg/dL served as control. A gas chromatography ion mobility spectrometer (GC-IMS) of the type "MultiMarkerMonitor™" from GRAUPNER medical solutions GmbH was used. Measurement was performed at T0 (within 24 h of admission), T1 (after 3-5 days) and T2 (after 8-10 days). RESULTS: Forty patients were enrolled in the study, 20 patients with severe ADHF and 20 control patients. In patients with severe ADHF, three clusters with significantly altered maximum peak heights were detected compared to control. There was no change in the peak height of clusters 8, 9 and 206 at the time points T1 and T2 (all p > 0.50). Also, NT-proBNP was stable over time (p = 0.247). Sixteen control patients (16/20, 80 %) and four with severe ADHF (4/20, 20 %) presented without cluster deviation. Patients with deviation in at least two clusters had longer hospital stay, 11 days (5.0-15.0) compared to those without deviation, 4 days (2.0-9.5), p = 0.028. CONCLUSION: Longer-term follow-up studies are needed to assess the stability and clinical significance of the identified clusters by IMS and their diagnostic and prognostic relevance.

Care Bundle for Acute Kidney Injury in Cardiac Patients: A Cluster-Randomized Trial.

Detection and timely intervention of acute kidney injury (AKI) is a major challenge worldwide. Electronic alerts for AKI may improve process- and patient-related endpoints. The present study evaluated the efficacy of an AKI electronic alert system and care bundle. This is a two-arm, prospective, cluster-randomized, controlled trial enrolling patients with AKI (KDIGO criteria) and cardiac diseases. Patients were randomly assigned to a routine care group or intervention group (DRKS-IDDRKS00017751). Two hundred patients (age 79 years, 46% female) were enrolled, with 100 patients in each group. The primary endpoint did not differ between patients in the routine care group 0.5 (-7.6-10.8) mL/min/1.73 m2 versus patients in the intervention group 1.0 (-13.5-15.1) mL/min/1.73 m2, p = 0.527. Proportions of patients in both study groups with hyperkalemia, pulmonary edema, and renal acidosis were comparable. The stop of antihypertensive medication during hypotensive periods was more frequent in patients in the intervention group compared to patients in the control group, p = 0.029. The AKI diagnosis and text module for AKI in the discharge letter were more frequently documented in patients in the intervention group (40%/48% vs. 25%/34%, p = 0.034; p = 0.044, respectively). Continued intake of RAAS inhibitors and the presence of a cardiac device were independently associated with a less pronounced decrease in eGFR from admission to the lowest value. In this RCT, electronic alerts for AKI and a care bundle improved process- but not patient-related endpoints.

Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms.

OBJECTIVES: EF is a rare disease characterized by fibrosis and inflammation of the fascia, scleroderma-like skin indurations and optional blood eosinophilia. We aimed to expand the knowledge about its aetiology and pathogenesis. METHODS: Biopsy specimens from 16 EF patients were assessed by histology, immunohistochemistry and quantitative reverse transcription PCR in comparison with anti-Mi-2+ DM patients and non-disease controls. RESULTS: Histologically, EF shows mild to severe inflammation at the muscle-fascia interface, with frequent involvement of the underlying muscle tissue, though varying in degree. CD206+ macrophages predominate and eosinophils are detected within the fascia in the majority of cases, however in quite small numbers, and seen infrequently within the muscle. Activators of the so-called Th2-M2 pathway like STAT6 and IL-4 are upregulated leading to high expression levels of CD206. Activators of the so-called Th1-M1 pathway like STAT1 and IFN-γ (IFNG) are also upregulated, though not translating into a significant upregulation of the effector molecule COX2. Interestingly, activators or chemoattractants of eosinophils show no significant upregulation in EF compared with DM. EF shows features of perifascicular pathology comparable to DM, with upregulation of MHC class I and II; however, this is not accompanied by perifascicular atrophy or any signs of a type I IFN response or hypoxia-mediated processes. CONCLUSIONS: Our findings highlight a specific immune phenotype of leucocyte infiltrates in EF along features of perifascicular pathology similar to DM, while there is no evidence of hypoxia-mediated or type I IFN-associated processes with perifascicular fibre atrophy, indicating different pathomechanisms of muscle involvement.

Progression of Chronic Kidney Disease and All-Cause Mortality in Patients with Tricuspid Regurgitation.

Aim: The impact of chronic kidney disease (CKD) on patient-related outcomes in patients with tricuspid regurgitation (TR) is well known. However, the impact of the progression of CKD in patients with TR and potentially modifiable risk factors of progressing CKD is unknown. Methods: 444 consecutive adult patients with TR and CKD stage 1−4 admitted in an inpatient setting between January 2010 and December 2017 were included. During a median follow-up of two years, eGFR and survival status were collected. Independent risk factors for CKD progression and all-cause mortality were determined. Patient survival statuses were grouped according to different combinations of the presence or absence of CKD progression and the TR grade. Results: Progression of CKD (OR 2.38 (95% confidence interval 1.30−4.35), p = 0.005), the grade of TR (OR 2.38 (1.41−4.00), p = 0.001) and mitral regurgitation (OR 1.72 (1.20−2.46), p = 0.003) were independent risk factors for all-cause mortality. Haemoglobin at admission (OR 0.80 (0.65−0.99), p = 0.043) and the presence of type 2 diabetes (OR 1.67 (1.02−2.73), p = 0.042) were independent risk factors for CKD progression. The combination of the status of CKD progression and the TR grade showed a stepwise pattern for all-cause mortality (p < 0.001). Patients with CKD progression and TR grade 1 had comparable all-cause mortality with patients without CKD progression but with TR grade 2 or 3. Even in patients with TR grade 1, the risk for all-cause mortality doubled if CKD progression occurred (OR 2.49 (95% CI 1.38−4.47), p = 0.002). Conclusion: CKD progression appears to be a risk factor for all-cause mortality in patients with TR. Anaemia and diabetes are potential modifiers of CKD progression.

Peripheral blood mononuclear cells are hypomethylated in active rheumatoid arthritis and methylation correlates with disease activity.

OBJECTIVE: Epigenetic modifications are dynamic and influence cellular disease activity. The aim of this study was to investigate global DNA methylation in peripheral blood mononuclear cells (PBMCs) of RA patients to clarify whether global DNA methylation pattern testing might be useful in monitoring disease activity as well as the response to therapeutics. METHODS: Flow cytometric measurement of 5-methyl-cytosine (5'-mC) was established using the cell line U937. In the subsequent prospective study, 62 blood samples were investigated, including 17 healthy donors and 45 RA patients at baseline and after 3 months of treatment with methotrexate, the IL-6 receptor inhibitor sarilumab, and Janus kinase inhibitors. Methylation status was assessed with an anti-5'-mC antibody and analysed in PBMCs and CD4+, CD8+, CD14+ and CD19+ subsets. Signal intensities of 5'-mC were correlated with 28-joint DASs with ESR and CRP (DAS28-ESR and DAS28-CRP). RESULTS: Compared with healthy individuals, PBMCs of RA patients showed a significant global DNA hypomethylation. Signal intensities of 5'-mC correlated with transcription levels of DNMT1, DNMT3B and MTR genes involved in methylation processes. Using flow cytometry, significant good correlations and linear regression values were achieved in RA patients between global methylation levels and DAS28-ESR values for PBMCs (r = -0.55, P = 0.002), lymphocytes (r = -0.57, P = 0.001), CD4+ (r = -0.57, P = 0.001), CD8+ (r = -0.54, P = 0.001), CD14+ (r = -0.49, P = 0.008) and CD19+ (r = -0.52, P = 0.004) cells. CONCLUSIONS: The degree of global DNA methylation was found to be associated with disease activity. Based on this novel approach, the degree of global methylation is a promising biomarker for therapy monitoring and the prediction of therapy outcome in inflammatory diseases.

[Current Recommendations for Diagnostics in Giant Cell Arteritis]. / Aktuelle Empfehlungen zur Diagnostik der Riesenzellarteriitis.

In Giant Cell Arteritis (GCA), a timely diagnosis is required to avoid severe complications such as blindness or structural vascular damage. The heterogeneous symptoms are mainly due to local and systemic inflammatory processes. Diagnostics are based on increased inflammation parameters in the laboratory, imaging, in which color-coded duplex sonography (FKDS), high-resolution magnetic resonance imaging (MRI), computer tomography (CT) or CT angiography (CTA) and 18F fluorodeoxyglucose-positron emission tomography with CT (FDG-PET-CT) have become established, as well as histopathological findings in temporal artery biopsy.

Improved adalimumab dose decision with comprehensive diagnostics data.

OBJECTIVES: Monoclonal antibodies are important in the treatment of rheumatoid arthritis (RA). This is the first trial to monitor the effect of adalimumab dose escalation in persistently active RA. The aim of this study was to identify the response to adalimumab to improve the basis for making decision in relation to actual drug capacity in serum. METHODS: The disease activity of RA patients was assessed with CDAI and DAS28 before administration of additional 40 mg adalimumab one week after standard injection. Serum samples were analysed using the recoveryELISA technology, a combination of sandwich ELISA and competitive assay. The recoveryELISA measure the concentrations of free TNF-α, drug level, and the remaining active adalimumab in the patients' sera. An adalimumab concentration of 5.0-10.0 g/mL was defined as the targeted therapeutic window. RESULTS: Five of 8 patients achieved moderate EULAR response by dose escalation. The results of the free adalimumab and TNF-α neutralisation measurements allowed a separation of the cohort (n=17) into three groups. Group 1 represents 18% of the patients with free adalimumab level higher 30.0 µg/mL and TNF-α neutralisation above 95%. Group 2 (47%) consists of patients within the therapeutic window with balanced free adalimumab and TNF-α neutralisation values. Group 3 contains 35% of the cohort with low concentrations of free adalimumab and lowest remaining TNF-α-neutralisation capacity. Anti-drug antibodies were detected in four patients but did not prevent response to treatment. CONCLUSIONS: Drug and antigen monitoring using recoveryELISA may support dose decision to avoid unnecessary switch in medication or possible overtreatment.

Increased Prevalence of Diastolic Heart Failure in Patients with Rheumatoid Arthritis Correlates with Active Disease, but Not with Treatment Type.

OBJECTIVE: Although heart failure (HF) is a major cause of premature mortality, there is little information regarding its prevalence and associated risk factors in patients with rheumatoid arthritis (RA). In this study, we evaluated the prevalence of HF in a community-based RA cohort. Further, we investigated the effect of RA activity and present treatment on HF rate and cardiac structure. METHODS: A diagnostic workup for HF according to the European Society of Cardiology recommendations was performed in 157 patients with RA fulfilling the American College of Rheumatology/European League Against Rheumatism criteria (68% women, age 61 ± 13 yrs) from our outpatient clinic and in 77 age- and sex-matched controls. RESULTS: The prevalence of HF in patients with RA (24%) was unexpectedly high and differed significantly from the control sample (6%, p = 0.001). Diastolic HF was the dominant type (23% vs 6%), and clinical symptoms alone were of low diagnostic value. Active RA (28-joint Disease Activity Score ≥ 2.6: OR 3.4, 95% CI 1.3-9.8) was an independent risk factor of HF, as well as systemic inflammation (erythrocyte sedimentation rate > 16 mm/h: OR 5.4, 95% CI 2.1-16; C-reactive protein > 10 mg/l: OR 2.6, 95% CI 0.8-8.0) and RA duration > 10 years (OR 2.6, 95% CI 1.2-5.8). HF in RA was associated with concentric hypertrophy (48% vs 17%, p < 0.001) and reduced longitudinal strain (-17.2% vs -19.7%, p < 0.001). However, the prevalence of HF was equivalent between the treatment groups [conventional synthetic disease-modifying antirheumatic drugs (DMARD) 25%, tumor necrosis factor inhibitors 22%, other biological DMARD 27%]. CONCLUSION: Recognition of all diastolic HF in RA requires a complex diagnostic approach. Active rather than inactive RA places patients at a higher risk for HF, whereas influence of RA treatment on HF risk needs to be elucidated in further studies.

Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis.

Although in normal lamina propria (LP) large numbers of eosinophils are present, little is known about their role in mucosal immunity at steady state. Here we show that eosinophils are needed to maintain immune homeostasis in gut-associated tissues. By using eosinophil-deficient ΔdblGATA-1 and PHIL mice or an eosinophil-specific depletion model, we found a reduction in immunoglobulin A(+) (IgA(+)) plasma cell numbers and in secreted IgA. Eosinophil-deficient mice also showed defects in the intestinal mucous shield and alterations in microbiota composition in the gut lumen. In addition, TGF-ß-dependent events including class switching to IgA in Peyer's patches (PP), the formation of CD103(+) T cells including Foxp3(+) regulatory (Treg), and also CD103(+) dendritic cells were disturbed. In vitro cultures showed that eosinophils produce factors that promote T-independent IgA class switching. Our findings show that eosinophils are important players for immune homeostasis in gut-associated tissues and add to data suggesting that eosinophils can promote tissue integrity.