Simultaneous Depression of Immunological Synapse and Endothelial Injury is Associated with Organ Dysfunction in Community-Acquired Pneumonia.

RATIONALE: A depressed expression of antigen presentation is, along with endothelial dysfunction, a recognized signature of severe community-acquired pneumonia (CAP). We aimed to evaluate the expression of a number of genes involved in the immunological synapse in non-critically ill CAP patients with or without organ dysfunction and to profile endothelial biomarkers such as proendothelin-1 (proET1) and proadrenomedullin (proADM). METHODS: A nested study in a prospective cohort in CAP patients was performed. Expression levels of major histocompatibility complex class II DR alpha (HLA-DRA), CD40 ligand (CD40LG), CD3E, CD28, and inducible T-cell costimulator (ICOS) were quantified by using droplet digital polymerase chain reaction and endothelial biomarkers by immunofluorescence. RESULTS: Ninety-four patients were included, 44.7% of whom had organ failure in one or more organs. A significant decrease in the expression of the five genes with increased levels of proadrenomedullin (proADM) and proendothelin-1 (proET1) was found in CAP with organ failure. The depressed expression of HLA-DRA (odds ratio (OR), 2.94), CD40LG (OR, 3.90), and CD28 (OR, 3.48) was independently associated with organ failure after adjustment for age, Charlson score, and severity. CONCLUSIONS: CAP with organ failure showed depressed expression of immunological synapse genes with increased levels of biomarkers denoting endothelial damage. Simultaneous profiling of immunological and endothelial signatures could help in the early identification of organ failure in CAP and in the implementation of personalized treatment.

Community-Acquired Pneumonia Patients at Risk for Early and Long-term Cardiovascular Events Are Identified by Cardiac Biomarkers.

BACKGROUND: Community-acquired pneumonia (CAP) increases the risk of cardiovascular complications during and following the episode. The goal of this study was to determine the usefulness of cardiovascular and inflammatory biomarkers for assessing the risk of early (within 30 days) or long-term (1-year follow-up) cardiovascular events. METHODS: A total of 730 hospitalized patients with CAP were prospectively followed up during 1 year. Cardiovascular (proadrenomedullin [proADM], pro-B-type natriuretic peptide (proBNP), proendothelin-1, and troponin T) and inflammatory (interleukin 6 [IL-6], C-reactive protein, and procalcitonin) biomarkers were measured on day 1, at day 4/5, and at day 30. RESULTS: Ninety-two patients developed an early event, and 67 developed a long-term event. Significantly higher initial levels of proADM, proendothelin-1, troponin, proBNP, and IL-6 were recorded in patients who developed cardiovascular events. Despite a decrease at day 4/5, levels remained steady until day 30 in those who developed late events. Biomarkers (days 1 and 30) independently predicted cardiovascular events adjusted for age, previous cardiac disease, Pao2/Fio2 < 250 mm Hg, and sepsis: ORs (95% CIs), proendothelin-1, 2.25 (1.34-3.79); proADM, 2.53 (1.53-4.20); proBNP, 2.67 (1.59-4.49); and troponin T, 2.70 (1.62-4.49) for early events. For late events, the ORs (95% CIs) were: proendothelin-1, 3.13 (1.41-7.80); proADM, 2.29 (1.01-5.19); and proBNP, 2.34 (1.01-5.56). Addition of IL-6 levels at day 30 to proendothelin-1 or proADM increased the ORs to 3.53 and 2.80, respectively. CONCLUSIONS: Cardiac biomarkers are useful for identifying patients with CAP at high risk for early and long-term cardiovascular events. They may aid personalized treatment optimization and for designing future interventional studies to reduce cardiovascular risk.

Association of erythrocyte deformability with red blood cell distribution width in metabolic diseases and thalassemia trait.

Increased red blood distribution width (RDW) in anemia is related to disturbances in the cellular surface/volume ratio, usually accompanied by morphological alterations, while it has been shown in inflammatory diseases that the activity of pro-inflammatory cytokines disturbing erythropoiesis increases RDW. Recently it has been reported that higher RDW is related with decreased erythrocyte deformability, and that it could be related with the association of RDW and increased risk of cardiovascular diseases. In order to analyze the influence of morphological alterations and proinflammatory status on the relationship between RDW and erythrocyte deformability, we analyzed erythrocyte deformability along with RDW and other hematological and biochemical parameters in 36 α-thalassemia, 20 ß-thalassemia, 20 δß-thalassemia trait carriers, 61 metabolic syndrome patients and 76 morbidly obese patients. RDW correlated inversely with erythrocyte deformability in minor ß-thalassemia (r =-0.530, p <  0.05), and directly in both metabolic syndrome and morbidly obese patients (ρ= 0.270, p <  0.05 and ρ= 0.258, p <  0.05, respectively). Minor ß-thalassemia is often accompanied by more marked cell-shaped perturbations than other thalassemia traits. This could be the reason for this negative association only in this setting. Higher anisocytosis seems to be associated with greater morphologic alterations (shape/volume), which reduce erythrocyte deformability. The proinflammatory profile in metabolic patients can be related to the positive association of RDW with erythrocyte deformability found in these patients. However, further research is needed to explain the mechanisms underlying this association.

Red blood cell distribution width and erythrocyte deformability in patients with acute myocardial infarction.

Increased RDW has been found to be a marker of adverse outcomes in cardiovascular disease (CVD), although the exact mechanism remains unclear. Recently, several authors have found that higher RDW is associated with decreased erythrocyte deformability, which can impair blood flow through microcirculation, a fact which may explain the increased risk for CVD events associated with elevated RDW. The aim of the present study was to investigate the association between RDW and erythrocyte deformability in patients with acute myocardial infarction (AMI). The study group comprised 60 AMI patients and 72 gender- and age-matched controls, in whom erythrocyte deformability was determined by means of the elongation index (EI) in a Rheodyn SSD, along with haematological, biochemical and inflammatory parameters. Patients showed higher RDW (p = 0.012) and lower EI (p < 0.05) than controls. When anaemic patients were removed from the study, AMI showed still lower EI than controls (p < 0.05), but no differences in RDW were observed (p = 0.141). RDW correlated inversely with haematimetric indices (p < 0.001), but not with inflammatory and biochemical parameters (p > 0.05). EI correlated inversely with Hb, MCHC (p < 0.001) and directly with MCV (p < 0.05). EI also correlated inversely with glucose (p < 0.05) and directly with HDL-cholesterol (p < 0.05). The multivariate regression model showed that only MCV and Hb were independent predictors of RDW (beta coefficients: -0.383, -0.208; p < 0.001, p = 0.050, respectively). In addition, MCV, MCHC and hyperlipidaemia were independent predictors of EI (beta coefficients: 0.366, -0.533, -0.192; p < 0.001, p < 0.001, p = 0.019 respectively). In AMI patients, increased RDW is not related with EI, so this mechanism does not seem to be responsible for an increased CDV risk in these patients.

Hemorheological parameters as independent predictors of venous thromboembolism.

The role played by hemorheological alterations in the development of deep vein thrombosis (DVT) has often been overlooked. Although marked rheological alterations and the relationship with thromboembolic events are well-defined in patients with hematological diseases such as myelom, Waldenström disease and polycythemia vera, the relationship is not so clear in patients without hematological diseases. In the present review, we analyzed studies evaluating the rheological profile in DVT patients. Among the cardiovascular risk factors, only hyperlipidemia, metabolic syndrome, tobacco and obesity increase DVT risk and, in addition, a disturbed rheological profile is shown which could further increase this risk. The significance of hematocrit and fibrinogen, the main factors influencing blood viscosity, is not sufficient to increase blood viscosity in any of the studies analyzed. DVT patients show increased fibrinogen levels and erythrocyte aggregation throughout all the studies despite patients not being in an acute reactant phase. In addition to rheological alterations, it is necessary to consider local conditions at pockets of venous valves which undergo deterioration with aging and play an important role equally to alterations in the rheological profile. Moreover, it is necessary to take into account that systemic rheological alterations are not comparable to those in low shear rate areas where minimum disturbances could be more relevant. It would be convenient to perform multicentric studies with the same rheological methodology and pre-analytical procedures to evaluate, in order to obviate the effect of thrombophilic and circumstantial risk factors, rheological parameters in patients with spontaneous DVT to elucidate their real contribution to the development of thromboembolic events.

Posterior ocular involvement in Behçet's disease and thrombophilic mutations.

It is not well established whether there is an association among common inherited gene defects, Factor V (FV) Leiden, the prothrombin (PT) G20210A mutation, C677T methylene tetrahydrofolate reductase (MTHFR) and ocular Behçet's disease (BD). We aimed to evaluate the association of these mutations with posterior ocular involvement in 89 BD patients from eastern Spain (48 men and 41 women) of whom 23 had posterior ocular involvement and 66 did not. None of the 23 BD patients with posterior ocular involvement was a carrier of either FV Leiden or the PTG20210A mutation. Only 1 patient was a carrier of the 677TT MTHFR mutation, whereas 4 patients carried FV Leiden, 3 the PTG20210A mutation and 10 the 677TT MTHFR mutation in the group without posterior ocular involvement (p = 0.227, p = 0.556, p = 0.144), respectively. In our geographical area, the commonest thrombophilic mutations do not seem to be related with posterior ocular involvement in BD patients.

Rheological red blood cell behaviour in minor α-thalassaemia carriers.

Although several studies have been published regarding rheological behaviour of red blood cells in beta and delta-beta thalassaemia traits, little information about erythrocyte deformability in alpha-thalassaemia carriers is available. We aimed to determine erythrocyte deformability in heterozygous (silent, -α/αα) and homozygous (minor alpha-thalassaemia, -α/-α) carriers of the alpha-thalassaemia trait for the alpha 3.7 deletion, the most common in our geographical area. We evaluated erythrocyte deformability by means of the elongation index (EI) in a Rheodyn SSD at 12, 30 and 60 Pa, along with basic haematological cell count, erythrocyte indices, reticulocytes, plasma lipids and iron metabolism parameters in 36 (18 women, 18 men) alpha-thalassaemia carriers (17 heterozygous, 19 homozygous) and 36 healthy subjects (23 women, 13 men). The molecular diagnosis of the alpha 3.7 deletion was evaluated by a PCR-based method. Alpha-thalassaemia carriers presented higher red blood cell counts, RDW-CV (p < 0.001) and lower haemoglobin, MCV, MCH and MCHC (p < 0.001) than controls. EI was statistically lower at 12, 30 and 60 Pa in cases than in controls (p = 0.001, p = 0.002, p = 0.010, respectively). No differences in either elongation indices or haematimetric values were observed when comparing silent heterozygous and minor homozygous alpha-thalassaemia carriers (p > 0.05). Pearson's bivariate correlation showed that EI60 correlated positively with haemoglobin and MCV, MCH, MCHC (p < 0.01), but negatively with ferritin (p< 0.05) and RDW-CV (p< 0.01). In the multivariate regression analysis, MCV (p = 0.001) and haemoglobin (p < 0.001) predicted EI60, with this model accounting for around 43% of variation in EI60 (R2 = 0.427). Alpha-thalassaemia carriers phenotypically showed mild microcytosis and hypochromia, irrespectively of them being silent heterozygous or minor homozygous alpha-thalassaemia carriers, which is associated with decreased erythrocyte deformability.

Metabolic alterations in morbid obesity. Influence on the haemorheological profile.

There are few studies on haemorheological disturbances in morbidly obese patients. The role played by the metabolic syndrome on the rheological profile of morbidly obese subjects has not yet been established, and it is not clear whether morbidly obese, but "metabolically healthy", show rheological alterations. We aimed to determine the whole rheological profile in 136 morbidly obese patients and 136 normo-weight volunteers, along with plasma lipids, inflammatory and insulin resistance parameters. Patients had statistically higher glucose, triglycerides, HbA1c, leptin, insulin, HOMA, CRP, leucocytes, fibrinogen, plasma viscosity (p < 0.001, respectively), erythrocyte aggregation at 3 s-1 (p = 0.011) and lower erythrocyte elongation index 60 Pa (p = 0.015). In the multivariate regression analysis, the anthropometric, lipidic, insulin resistance and inflammatory parameters predicted haemorheological variables (p < 0.001). No differences were observed for the rheological parameters when morbidly obese subjects with (n = 75) and without (n = 61) the metabolic syndrome were compared (p > 0.05), indicating that the altered rheological profile not only related to the metabolic syndrome, but to obesity itself. When further patients were classified as "metabolically healthy" obese (n = 23) and "metabolically unhealthy" obese (n = 113), the latter presented higher insulin resistance (insulin p < 0.01, HOMA p < 0.05, glucose p < 0.001, triglycerides p < 0.05 and HbA1c p < 0.01) than the former, but no differences in the rheological parameters (p > 0.05) were observed. When "metabolically healthy" obese (n = 23) were compared with "metabolically healthy" controls (n = 81), the former still showed higher HOMA (p < 0.001), triglycerides (p < 0.05), CRP (p < 0.001) and HbA1c (p < 0.05), higher fibrinogen (p < 0.001), plasma viscosity (p < 0.001), erythrocyte aggregation at 3 s-1 (p < 0.05), but a lower erythrocyte elongation index 60 Pa (p < 0.05). Morbidly obese subjects present a more pronounced altered rheological profile in those with metabolic alterations, although the "metabolically healthy" obese also displayed rheological alterations if compared with "metabolically healthy" non-obese controls. These rheological alterations relate to both insulin resistance and inflammation.

Hemorheological profile in primary Sjögren's syndrome: a case-control study.

Rheological blood behavior in primary Sjögren's syndrome (SS) has been scarcely investigated. We evaluated the rheological profile (blood viscosity, plasma viscosity, erythrocyte deformability, erythrocyte aggregation, erythrocyte aggregation time and erythrocyte disaggregation threshold) along with fibrinogen, high-sensitive C reactive protein, plasma lipids, immunoglobulins, total proteins and erythrocyte sedimentation rate in 22 patients with primary SS (2 males, 20 females, aged 58 ± 9 years) and in 22 healthy volunteers (3 males, 19 females, aged 57 ± 5 years). Patients showed statistically higher plasma viscosity, erythrocyte sedimentation rate and G immunoglobulin (IgG) levels and lower total cholesterol than controls (p = 0.006, p = 0.023, p = 0.034, p = 0.036, respectively). Three patients with extraglandular involvement showed the highest plasma viscosity values: 1.98 cP, 1.70 cP and 1.65 cP, respectively. No differences were observed for the other rheological parameters analyzed. In a multivariate regression analysis, only fibrinogen, triglycerides and IgG were independent determinants for plasma viscosity values (beta coefficient: 0.335; p = 0.001; beta coefficient: 0.242; p = 0.019; beta coefficient: 0.660; p < 0.001, respectively). Our results indicate that patients with primary SS show increased plasma viscosity, mostly related with IgG levels without other alterations in the rheological profile. Further research with a larger sample size achieved by multicenter studies would be desirable.