Churg-Strauss syndrome (CSS) is a rare systemic vasculitis associated with eosinophilia and asthma. We assessed the local immune response in airways of CSS patients with different activity of the ...disease.
Concentration of IL-5, CCL17, CCL22 and CCL26 (ELISA) together with cell expression of T-helper-related genes (real-time PCR array) were measured in bronchoalveolar lavage fluid (BALF) sampled from 11 patients with active CSS, 11 patients with CSS in remission and 9 control subjects with bronchial asthma.
In active CSS, both BALF and blood eosinophil counts were increased (P<0.01). BALF cells in active disease were characterized by an increased expression of Th2 and regulatory-type transcripts: STAT6, STAT3, GATA3, IL4, IL5 and IL10 as compared with asthmatics, and STAT5A, CCR4, FOXP3, IL4, IL5 and IL10 when compared with inactive CSS. There was significant increase in BALF concentration of IL-5 and CCL26 in exacerbation of CSS. CCR4-active chemokines were detected more frequently in active disease. We found a strong positive correlation between clinical parameters of disease activity (BVAS, eosinophilia) and expression of IL4, IL5, IL10 and STAT5A.
These results indicate that as compared with asthma, active-CSS patients have much stronger local Th2 response in the airways. Airway cells may contribute to lung eosinophilia in CSS by producing IL-5 and eosinophil active chemokines.
Given increased risk of cardiovascular events in asthma we hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme involved in atherosclerosis, is associated with ...proinflammatory and prothrombotic blood alterations in this disease.
In 164 adult asthmatics (63 with severe asthma) we measured plasma Lp-PLA2 activity using the PLAC test. We determined its relations to inflammation and prothrombotic blood alterations.
In asthma, Lp-PLA2 was inversely related to the age (β = −0.1 −0.18 to −0.02) and was lower in women (n = 122 74%, 205 182–242 vs. 243 203–262 nmol/min/ml, p = 0.001). Interestingly, Lp-PLA2 correlated negatively with the asthma severity score (β = −0.15 −0.23 to −0.07), being 10.3% higher in those with non-severe (mild or moderate) asthma (n = 101, 62%) as compared to the severe disease subtype (224 191–261 vs. 203 181–229, p = 0.006 after adjustment for potential confounders). Lp-PLA2 activity was positively related to the levels of low-density lipoprotein (β = 0.1 0.02–0.18), triglycerides (β = 0.11 0.03–0.19) and glucose (β = 0.1 0.02–0.18) and inversely to the tumor necrosis factor α (β = −0.27 −0.35 to −0.2), high sensitivity C-reactive protein (β = −0.1 −0.19 to −0.02) and fibrinogen (β = −0.12 −0.21 to −0.03), as well as prothrombin (β = −0.16 −0.24 to −0.08), and parameters describing thrombin generation potential, such as endogenous thrombin potential (β = −0.14 −0.21 to −0.06) and peak thrombin generated (β = −0.2 −0.28 to −0.12).
Elevated Lp-PLA2 activity in non-severe asthmatics suggests increased atherosclerotic risk in this group. Lower Lp-PLA2 activity accompanied by its inverse relationship to inflammatory or prothrombotic blood biomarkers observed in turn in severe asthmatics might be related to the pathogenesis of more severe asthma phenotype.
Background
Induced sputum (IS) allows to measure mediators of asthmatic inflammation in bronchial secretions. NSAID‐exacerbated respiratory disease (NERD) is recognized as a distinct asthma ...phenotype, usually with a severe course, eosinophilic airway inflammation, and increased production of pro‐inflammatory eicosanoids. A more insightful analysis of NERD patients has shown this phenotype to be nonhomogeneous.
Objective
We aimed to identify possible subphenotypes in a cohort of NERD patients with the means of latent class analysis (LCA).
Methods
A total of 95 asthma patients with aspirin hypersensitivity underwent sputum induction. High‐performance liquid chromatography or gas chromatography coupled with mass spectrometry was used to profile eicosanoids in induced sputum supernatant (ISS). Sixteen variables covering clinical characteristics, IS inflammatory cells, and eicosanoids were considered in the LCA.
Results
Three classes (subphenotypes) were distinguished within the NERD cohort. Class 1 subjects had mild‐to‐moderate asthma, an almost equal distribution of inflammatory cell patterns, the lowest concentrations of eicosanoids, and logLTE4/logPGE2 ratio. Class 2 represented severe asthma with impaired lung function despite high doses of steroids. High sputum eosinophilia was in line with higher pro‐inflammatory LTE4 in ISS and the highest logLTE4/logPGE2 ratio. Class 3 subjects had mild‐to‐moderate asthma and were also characterized by eosinophilic airway inflammation, yet increased production of pro‐ (LTE4, PGD2 and 11‐dehydro‐TBX2) was balanced by anti‐inflammatory PGE2. The value of logLTE4/logPGE2 was between values calculated for classes 1 and 3, similarly to disease control and severity.
Conclusions
LCA revealed three distinct NERD subphenotypes. Our results support a more complex pathobiology of aspirin hypersensitivity. Considering NERD heterogeneity, the relationship between inflammatory pathways and clinical manifestations of asthma may lead to more individualized treatment in difficult to treat patients in the future.
Heterogeneity of NERD phenotype reflects differences in inflammatory response measured by airway cells and eicosanoids. Identifying subphenotypes provides a more insightful perception and suggests a need for more individualized approach. In aspect of logLTE4/logPGE2 ratio, latent class analysis assigned subject to different groups better than identification by disease severity or control emphasizing the heterogeneity in NERD subgroup. Abbreviations: LTE4, Leukotriene E4; NERD, NSAID‐exacerbated respiratory disease; PGE2, Prostaglandin E2
Introduction
Aspirin‐exacerbated respiratory disease (AERD) is a phenotype of asthma characterized by eosinophilic inflammation in the airways, mast cell activation, cysteinyl leukotriene ...overproduction, and acute respiratory reactions on exposure to cyclooxygenase‐1 inhibitors. Aspirin desensitization followed by daily high‐dose aspirin therapy is a safe and effective treatment option for the majority of patients with AERD. However, there is still some percentage of the population who do not derive benefits from daily aspirin use.
Methods
Based on the current literature, the biomarkers, which might predict aspirin treatment outcomes in AERD patients, were evaluated.
Results and conclusions
Patients with severe symptoms of chronic rhinosinusitis, type 2 asthma based on blood eosinophilia, non‐neutrophilic inflammatory phenotype based on sputum cells, as well as high plasma level of 15‐hydroxyeicosatetraenoic acid (15‐HETE) are potentially good responders to long term high‐dose aspirin therapy. Additionally, high expression of the hydroxyprostaglandin dehydrogenase gene, HPGD encoding prostaglandin‐degrading enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) and low expression of the proteoglycan 2 gene, PRG2 encoding constituent of the eosinophil granule in sputum cells might serve as a predictor of good response to aspirin therapy. Variations in the expression of cysteinyl leukotriene receptor 1 in the airways could additionally influence the response to long‐term aspirin therapy. Arachidonic acid metabolites levels via the 5‐lipoxygenase as well as via the cyclooxygenase pathways in induced sputum supernatant do not change during high dose long‐term aspirin therapy and do not influence outcomes of aspirin treatment.
Recently, we have reported that asthma is characterized by prothrombotic blood alterations, which were related to the low-grade inflammatory state. Inflammation, however, may also lead to vascular ...dysfunction. The aim of this study was to evaluate plasma levels of cellular fibronectin (cFN), a marker of vascular injury in asthmatics, and to analyze their impact on described previously prothrombotic blood alterations.
In a cross-sectional study, we investigated 164 adult stable asthmatics and 72 matched controls. Plasma cFN was measured using an ELISA. Its relations to inflammation, thrombin generation, fibrinolytic capacity, expressed as clot lysis time (CLT), and platelet markers were evaluated.
Asthma was associated with 50.1% higher plasma cFN levels as compared with controls (p < 0.001, after adjustment for potential confounders). There was a positive association of cFN with asthma severity and inverse with the FEV1/VC index (β = 0.2 95%CI:0.13–0.28 and β = −0.15 95%CI: −0.23 to −0.07, respectively). In asthmatics cFN positively correlated with high-sensitivity C-reactive protein (β = 0.24 95%CI:0.16–0.32), fibrinogen (β = 0.13 95%CI:0.04–0.21), interleukin-6 (β = 0.23 95%CI:0.15–0.3), platelet factor 4 (β = 0.14 95%CI:0.06–0.21), plasminogen (β = 0.11 95%CI:0.04–0.19) and CLT (β = 0.35 95%CI:0.28–0.42). In both groups cFN was related to the endogenous thrombin potential (ETP) (β = 0.51 95%CI:0.44–0.57, and β = 0.17 95%CI:0.07–0.27, respectively). Multiple regression models showed that cFN was the most potent independent predictor of both ETP and CLT in asthmatics.
Presented study is the first to show increased plasma cellular fibronectin in asthma, which is associated with disease severity, inflammation, and prothrombotic blood alterations. This novel observation suggests a previously unknown modulator of prothrombotic plasma properties in asthmatics.
•Blood cellular fibronectin, a marker of vascular injury, is increased in asthma.•Its levels are related to the asthma severity, inflammation and prothrombotic state.•It may have potential links to the increased risk of cardiovascular events in asthma.
Updates in AERD: What is needed further? Mastalerz, Lucyna; Sanak, Marek
Journal of allergy and clinical immunology,
12/2023, Letnik:
152, Številka:
6
Journal Article
Background: Cardiac involvement in Churg-Strauss syndrome (CSS) is not uncommon, but its frequency varies widely and may depend on the activity of the disease. Therefore, the cardiac involvement in ...CSS patients in clinical remission was assessed in the present study. Methods and Results: In 20 CSS patients in remission and 20 sex- and age-matched healthy controls, an ECG stress test, echocardiography, and 24-h ECG Holter monitoring were performed, together with cardiac magnetic resonance imaging (cMRI). Cardiac involvement was present in 90% (18/20) of CSS patients. Left ventricular ejection fraction (LVEF) was on average lower in the CSS group than in controls (P<0.05), with 7 patients showing systolic heart failure (LVEF <50%). cMRI changes included late gadolinium enhancement lesions in the LV in 89% of patients (17/19), present in all layers of the myocardium. Signs of ongoing inflammation (early gadolinium enhancement) and edema (T2-weighted imaging) were present in 6/19 patients. Holter monitoring revealed both supraventricular and ventricular arrhythmias more frequently in CSS patients when compared with controls (P<0.05). Absolute eosinophil count before the initiation of treatment was higher in rhythm disturbances (P<0.05), and inversely correlated with LV systolic function (rho -0.65). Conclusions: Heart involvement in CSS patients who are in clinical remission is very common. It is characterized not only by fibrosis, but also by an active inflammatory process. The latter finding might influence therapeutic decisions in CSS patients in full clinical remission. (Circ J 2011; 75: 649-655)
Aspirin-exacerbated respiratory disease (AERD) is characterized by overproduction of the pro-inflammatory eicosanoids. Although immunoglobulin E-mediated sensitization to aeroallergens is common ...among AERD patients, it does not belong to the defining disease characteristics. In this study of 133 AERD patients, we sought to find a relationship between sensitization to aeroallergens and local (leukotriene E
, prostaglandin E
and prostaglandin D
) and/or systemic (leukotriene E
) production of arachidonic acid metabolites. Interestingly, a negative association between pro-inflammatory eicosanoid levels in induced sputum supernatant or urine and sensitization to aeroallergens was observed. This inverse relationship might suggest the presence of a protective effect of atopic sensitization to aeroallergens against stronger local airway inflammation and higher systemic AERD-related inflammatory activity.
Given reports on the increased prevalence of thromboembolic incidents in patients with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss syndrome), we investigated whether fibrin ...clot properties are unfavorably altered in EGPA.
Ex vivo plasma fibrin clot characteristics, including clot permeability, turbidimetry and efficiency of fibrinolysis using two assays, were investigated in 34 consecutive patients with remission in EGPA according to the Birmingham Vasculitis Activity Score version 3 (23 female, 11 male), aged 48 (range, 21-80) years. The control group comprised 34 age- and sex- matched volunteers.
Compared with controls, patients with EGPA were characterized by denser fiber clots (estimated pore size, Ks, 7.30±0.93 vs 10.14±1.07 10-9 cm2), faster fibrin polymerization (lag phase in a turbidimetric curve, 41.8±3.6 vs 47.4±2.9 s), thicker fibrin fibers (maximum absorbance, ΔAbs, 0.87±0.09 vs 0.72±0.07), higher maximum levels of D-dimer released from clots (DDmax 4.10±0.46 vs 3.54±0.35 mg/L), and prolonged clot lysis time (t50%; 9.50±1.45 vs 7.56±0.87 min); all p<0.0001. Scanning electron microscopy images confirmed denser plasma fibrin networks composed of thinner fibers formed in EGPA. Antineutrophil cytoplasmic antibody status and C-reactive protein did not affect clot variables. Multivariate analysis adjusted for fibrinogen showed that Ks was predicted by eosinophil count, peak thrombin generation, factor VIII, and soluble CD40 ligand, whereas eosinophil count, peak thrombin generation and antiplasmin predicted t50%.
This study is the first to show that EGPA is associated with prothrombotic plasma fibrin clot phenotype, which may contribute to thromboembolic manifestations reported in this disease.
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