Induced sputum supernatant bioactive lipid mediators can identify subtypes of asthma.

BACKGROUND: Induced sputum (IS) allows to measure mediators of asthmatic inflammation in bronchial secretions. The specific role of induced sputum supernatant (ISS) endogenous bioactive lipid mediators in subtypes of asthma is not well understood. OBJECTIVE: To investigate the interactions between airway inflammation and clinical phenotypes of asthma, we integrated induced sputum supernatant (ISS) eicosanoids and quantitative assessment of infiltrating cells into new subtypes with the means of latent class analysis (LCA). METHODS: One hundred and thirty-nine asthmatics with and without aspirin hypersensitivity underwent sputum induction. High-performance liquid chromatography or gas chromatography coupled with mass spectrometry was used to profile eicosanoids. Nineteen variables covering clinical characteristics, IS inflammatory cells and eicosanoids were considered in the LCA. RESULTS: Four phenotypic asthma classes were distinguished. Class 1 with mild-to-moderate asthma, chronic rhinosinusitis (CRS), high PGA2 in ISS and almost equal distribution of inflammation cell patterns. Class 3 subjects also had mild-to-moderate asthma but without upper airway symptoms. Induced sputum was often paucigranulocytic with low levels of lipid mediators. Classes 2 and 4 represented severe asthma with CRS and impaired lung function despite high doses of steroids. High blood and sputum eosinophilia was in line with high cysteinyl leukotrienes and PGD2 in ISS only in class 2. Class 4 subjects tended to have increased sputum neutrophilia and PGE2 in ISS. Aspirin hypersensitivity was most frequent among class 2 subjects. CONCLUSIONS & CLINICAL RELEVANCE: The LCA revealed four distinct asthma classes differing in eicosanoid pathways.

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.

12-hydroxy-eicosatetraenoic acid (12-HETE): a biomarker of Churg-Strauss syndrome.

BACKGROUND: Churg-Strauss syndrome (CSS) shares similarities with asthma and hypereosinophilic syndrome (HES). Eicosanoids--important inflammatory and signaling molecules--are present in exhaled breath condensate (EBC) and broncho-alveolar lavage fluid (BALF). OBJECTIVES: To assess eicosanoid profile both in EBC and BALF of CSS subjects searching for a pattern characteristic of this syndrome. METHODS: EBCs from 23 CSS patients, 30 asthmatics, 12 HES patients and 54 healthy controls (HC) were assessed quantitatively for 19 eicosanoids by a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). In addition, in 21 of 23 CSS subjects and in nine asthmatics, eicosanoids were determined in BALF. RESULTS: EBC from CSS patients showed markedly elevated levels of 12-HETE as compared with other studied groups. BALF was characterized by a significant elevation of 12-HETE and its metabolite 12-tetranor HETE in CSS as compared with asthma. Clinical activity of CSS correlated with 12-HETE and its metabolites levels in BALF, but not in EBC. CONCLUSION AND CLINICAL RELEVANCE: CSS is clearly distinguished from bronchial asthma, and HES by a marked increase in 12-HETE concentration in both EBC and BALF. This points to a possible new pathogenic mechanism in CSS and may help in future in establishing the diagnosis of CSS.

Exhaled Eicosanoids following Bronchial Aspirin Challenge in Asthma Patients with and without Aspirin Hypersensitivity: The Pilot Study.

Background. Special regulatory role of eicosanoids has been postulated in aspirin-induced asthma. Objective. To investigate effects of aspirin on exhaled breath condensate (EBC) levels of eicosanoids in patients with asthma. Methods. We determined EBC eicosanoid concentrations using gas chromatography/mass spectrometry (GC-MS) and high-performance liquid chromatography/mass spectrometry (HPLC-MS(2)) or both. Determinations were performed at baseline and following bronchial aspirin challenge, in two well-defined phenotypes of asthma: aspirin-sensitive and aspirin-tolerant patients. Results. Aspirin precipitated bronchial reactions in all aspirin-sensitive, but in none of aspirin-tolerant patients (ATAs). At baseline, eicosanoids profile did not differ between both asthma groups except for lipoxygenation products: 5- and 15-hydroxyeicosatetraenoic acid (5-, 15-HETE) which were higher in aspirin-induced asthma (AIA) than inaspirin-tolerant subjects. Following aspirin challenge the total levels of cysteinyl-leukotrienes (cys-LTs) remained unchanged in both groups. The dose of aspirin had an effect on magnitude of the response of the exhaled cys-LTs and prostanoids levels only in AIA subjects. Conclusion. The high baseline eicosanoid profiling of lipoxygenation products 5- and 15-HETE in EBC makes it possible to detect alterations in aspirin-sensitive asthma. Cysteinyl-leukotrienes, and eoxins levels in EBC after bronchial aspirin administration in stable asthma patients cannot be used as a reliable diagnostic index for aspirin hypersensitivity.

Serum tryptase level is a better predictor of systemic side effects than prostaglandin D2 metabolites during venom immunotherapy in children.

OBJECTIVES: We performed a prospective study to analyze mast cell mediators as predictors of systemic adverse reactions during rush venom-specific immunotherapy (VIT) in children. PATIENTS AND METHODS: Nineteen children aged 5-17 years received VIT with Venomenhal (HALAllergy). We analyzed serum tryptase (CAP, Phadia), plasma prostaglandin (PG) D2 metabolites (9alpha, 11beta-PGF2), and urine PGD2 metabolites (9alpha, 11beta-PGF2, tetranor-PGD-M) using gas chromatography mass spectrometry before and after the rush protocol. RESULTS: Three boys with high baseline serum tryptase values (>7.76 g/L) (P < .001) and low 9alpha, 11beta-PGF2 concentrations developed grade III systemic adverse reactions during VIT. Baseline serum tryptase was lowest in children who had a Mueller grade II reaction (1.93 [0.36]) before VIT and highest in children with a Mueller grade III reaction (6.31 [4.80]) (P = .029). Repeated measures analysis of variance confirmed that, in children who developed systemic adverse reactions during VIT, serum tryptase was higher both before and after desensitization and increased significantly following the procedure. Analysis of PGD2 metabolites in the prediction of systemic adverse reactions during VIT was inadequate (sensitivity 67% and specificity 0.53%), whilst prediction based on serum tryptase was accurate. CONCLUSIONS: In children with severe systemic adverse reactions to Hymenoptera sting, the evaluation of baseline tryptase levels should be a standard procedure. Children with Apis mellifera venom allergy and baseline tryptase levels higher than 7.75 g/L are at risk of anaphylaxis during buildup. Lower baseline values of plasma and urinary PGD2 metabolite concentration in patients with systemic adverse reaction during VIT suggest that prostaglandin catabolism is altered.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 21-25% of reported adverse drug events which include immunological and nonimmunological hypersensitivity reactions. This study presents up-to-date information on pathomechanisms, clinical spectrum, diagnostic tools and management of hypersensitivity reactions to NSAIDs. Clinically, NSAID hypersensitivity is particularly manifested by bronchial asthma, rhinosinusitis, anaphylaxis or urticaria and variety of late cutaneous and organ-specific reactions. Diagnosis of hypersensitivity to a NSAID includes understanding of the underlying mechanism and is necessary for prevention and management. A stepwise approach to the diagnosis of hypersensitivity to NSAIDs is proposed, including clinical history, in vitro testing and/or provocation test with a culprit or alternative drug depending on the type of the reaction. The diagnostic process should result in providing the patient with written information both on forbidden and on alternative drugs.

Gender gap in psychogenic factors may affect perception of asthma symptoms.

BACKGROUND AND OBJECTIVE: Clinical practice suggests that asthma coping strategies might be different in women and men. The aim of this study was to compare the relationship between psychological variables and the perception of asthma symptoms in women and men. PATIENTS AND METHODS: A total of 165 adult asthma patients with mild to severe persistent asthma were studied. We performed spirometric tests, measured dyspnea on the Borg scale, assessed psychological health using the Goldberg 28-item General Health Questionnaire (GHQ-28), and measured the tendency towards social desirability using the lie scale from the Eysenck Personality Questionnaire. RESULTS: Women had significantly worse results than men on the GHQ somatic symptoms and anxiety/insomnia subscales and on the overall scale that measures the general index of perceived health. Sex was a statistically significant moderator on the correlation between dyspnea and both the tendency to lie and the GHQ-28 functional disorders/social dysfunction subscale. The correlation between dyspnea and the tendency to lie was positive in women and negative in men. CONCLUSIONS: Perceived dyspnea is correlated with psychological health and the tendency to lie and the correlation between perceived dyspnea and certain psychological variables is different in women and men.

Ex vivo thrombin generation in patients with venous thromboembolic disease or atrial fibrillation on long-term oral anticoagulation.

International normalized ratio (INR) is used to monitor chronic oral anticoagulant (OA) treatment; however, it is poorly understood how this simple test reflects in vivo hemostatic reactions, culminating in thrombin generation and clot formation. We studied the process of thrombin generation using an ex vivo model, where thrombin-antithrombin (TAT) complexes are measured in blood emerging from standardized skin incisions in 55 patients (35 with venous thromboembolism [VTE] and 20 with sustained atrial fibrillation [AF]) treated with acenocoumarol (INR 2.0-3.0). In addition, in venous blood, we measured the activity of factor VIII (FVIII) and vitamin K-dependent coagulation proteins. Chronic anticoagulation led to significant reductions in maximum TAT concentrations as compared to 35 healthy controls, in maximum TAT generation rates, and in mean amount of thrombin generated. Parameters of thrombin generation did not correlate with INR or any coagulation factor measured. International normalized ratio was significantly and independently affected by the decrease in the activity of all vitamin K-dependent coagulation proteins. The strongest influence was shown for FVII. Factor VIII activity was increased in all patients studied independently of the duration of anticoagulation and did not change over time. In conclusion, in patients with VTE and AF on OA, there is no correlation between INR values and parameters of ex vivo thrombin generation. This may indicate an important role of protein C (PC) system and possibly other endothelium-dependent mechanisms in controlling hemostasis. Increased FVIII activity in patients with VTE and AF does not change significantly during anticoagulation and is probably related to the pretreatment prothrombotic state.

Pharmacological inhibition of leukotriene biosynthesis: effects on the heart conductance.

Leukotrienes are lipid mediators produced via 5-lipooxygenase pathway of arachidonic acid. At least two cysteinyl-leukotrienes receptors are highly expressed in the heart, including the conduction system. Coronary angiography or angioplasty is accompanied by release of cysteinyl leukotrienes into coronary circulation and into urine. We tested the hypothesis that inhibition of leukotrienes biosynthesis would affect the conductance system function. In a double-blind placebo controlled study, patients with stable angina undergoing elective coronary catheterization or angioplasty were randomly assigned to 48 hrs treatment with a 5-lipoxgenase inhibitor (n=54) or placebo (n=49). ECG Holter recording was carried out for 24 hrs before and after the procedure and urinary leukotriene E(4) measurements were done. Inhibition of 5-lipoxygenase caused 26% reduction of urinary leukotriene E(4), associated with: 1) decrease in heart rate by about 7%, 2) enhanced heart rate variability; 3) protection against depressions in atrioventricular conductance and ventricular repolarization induced by the procedure. No effects on either arrhythmias, or ECG patterns of ischemia were noted. We conclude that pharmacological inhibition of 5-lipoxygenase, shortly before percutaneous coronary intervention, reveals specific actions of leukotrienes on the heart rhythm. Inhibitors of 5-lipoxygenase might be of interest as a novel class of cardiac drugs affecting the conductive system.

Interaction of functional FCER2 promoter polymorphism and phenotype-associated haplotypes.

Low-affinity IgE receptor gene (FCER2) rs3760687 polymorphism was found to be associated with differential binding affinity of transcription factors Sp1 and Sp3 leading to altered transcriptional activity. Haplotypic interaction of functional FCER2 polymorphisms (rs28364072, rs2228137 and rs3760687) might potentially provide a background for genotype-phenotype associations previously observed for some rather non-functional FCER2 variants.

Dyspnea is related to family functioning in adult asthmatics.

OBJECTIVE: The aim of the study was to assess links between family relationships and severity of dyspnea identified in asthmatic adults. MATERIALS: A total of 131 consecutive, non-selected patients with asthma participated in the study: 88 women (67.18%) and 43 men (32.82%). The mean age of the studied patients was 49.87 years, SD = 13.73. The majority of the study population consisted of patients with grade II (37.74%) and IV (34.91%) of the disease in terms of severity (according to the GINA classification, 2006). STUDY PROTOCOL: All patients underwent functional respiratory tests. The subjective severity of dyspnea was assessed according to the ten-tier Borg scale. To evaluate family functioning values, the Family Assessment Questionnaire (FAQ) was used. Spouses of the asthmatic patients also completed questionnaires. RESULTS: A significant relationship was identified between the values of the dimension: affective expression (assessment of the family performed by the asthmatic patient) and the severity of dyspnea (p = 0.03, r = -0.24) as well as between values of the dimensions: affective expression and affective involvement (as assessed by the spouse of the patient) and severity of dyspnea (p = 0.01, r = 0.39; p = 0.02, r = 0.34, respectively). The relationship between the severity of dyspnea declared by the patient and the FAQ dimension: Task accomplishment (as assessed by the spouse of the patient) was borderline (statistical significance [p = 0.06]). CONCLUSIONS: (1) A relationship can be observed between the functioning of the asthmatic patient's family and the severity of the patient's declared dyspnea. Dyspnea constitutes a specific form of emotional communication in the inter-spouse relationships. (2) An analysis of the severity of dyspnea in asthmatic patients should take into account the context of the functioning of the patient's family.

Important research questions in allergy and related diseases: 3-chronic rhinosinusitis and nasal polyposis - a GALEN study.

Chronic rhinosinusitis is one of the most common health care challenges, with significant direct medical costs and severe impact on lower airway disease and general health outcomes. The diagnosis of chronic rhinosinusitis (CRS) currently is based on clinical signs, nasal endoscopy and CT scanning, and therapeutic recommendations are focussing on 2 classes of drugs, corticosteroids and antibiotics. A better understanding of the pathogenesis and the factors amplifying mucosal inflammation therefore seems to be crucial for the development of new diagnostic and therapeutic tools. In an effort to extend knowledge in this area, the WP 2.7.2 of the GA(2)LEN network of excellence currently collects data and samples of 1000 CRS patients and 250 control subjects. The main objective of this project is to characterize patients with upper airway disease on the basis of clinical parameters, infectious agents, inflammatory mechanisms and remodeling processes. This collaborative research will result in better knowledge on patient phenotypes, pathomechanisms, and subtypes in chronic rhinosinusitis. This review summarizes the state of the art on chronic rhinosinusitis and nasal polyposis in different aspects of the disease. It defines potential gaps in the current research, and points to future research perspectives and targets.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

FCER1A gene proximal promoter polymorphisms in Caucasians and East Asians.

Two FCER1A gene proximal promoter polymorphisms, -344C > T and -95T > C, both associated with total serum IgE and/or allergic disorders in Caucasians and East Asians, were shown to influence the gene expression in additive manner. In face of the rarity of other proximal promoter variants in Caucasians or their lack in East Asians, future investigations of the FCER1A locus in these ethnic groups should probably focus on three common haplotypes of the common -344C > T and -95T > C polymorphisms.

Prostaglandin E2 systemic production in patients with asthma with and without aspirin hypersensitivity.

BACKGROUND: A special regulatory role for prostaglandin E2 has been postulated in aspirin-induced asthma. A study was undertaken to investigate the effects of aspirin on the systemic production of prostaglandin E2 and cysteinyl leucotrienes in patients with asthma. METHODS: The urinary concentrations were determined of two main prostaglandin E2 metabolites (13,14-dihydro-15keto-PGE2 using a commercial enzyme immunoassay and 9,15-dioxo-11alpha-hydroxy-2,3,4,5-tetranor-prostane-1,20-dioic acid by gas chromatography/mass spectrometry) and leucotriene E4 using an immunoassay. Determinations were performed at baseline and following oral aspirin and celecoxib challenges in two well-defined asthma phenotypes: aspirin-sensitive and aspirin-tolerant patients. RESULTS: Aspirin precipitated bronchial reactions in all aspirin-sensitive patients but in none of the aspirin-tolerant patients. Celecoxib 400 mg was well tolerated by all patients except for one with aspirin-induced asthma. At baseline, the mean levels of prostaglandin E2 metabolites did not differ between the groups. Following different aspirin provocation doses, the mean levels of the two main prostaglandin E2 metabolites were decreased in the aspirin-tolerant group but remained unchanged in the aspirin-sensitive group. The dose of aspirin had no effect on the magnitude of the response on the prostaglandin E2 metabolites and its duration. In both groups, urinary prostaglandin E2 metabolites decreased following celecoxib challenge. No correlation was found between prostaglandin E2 metabolites and leucotriene E4. CONCLUSIONS: Aspirin-precipitated asthmatic attacks are not associated with changes in the systemic production of prostaglandin E2. In contrast, the systemic production of prostaglandin E2 becomes depressed by aspirin in non-sensitive patients. This different response might indicate COX-1-dependent prostaglandin E2 control of inflammatory cells in aspirin-induced asthma. Thus, PGE2 is released during the clinical reactions to aspirin through an alternative COX-2 pathway. The clinical implications of this finding are in line with current observations of good tolerance of the selective COX-2 inhibitors in aspirin-sensitive patients.

Association between inflammatory markers and the interleukin-6 -174 G/C polymorphism is abolished in peripheral arterial occlusive disease.

AIM: The interleukin-6 (IL-6) -174 G/C polymorphism has been reported to determine IL-6 levels and contribute to the development of cardiovascular disorders. The aim of our study was to evaluate the effect of the IL-6 -174 G/C polymorphism on hemostatic or inflammatory markers in patients with peripheral arterial occlusive disease (PAOD), a common manifestation of obliterative atherosclerosis. METHODS: Plasma IL-6, fibrinogen, C-reactive protein (CRP), tissue plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), fibrinopeptide A and intercellular adhesion molecule-1 levels were determined in PAOD patients (n=50) and healthy controls (n=30) genotyped for the IL-6 -174 G/C polymorphism. RESULTS: In the control group, IL-6, CRP and fibrinogen levels were significantly associated with the IL-6 -174 G/C polymorphism with a gene-dosage effect being the highest in the CC subjects and the lowest in those with the GG genotype (P<0.0001, P=0.0002 and P=0.0001, respectively). Interestingly, the CC homozygotes had lower PAI-1 levels than carriers of the G allele (P=0.04). In PAOD patients, the IL-6 -174 G/C polymorphism had no effect on all the variables measured. CONCLUSION: In contrast to apparently healthy subjects, the IL-6 -174 G/C polymorphism showed no association with plasma IL-6, CRP, fibrinogen and PAI-1 levels in PAOD patients.