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Background There is evidence that altered blood coagulation and fibrinolysis are involved in the pathogenesis of asthma. Increased thromboembolic risk has been reported in asthmatics. Objective To investigate whether enhanced thrombin generation and impaired fibrinolysis occur in asthmatics. Methods Plasma thrombin generation profile together with a computational assessment of thrombin dynamics and fibrinolytic capacity expressed as clot lysis time ( CLT) were determined in 164 consecutive patients with stable asthma and 72 controls matched for age, gender, weight and smoking. Results Asthma patients had 20.2% increased endogenous thrombin potential ( ETP), 41.4% higher peak thrombin concentration, 61% higher maximal prothrombin conversion rate, 15.5% faster rate of thrombin formation (all, P < 0.0001) and 10% lower thrombin decay capacity ( P = 0.0004) compared with controls. Asthmatics had also 14.4% longer CLT ( P = 0.001) associated with 21.3% higher plasminogen activator inhibitor-1 ( PAI-1) ( P < 0.0001), and 13% higher plasma α2-macroglobulin ( P = 0.0002). Using ETP and CLT above 75th percentile of the control values as the cut-off levels, we found increased risks of enhanced thrombin generation and hypofibrinolysis in asthmatics, also after correction for potential confounders. ETP and CLT were associated inversely with forced expiratory volume in 1 s/vital capacity ( FEV1/ VC) index, after adjustment for age and body mass index. Non-allergic asthma ( n = 70, 42.6%) was characterized by 17.5% longer CLT ( P = 0.02), which positively associated with PAI-1. Thrombin generation profile was not affected by allergy. Conclusion and Clinical Relevance Asthma is associated with enhanced thrombin generation and impaired fibrinolysis, which might contribute to thromboembolic events in this disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins α4β1 and α4β7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (α1β1 and α2β1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of α1β1 and α2β1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors ( n=13) and patients with moderate persistent atopic bronchial asthma ( n=15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both α1β1 and α2β1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of α1β1 integrin. Conclusion We demonstrated for the first time that collagen receptors: α1β1 and α2β1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma. [ABSTRACT FROM AUTHOR]

Aspirin-induced asthma (AIA), a distinct clinical syndrome, affects about 10% of adult asthmatics. Attacks of asthma precipitated by aspirin are related to the inhibition of cyclo-oxygenase in the lungs of sensitive patients, and not to the body's reaction to the allergen. Immunologic mechanisms may, however, become involved in the course of the disease. Recently, signs of autoimmunity have been observed in some patients with AIA. A 46-year-old woman had been in good health until the age of 21, when she developed chronic watery rhinitis.

The Saudi Initiative for Asthma 2024 (SINA-2024) is the sixth version of asthma guidelines for the diagnosis and management of asthma for adults and children that was developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up-to-date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA Panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5–12 years, and children aged <5 years. SINA guidelines have focused more on personalized approaches reflecting a better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient–doctor partnership in the management that also includes a self-management plan. [ABSTRACT FROM AUTHOR]

Bronchial asthma is the most frequent inflammatory non-communicable condition affecting the airways worldwide. It is commonly associated with concomitant conditions, which substantially contribute to its burden, whether they involve the lung or other districts. The present review aims at providing an overview of the recent acquisitions in terms of asthma concomitant systemic conditions, besides the commonly known respiratory comorbidities. The most recent research has highlighted a number of pathobiological interactions between asthma and other organs in the view of a shared immunological background underling different diseases. A bi-univocal relationship between asthma and common conditions, including cardiovascular, metabolic or neurodegenerative diseases, as well as rare disorders such as sickle cell disease, α1-Antitrypsin deficiency and immunologic conditions with hyper-eosinophilia, should be considered and explored, in terms of diagnostic work-up and long-term assessment of asthma patients. The relevance of that acquisition is of utmost importance in the management of asthma patients and paves the way to a new approach in the light of a personalized medicine perspective, besides targeted therapies. [ABSTRACT FROM AUTHOR]

Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using recently developed real-time monitoring of the protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also investigated the relation of the systemic oxidative stress response in asthma to disease severity, lung function, airway remodeling indices (lung computed tomography and histology), and blood and bronchoalveolar lavage fluid (BAL) inflammatory biomarkers. We documented enhanced systemic oxidative stress in asthma, reflected by 35% faster and 58% higher cumulative fluorescent product generation in the CBA assay (p < 0.001 for both). The dynamics of HP generation correlated inversely with lung function but not with asthma severity or histological measures of airway remodeling. HP generation was associated positively with inflammatory indices in the blood (e.g., C-reactive protein) and BAL (e.g., interleukin [IL]-6, IL-12p70, and neutrophil count). Bronchial obstruction, thicker airway walls, increased BAL IL-6, and citrullinated histone 3 in systemic circulation independently determined increased HP formation. In conclusion, a real-time CBA assay showed increased systemic HP generation in asthma. In addition, it was associated with inflammatory biomarkers, suggesting that proper disease control can also lead to a decrease in oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Airway remodeling in patients with asthma, which leads to a decline in pulmonary function, is likely the result of repeated exacerbations often provoked by aeroallergen exposures. Aeroallegen exposure triggers a stereotypic response orchestrated by growth factor cytokines and other protein mediators. This results in a late-phase allergic reaction characterized by vascular permeability, recruitment of activated leukocytes, and activation of structural cells of the airway. The spectrum of protein mediators and their functions are incompletely understood. Methods: Bronchoalveolar lavage fluid (BALF) samples were obtained from 12 volunteers who exhibited robust eosinophilic recruitment following segmental bronchial provocation with allergen (SBP-Ag). We systematically identified and quantified proteins in BALF using high-performance liquid chromatography–high-resolution mass spectrometry (LC–MS/MS) followed by pathway analysis and correlations with airway physiology. Results: Pairwise analysis of protein abundance in BALF pre- vs post-SBP-Ag revealed that 55 proteins were upregulated and 103 proteins were downregulated. We observed enrichment of groups of proteins mapping to hemostasis/fibrin clot, platelet activation, lipoprotein assembly, neutrophil degranulation proteins, and acute-phase inflammation-airway remodeling pathways. The abundances of F2 and Fibrinogen γ (FGG) correlated with eosinophil numbers, whereas SERPINA3 negatively correlated with change in FeNO. The coagulation proteins F2 and KNG negatively correlated with FN1 an index of airway remodeling. Interestingly, patients with lower FEV1 showed distinct allergen-induced patterns of 8 BALF proteins, including MUC1, alarmins (HSPB1), and actin polymerization factors. Conclusions: Protein abundance of the fibrin formation cascade, platelet activation and remodeling are associated with late-phase leukocyte numbers and markers of remodeling. Patients with lower FEV1 have distinct dynamic responses to allergen. [ABSTRACT FROM AUTHOR]

Much emphasis is being placed on the role of music therapy as an easy-to-use, noninvasive and relatively cheap method of asthma treatment. The objective of this interventional double-blinded randomized controlled trial was to assess whether music therapy, as a complementary modality to pulmonary rehabilitation, can help to improve respiratory drive, asthma control and quality of life in patients with asthma exacerbation. Hospitalized patients with asthma exacerbation enrolled in the study were randomly assigned to experimental (music therapy) or control (popular science program) group. Both groups during hospitalization received standard pharmacotherapy accompanied by respiratory physiotherapy. Respiratory drive, asthma control, quality of life and serum cortisol in all participants were assessed at the beginning and at the end of their hospitalizations. The experimental group consisted of 39 asthmatics and 34 subjects with asthma were assigned to the control group. During the hospitalization, the levels of the inspiratory occlusion pressure for the first 0.1 s of inspiration (P0.1) decreased (p = 0.004) and the maximum P0.1 increased (p = 0.041) only in the experimental group. The serum cortisol level decreased in both groups (p = 0.001). The changes in asthma control and quality of life did not reach significant levels in either subject group. Passive music therapy and its effects on the mental state of patients seem to improve the efficiency of the respiratory system. The results of this experimental study demonstrate that a complementary music therapy has beneficial effects on the treatment of asthma exacerbations in adults. [ABSTRACT FROM AUTHOR]

The cytokine interleukin‐31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper‐reactivity. In AD, IL‐31 has been identified as one of the main "drivers" of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL‐31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2‐associated cytokines including IL‐31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL‐31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL‐31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti‐IL‐31 antibody. Accordingly, inhibition of IL‐31‐downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL‐31‐mediated‐signaling needs to be clarified. Targeting the IL‐31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future. [ABSTRACT FROM AUTHOR]

The Saudi Initiative for Asthma 2021 (SINA-2021) is the fifth version of asthma guidelines for the diagnosis and management of asthma for adults and children, which is developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5–12 years, and children aged less than 5 years. SINA guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. Medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient–doctor partnership in the management that also includes a self-management plan. [ABSTRACT FROM AUTHOR]

Background: Asthma and bronchiectasis are 2 heterogeneous diseases that frequently coexist, particularly in severe asthma. Recognition of this co-diagnosis may importantly affect treatment decisions and outcome. Previous studies in asthma with bronchiectasis show inconsistent outcomes, probably due to the heterogeneity of the included asthma cohorts. Objectives: We hypothesized that bronchiectasis contributes to asthma severity and that patients with severe asthma and bronchiectasis present with distinct characteristics resulting in different treatable traits. In addition, we explored whether bronchiectasis in severe asthma is more common in a specific phenotype. Methods: This is a single-center study consecutively including patients with severe asthma from a tertiary referral center. Severe asthma was diagnosed according to the ATS/ERS guidelines. Asthma and infectious exacerbations were defined by the attending specialist as respiratory symptoms requiring treatment with systemic steroids or antibiotics, respectively. Two independent blinded radiologists evaluated each CT. Results: 19% of patients with severe asthma showed bronchiectasis on CT. Patients with bronchiectasis had a lower FEV1% predicted (p = 0.02) and FEV1/FVC (p = 0.004) and more infectious exacerbations (p = 0.003) compared to patients without bronchiectasis. Bronchiectasis is more common in patients with a longer duration of asthma, sensitization to A. fumigatus or a positive sputum culture. Sputum cultures of patients with severe asthma and bronchiectasis revealed more P. aeruginosa, S. maltophilia, H. parainfluenzae, and A. fumigates compared to the non-bronchiectasis group. The adult-onset, eosinophilic asthma phenotype showed the highest prevalence of bronchiectasis (29.4%). Conclusions: Patients with severe asthma and coexisting bronchiectasis were found to represent a distinct group, in terms of disease severity, microbiology, and asthma phenotype. Performing (HR)CT and sputum cultures can help to identify these patients. These results can possibly contribute to early recognition and targeted treatment of this patient group. [ABSTRACT FROM AUTHOR]

Objective: The inflammatory mechanisms underpinning asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) have not been fully elucidated. Here, we examined the levels of cysteinyl leukotrienes (cys-LTs), prostaglandin D2 (PG-D2), prostaglandin E2 (PG-E2), interleukin 5 (IL-5), and a disintegrin and metalloprotease domain (ADAM 33) in ACOS patients to determine the relationship between levels of these inflammatory markers and pulmonary functions. Methods: Blood samples were obtained from asthma, COPD, and ACOS patients who received combined therapy and were stable for the last month to measure cys-LTs, PG-D2, PG-E2, IL-5, and ADAM33 levels. Differences between groups and their correlations with pulmonary function tests were evaluated. Results: In total, 24 ACOS, 27 asthma, and 35 COPD patients were included.. PG-D2 levels were higher in ACOS (120.9 ± 117.2 ng/L) and asthma (119.6 ± 111.7 ng/L) patients than in COPD (82.6 ± 46.7 ng/L) patients (p = 0.036 and p = 0.038, respectively). In ACOS patients, PG-D2, cys-LTs, and ADAM33 levels were negatively correlated with FEV1/FVC% values (p = 0.021, p = 0.008, and p = 0.028, respectively). In COPD patients, a negative correlation was detected between PG-E2 and FEV1/FVC% (p = 0.007), whereas positive correlations were detected between IL-5 and pulmonary function tests, including FVC, FVC%, FEV1, FEV1%, FEF25-75, and FEF25-75% (p = 0.047, p = 0.005, p = 0.002, p = 0.002, p = 0.010, and p = 0.005, respectively). In asthma patients, cys-LTs levels were negatively correlated with FEV1 and FEF25-75 values (p = 0.045 and p = 0.037, respectively). Conclusions: PG-D2 levels may be a valuable biomarker to differentiate COPD in asthma and ACOS patients. [ABSTRACT FROM AUTHOR]

Background: Asthma is a heterogeneous disease of a complex etiology in which genetic, environmental and personality variables are important factors determining the development of complicated strategies related to coping with stress and temperament traits. Our thesis is that coping styles in asthmatic patients are modified by the environment (chronic inflammation and stress) which affects individual temperament traits in the course of time. Thus, patient age is one of factors which determine the clinical image of asthma and its natural history. Aim: The aim of the study was to evaluate the variables describing stress coping styles and temperament in young (18 to 35 years old) and elderly asthmatics (aged ≥60 years). Material and methods: A total of 200 patients, 104 elderly and 96 young asthmatics were enrolled in the study. Apart from medical examination, the following tests were performed in all subjects: the Formal Characteristics of Behavior- Temperament Inventory (FCB-TI), Coping Inventory for Stressful Situations (CISS), Beck Depression Inventory, State-Trait Anxiety Inventory, and Borg Rating of Perceived Exertion (RPE) Scale. Results: Elderly patients with asthma exhibited higher intensity of anxiety as a trait, a higher level of depression and experienced dyspnea, as well as higher levels of stress coping strategies such as Avoidance-Oriented Coping (AOC), Distraction Seeking (DS) and Social Diversion (SD) compared to young asthmatics. In elderly patients, Perseverance and Sensory Sensitivity traits have been observed to decline with the duration and development of asthma at later life stages as opposed to young asthmatics, in whom these temperament characteristics are elevated. Conclusions: Asthma is a heterogeneous disease of a complex etiopathogenesis that has a complex interplay with mental health. The present study confirms a relationship between age and stress coping strategies as well as temperament traits. [ABSTRACT FROM AUTHOR]

Objective: The inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fluticasone propionate/formoterol fumarate (FP/FORM; Flutiform®) has been available as fixed-dose combination (FDC) therapy for asthma patients aged ≥ 12 years in the UK since 2012. This post-authorisation safety study examined adverse outcomes and prescribing practices for FP/FORM and other FDC ICS/LABA therapies in a real-life clinical setting over 36 months. Methods: Historical, longitudinal cohort database study using UK primary care data from the Clinical Practice Research Datalink (CPRD) database, for patients initiated on or switched to an FDC ICS/LABA (ENCePP study number: EUPAS12330). The main cohort was adults aged ≥ 18 years with asthma. The primary outcome was incidence of new adverse outcomes after initiation of ICS/LABA; hazard ratios (HRs) and 95% confidence intervals were estimated for FP/FORM versus other FDC ICS/LABAs using Cox regression models. Results: A total of 241,007 patients with an FDC ICS/LABA prescription were identified. In the adult asthma cohort (N = 41,609), the incidence rate of new adverse outcomes [in 100 patient-years (py)] was significantly lower for FP/FORM (24.75) versus fluticasone/salmeterol metered-dose inhaler [8.86; HR 1.14 (1.04, 1.25)], fluticasone/salmeterol dry powder inhaler [31.19; HR 1.18 (1.08, 1.29)], budesonide/formoterol [25.16; HR: 1.13 (1.03, 1.25)] and beclometasone/formoterol [25.47; HR 1.14 (1.04, 1.25)]. The overall prescribing rate was lower for FP/FORM (13.85 per 1000/py) than licensed FDC ICS/LABA comparators (20.30–28.13 per 1000/py). Of those prescribed FP/FORM, 80.8% were adults with asthma and < 7% were prescribed FP/FORM "off-label". Conclusions: The results suggest that FP/FORM was associated with an overall lower adverse outcome rate than the licensed comparators. [ABSTRACT FROM AUTHOR]

During the last decades, progression of research has led to great achievements for treatment and therapy of several disabling disorders, particularly in the field of chronic inflammatory diseases. The increased knowledge of the molecular mechanisms operating in such diseases has represented the first step in this process, and the discovery of molecules able to interfere with the natural history of the diseases, has been the second. This review is focused on the effects of biologics on type 2 diseases such as asthma, chronic urticaria and atopic dermatitis, both biologics just approved for clinical application and also those that are currently undergoing clinical trials. We will also discuss aspects and emphasize clinical trials and recently published studies, as well as research that is currently in the progress, which will be highly relevant for basic immunologists. Likewise, we will cover aspects that are pertinent for clinical immunologists and highlight translational studies that are evaluating novel biologicals in animal models. [ABSTRACT FROM AUTHOR]

This is the fourth version of the updated guidelines for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is now more aligned for different age groups. The guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and current situation at national and regional levels. There is also an emphasis on patient–doctor partnership in the management that also includes a self-management plan. [ABSTRACT FROM AUTHOR]

A striking feature underlying all atopic disorders, such as asthma, atopic dermatitis, and food allergy, is the presence of pathologic sensory responses, reflexes, and behaviors. These symptoms, exemplified by chronic airway irritation and cough, chronic itch and scratching, as well as gastrointestinal discomfort and dysfunction, are often cited as the most debilitating aspects of atopic disorders. Emerging studies have highlighted how the immune system shapes the scope and intensity of sensory responses by directly modulating the sensory nervous system. Additionally, factors produced by neurons have demonstrated novel functions in propagating atopic inflammation at barrier surfaces. In this review, we highlight new studies that have changed our understanding of atopy through advances in characterizing the reciprocal interactions between the immune and sensory nervous systems. [ABSTRACT FROM AUTHOR]

Objectives: The present study was conducted to assess the efficacy, safety and tolerability of fluticasone propionate/formoterol fumarate combination therapy (FP/FORM; Flutiform®) compared with fluticasone propionate/salmeterol xinafoate (FP/SAL; Seretide® Evohaler®) in children with asthma. Methods: This was an open-label, randomized, controlled, phase III trial and extension. Patients aged 4–12 years with reversible asthma [% predicted forced expiratory volume in 1 second (FEV1) 60–100%; documented reversibility of ⩾15% in FEV1] were randomized to receive FP/FORM (100/10 µg b.i.d.) or FP/SAL (100/50 µg b.i.d.) for 12 weeks. Eligible patients completing the 12-week core phase entered a 24-week extension phase with FP/FORM (100/10 µg b.i.d.). The primary efficacy endpoint was the change in predose FEV1 from day 0 to day 84. Secondary efficacy endpoints included change in predose to 2-hours postdose FEV1 from day 0 to day 84, peak expiratory flow rate (PEFR), patient-reported outcomes, rescue-medication use and asthma exacerbations. Results: In total, 211 patients were randomized and 210 completed the core phase; of these patients, 208 entered and 205 completed the extension phase of the study. Predose FEV1 increased from day 0 to day 84 [FP/FORM, 182 ml; 95% confidence interval (CI), 127, 236; FP/SAL, 212 ml, 95% CI, 160, 265] and FP/FORM was noninferior to FP/SAL: least squares (LS) mean treatment difference: –0.031 (95% CI, –0.093, 0.031; p = 0.026). Secondary efficacy analyses indicated similar efficacy with both therapies. There were no notable differences observed in the safety and tolerability profile between treatments. No safety concerns were identified with long-term FP/FORM therapy, and there was no evidence of an effect of FP/FORM on plasma cortisol. Conclusions: FP/FORM improved lung function and measures of asthma control with comparable efficacy to FP/SAL, and demonstrated a favourable safety and tolerability profile in children aged 4–12 years. [ABSTRACT FROM AUTHOR]

Asthma is characterized by airway inflammation rich in eosinophils. Airway eosinophilia is associated with exacerbations and has been suggested to play a role in airway remodelling. Recruitment of eosinophils from the circulation requires that blood eosinophils become activated, leading to their arrest on the endothelium and extravasation. Circulating eosinophils can be envisioned as potentially being in different activation states, including non-activated, pre-activated or 'primed', or fully activated. In addition, the circulation can potentially be deficient of pre-activated or activated eosinophils, because such cells have marginated on activated endothelium or extravasated into the tissue. A number of eosinophil surface proteins, including CD69, L-selectin, intercellular adhesion molecule-1 (ICAM-1, CD54), CD44, P-selectin glycoprotein ligand-1 (PSGL-1, CD162), cytokine receptors, Fc receptors, integrins including αM integrin (CD11b), and activated conformations of Fc receptors and integrins, have been proposed to report cell activation. Variation in eosinophil activation states may be associated with asthma activity. Eosinophil surface proteins proposed to be activation markers, with a particular focus on integrins, and evidence for associations between activation states of blood eosinophils and features of asthma are reviewed here. Partial activation of β1 and β2 integrins on blood eosinophils, reported by monoclonal antibodies ( mAbs) N29 and KIM-127, is associated with impaired pulmonary function and airway eosinophilia, respectively, in non-severe asthma. The association with lung function does not occur in severe asthma, presumably due to greater eosinophil extravasation, specifically of activated or pre-activated cells, in severe disease. [ABSTRACT FROM AUTHOR]

Introduction: In cell trafficking to the airways in asthma, among integrins the most important are those containing α4 and β2 subunits. We have previously shown that also blocking of collagen receptors, α1β1 and α2β1 integrins, inhibits transmigration of eosinophils of asthmatic subjects through a monolayer of skin microvascular endothelial cells seeded on collagen IV coated inserts. However, it was not clear whether this observation was limited to asthma or depended on the type of microvascular cell and collagen IV used as a base. Materials & methods: In the current study we performed a transmigration assay using human lung microvascular endothelial cells seeded directly on a plastic surface as a base and blood cells isolated from 12 representatives of each of two groups, asthmatics and healthy donors, by gradient centrifugation, followed by immunomagnetic negative separation of eosinophils. Isolated eosinophils and peripheral blood mononuclear cells (PBMC) were inhibited by snake venom-derived integrin antagonists including viperistatin and VP12, as inhibitors of α1β1 and α2β1 integrin, respectively, and VLO5 and VLO4, as inhibitors of α4β1 and α5β1 integrin, respectively. Results: All snake venom-derived anti-adhesive proteins were effective in inhibiting eosinophil transmigration, whilst only VLO5 and VLO4 reduced PBMC mobility in this assay. This observation was similar in both groups of subjects studied. Discussion: α1β1 and α2β1 integrins could be involved in transmigration of eosinophil to the inflammatory site. Migratory inhibition was observed in asthma subjects as well as in healthy donors, and did not depend on origin of endothelial cells or the extracellular matrix component used as a base. [ABSTRACT FROM AUTHOR]

Introduction: The economic burden of asthma on the UK National Health Service (NHS) is the largest among allergic diseases. Current asthma guidelines recommend adding a long acting β 2-agonist (LABA) to a low-dose inhaled corticosteroid (ICS) in patients who are on ICS monotherapy and have uncontrolled asthma. The fixed-dose combination of fluticasone propionate and salmeterol xinafoate (FP/SAL), available in a pressurized metered-dose inhaler (pMDI) device, is the most commonly prescribed ICS/LABA combination. An additional fixed-dose combination of fluticasone propionate and formoterol fumarate (FP/FORM) in pMDI is now available. In a 12-week non-inferiority study, FP/FORM demonstrated comparable efficacy to FP/SAL. The present analysis estimates the annual budget impact for the UK NHS using FP/FORM as an alternative to FP/SAL. Methods: Current pMDI prescribing data were from a real-world UK patient database (Cegedim Strategic Data). Annual costs to the NHS for drug acquisition, administration, and monitoring were estimated for FP/FORM and FP/SAL and used to assess the potential budget impact for the NHS for the use of FP/FORM instead of FP/SAL. Varying rates of uptake, adherence, adverse event-related costs, and resource use associated with switching treatment were assessed in scenario analyses. Results: Assuming similar levels of ICS use with both regimens, annual drug acquisition costs per person were lower with FP/FORM (£412) than with FP/SAL (£509). The difference in acquisition costs and otherwise comparable input costs between the treatments, results in potential annual savings of £15,110,279 to the NHS, assuming uptake of FP/FORM over FP/SAL in 50% of existing patients. The introduction of FP/FORM results in cost savings for the NHS in all of the assessed scenario analyses. Conclusions: The comparable efficacy and lower acquisition costs of FP/FORM compared with FP/SAL make it a cost-saving option for the UK NHS for the treatment of asthma patients requiring combination maintenance therapy using a pMDI. [ABSTRACT FROM AUTHOR]

Objectives. The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting β2 agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform®). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort® Turbohaler®). Methods. A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7- (±3) day screening, 2-4-week run-in, and 12-week treatment periods. Patients aged ≥12 years with moderate to severe persistent asthma for ≥6 months before screening and forced expiratory volume in one second (FEV1) 50-80% predicted and ≥15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 pg twice daily (n = 140) or budesonide/formoterol 400/12 pg twice daily (n = 139). Results. Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. The LS mean treatment difference was --0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non-inferiority limit of -0.2 L (95% CI: --0.130,0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV1 from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol. Conclusions. This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints. [ABSTRACT FROM AUTHOR]

Introduction: Recruitment of the inflammatory cells from blood to the airways in asthma is mediated by adhesive molecules, e.g. selectins and integrins. The most important integrins in cells trafficking are molecules containing α4 and β2 subunits. We hypothesized that also α1β1 and α2β1 integrins (both found by us on blood eosinophils of asthmatic subjects) are important in asthma pathogenesis. Aim: To assess the expression of selected very late antigen (VLA) subunits (α1, α2, α4 and β1) on blood CD4 and CD8 T lymphocytes from stable atopic asthmatic patients. Material and methods: The study was conducted on 25 adult atopic asthmatics (mild to moderate persistent asthma in a stable clinical condition) and 17 matched healthy controls using flow cytometry. Results: Expression of α4 and β1 on CD4 T cells was significantly higher in asthma than in controls. The α1 subunit was absent from blood lymphocytes. The α2 chain hardly detected on lymphocytes from healthy subjects was distinctively present in asthmatics. Surprisingly, in subjects suffering from asthma for longer than 4 years (n = 15), the overexpression of α2, α4 and β1 was observed on both: CD4 and CD8 T cells. Conclusions: Expression of selected VLA subunits on blood T cells may depend on asthma duration. The biological role of α2β1 integrin in asthma is unknown, but as it was described as a stimulator of collagen accumulation in the airways, α2β1 integrin could be, at least in part, responsible for asthma airway remodelling. [ABSTRACT FROM AUTHOR]

Objective. The aim of the study was to evaluate the effectiveness of pulmonary rehabilitation with music therapy in patients with asthma. Methods. Seventy-six selected inpatients (54 women and 22 men; mean age = 56.4 years; SD = 11.8) with stable asthma underwent pulmonary rehabilitation in two groups: standard versus music therapy. Results. After the intervention, an increase in analyzed spirometric values (forced expiratory volume at the first second (FEV1), FEV1 as a percentage of vital capacity (FEV1 % FVC), forced expiratory flow at 25%, 50%, and 75% of vital capacity (FEF25, FEF50, and FEF75, respectively), and peak expiratory flow) was observed in both the groups ( p < .05) but without any intergroup differences ( p > .05). A greater increase of mean FEV1 % FVC, FEF50, and FEF75 values was observed only in the patients with mild asthma from the music therapy group ( p < .05). In both the groups, a dyspnea reduction was noted ( p < .001). However, it was influenced neither by the type of rehabilitation nor by the gender ( p > .05), but the interaction of these variables was significant ( p = .044). A dyspnea reduction was observed in women in both the groups ( p < .001) and in men in the music therapy group only ( p = .001). A change in the value of anxiety (6.43, SD = 7.73) on the 10th day compared with the first day of the study was noticed ( p < .001). However, this change was not influenced by the type of rehabilitation, gender, or a combination of these two variables ( p > .05). Conclusion. Music therapy improves the respiratory function in patients with mild asthma and reduces dyspnea mainly in men with asthma. [ABSTRACT FROM AUTHOR]

Background: Airway remodelling is a feature of asthma including fragmentation of elastic fibres observed in the superficial elastin network of the airway wall. Fibered confocal fluorescence microscopy (FCFM) is a new and non-invasive imaging technique performed during bronchoscopy that may visualize elastic fibres, as shown by in vitro spectral analysis of elastin powder. We hypothesized that FCFM images capture in vivo elastic fibre patterns within the airway wall and that such patterns correspond with airway histology. We aimed to establish the concordance between the bronchial elastic fibre pattern in histology and FCFM. Second, we examined whether elastic fibre patterns in histology and FCFM were different between asthmatic subjects and healthy controls. Finally, the association between these patterns and lung function parameters was investigated.Methods: In a cross-sectional study comprising 16 subjects (8 atopic asthmatic patients with controlled disease and 8 healthy controls) spirometry and bronchoscopy were performed, with recording of FCFM images followed by endobronchial biopsy at the airway main carina. Elastic fibre patterns in histological sections and FCFM images were scored semi-quantitatively. Agreement between histology and FCFM was analysed using linearly weighted kappa κw.Results: The patterns observed in histological sections and FCFM images could be divided into 3 distinct groups. There was good agreement between elastic fibre patterns in histology and FCFM patterns (κw 0.744). The semi-quantitative pattern scores were not different between asthmatic patients and controls. Notably, there was a significant difference in post-bronchodilator FEV1 %predicted between the different patterns by histology (p = 0.001) and FCFM (p = 0.048), regardless of asthma or atopy.Conclusion: FCFM captures the elastic fibre pattern within the airway wall in humans in vivo. The association between post-bronchodilator FEV1 %predicted and both histological and FCFM elastic fibre patterns points towards a structure-function relationship between extracellular matrix in the airway wall and lung function.Trial Registration: Netherlands Trial Register NTR1306. [ABSTRACT FROM AUTHOR]

Background: The inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) and the long-acting b2-agonist (LABA) formoterol fumarate (formoterol) are being made available as a combination product (fluticasone/ formoterol, flutiform®) in a single aerosol inhaler. This 12-week, open-label, randomized, active-controlled, parallelgroup, multicentre, phase 3 study compared the efficacy and safety of fluticasone/formoterol with the commercially available combination product fluticasone/salmeterol. Methods: Patients aged ⩾ 18 years (N = 202) with mild-to-moderate-severe, persistent asthma for ⩾ 6 months prior to screening were included in the study. After a screening phase (4-10 days), eligible patients were randomized 1:1 to receive fluticasone/formoterol or fluticasone/salmeterol during the 12-week treatment period. The primary objective was to demonstrate non-inferiority of fluticasone/formoterol versus fluticasone/salmeterol, measured by pre-dose forced expiratory volume in the first second (FEV1), at week 12. Results: Fluticasone/formoterol was comparable to fluticasone/salmeterol for the primary efficacy endpoint, mean pre-dose FEV1 at week 12. The new combination was also comparable to fluticasone/salmeterol for change from baseline to week 12 in pre-dose FEV1, change from pre-dose FEV1 at baseline to 2-hour post-dose FEV1 at week 12 and discontinuations due to lack of efficacy. Importantly, fluticasone/formoterol was superior to fluticasone/ salmeterol in time to onset of action throughout the duration of the study. The two treatments demonstrated similar results for various other secondary efficacy parameters, including other lung function tests, patient-reported outcomes, rescue medication use, asthma exacerbations and Asthma Quality of Life Questionnaire scores. Fluticasone/formoterol was well tolerated and had a good safety profile that was similar to fluticasone/salmeterol. Conclusions: The results of this study indicate that fluticasone/formoterol is as effective as fluticasone/salmeterol, and has a more rapid onset of action, reflecting the faster bronchodilatory effects of formoterol compared with those of salmeterol. If patients perceive the benefits of therapy with fluticasone/formoterol more rapidly than with fluticasone/salmeterol, this could have a positive impact on preference and adherence. [ABSTRACT FROM AUTHOR]

To cite this article: Contoli M, Bousquet J, Fabbri LM, Magnussen H, Rabe KF, Siafakas NM, Hamid Q, Kraft M. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy 2010; 65: 141–151. The involvement of small airways in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been debated for a long time. However, a proper definition of small airway disease is still lacking, and neither a widely accepted biomarker nor a functional parameter to assess small airway abnormalities and to explore the effect of tested compounds on small airways is available. Aiming towards increased knowledge and consensus on this topic, this perspective paper intends to (i) strengthen awareness among the scientific community on the role of small airways in asthma and COPD; (ii) examine the pros and cons of some biological, functional and imaging parameters in the assessment of small airway abnormalities; and (iii) discuss the evidence for distal airway pharmacological targeting in asthma and COPD. [ABSTRACT FROM AUTHOR]

Asthma is an increasingly common chronic medical condition that affects not only patients but their families. Because this condition has significant psychosocial impact, effective treatment requires an integration of psychosocial treatment--including individual, couples, and family counseling--with conventional medical treatment. Individual psychological dynamics as well as couple and family dynamics that influence the treatment process are described along with implications for family counseling. An illustrative case example is included. [ABSTRACT FROM AUTHOR]

The asthma prevalence was increasing over the past two decades worldwide. Allergic asthma, caused by inhaled allergens of different origin or by food, is mediated by inflammatory mechanisms. The action of non-allergic asthma, induced by cold air, humidity, temperature or exercise, is not well understood. Asthma affects up to 15% of the population and is treated with anti-inflammatory and muscle relaxing drugs which allow symptom control. Asthma was first defined as a malfunction of the airway smooth muscle, later as an imbalanced immune response of the lung. Recent studies placed the airway smooth muscle again into the focus. Here we summarize the molecular biological basis of the deregulated function of the human airway smooth muscle cell as a cause or important contributor to the pathology of asthma. In the asthmatic human airway smooth muscle cells, there is: (i) a deregulation of cell differentiation due to low levels of maturation-regulating transcription factors such as CCAAT/enhancer binding proteins and peroxisome proliferator-activated receptors, thereby reducing the cells threshold to proliferate and to secrete pro-inflammatory cytokines under certain conditions; (ii) a higher basal energy turnover that is due to increased number and activity of mitochondria; and (iii) a modified feedback mechanism between cells and the extracellular matrix they are embedded in. All these cellular pathologies are linked to each other and to the innate immune response of the lung, but the sequence of events is unclear and needs further investigation. However, these findings may present the basis for the development of novel curative asthma drugs. [ABSTRACT FROM AUTHOR]

Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control interferon-? (IFN-?) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene,TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the humanTBX21gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T?C SNP, which is in linkage disequilibrium with a synonymous coding 390A?G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA;P=0.004,Pc=0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P=0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T?C substitution increases the affinity of a particular nuclear protein to the binding site ofTBX21covering the -1993 position, resulting in increased transcriptional activity of theTBX21gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-?) production in human airways of individuals with the -1993T?C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA. [ABSTRACT FROM AUTHOR]

Aspirin (acetylsalicylic acid)-induced asthma (AIA) consists of the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and precipitation of asthma and rhinitis attacks in response to aspirin and other NSAIDs. The prevalence of the syndrome in the adult asthmatic populations is approximately 4–10%. Respiratory disease in these patients may be aggressive and refractory to treatment. The aetiology of AIA is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Cyclo-oxygenase (COX), the rate-limiting enzyme in AA metabolism, exists as two main isoforms. COX-1 is the constitutive enzyme responsible for synthesis of protective prostanoids, whereas COX-2 is induced under inflammatory conditions. A number of theories regarding its pathogenesis have been proposed. The shunting hypothesis proposes that inhibition of COX-1 shunts AA metabolism away from production of protective prostanoids and towards cysteinyl leukotriene (cys-LT) biosynthesis, resulting in bronchoconstriction and increased mucus production. The COX-2 hypothesis proposes that aspirin causes a structural change in COX-2 that results in the generation of products of the lipoxygenase pathway. It is speculated that this may result in the formation of mediators that cause respiratory reactions in AIA. Related studies provide evidence for abnormal regulation of the lipoxygenase pathway, demonstrating elevated levels of cys-LTs in urine, sputum and peripheral blood, before and following aspirin challenge in AIA patients. These studies suggest that cys-LTs are continually and aggressively synthesised before exposure to aspirin and, during aspirin-induced reactions, acceleration of synthesis occurs. A genetic polymorphism of the LTC4S gene has been identified consisting of an A to C transversion 444 nucleotides upstream of the first codon, conferring a relative risk of AIA of 3.89. Furthermore, carriers of the C444 allele demonstrate a dramatic rise in urinary LTE4 following aspirin provocation, and respond better to the cys-LT antagonist pranlukast than A444 homozygotes. AIA patients have an aggressive form of disease, and treatment should include combination therapy with inhaled corticosteroids, β2-adrenoceptor agonists and LT modifiers. Furthermore, recently developed inhibitors of COX-2 may be safer in patients with AIA. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment with antileukotriene drugs results in clinical improvement in many, though not all, patients with asthma. It can be hypothesized that the subpopulation of asthmatic patients, characterized by aspirin intolerance and cysteinyl-leukotriene overproduction, might profit most from antileukotriene treatment. Materials and methods We compared the clinical response to montelukast in two well-matched groups of patients with mild asthma: 26 aspirin-intolerant asthmatics (AIAs) and 33 aspirin-tolerant asthmatics (ATAs). We also searched for possible predictors of the clinical response among the parameters reflecting the expression and production of cysteinyl-leukotrienes (cys-LTs). This was an 8-week, single-blind, placebo-controlled trial. Results Following a 3-week montelukast 10 mg day-1 treatment compared with placebo, there was a statistically significant reduction in the mean daytime and nocturnal asthma symptoms and β2 -agonist use, as well as a significant improvement in the morning and evening peak expiratory flows and quality of life. Both groups showed a similar significant improvement in the parameters studied. Clinical response did not correlate with the baseline urinary LTE4 excretion level. Improvement of asthma was observed mostly in patients with a low baseline and non-IL-5 inducible expression of LTC4 synthase (LTC4 S) mRNA in eosinophils. There was a trend toward a better response in carriers of LTC4 S allele C, but no relationship to the CC10 genetic polymorphism. Conclusions No difference in the clinical response to the montelukast treatment was observed between the AIAs and the ATAs. [ABSTRACT FROM AUTHOR]

Increased airway wall thickness and remodeling of bronchial mucosa are characteristic of asthma and may arise from altered integrin signaling on airway cells. Here, we analyzed the expression of β1-subfamily integrins on blood and airway cells (flow cytometry), inflammatory biomarkers in serum and bronchoalveolar lavage, reticular basement membrane (RBM) thickness and collagen deposits in the mucosa (histology), and airway geometry (CT-imaging) in 92 asthma patients (persistent airflow limitation subtype: n = 47) and 36 controls. Persistent airflow limitation was associated with type-2 inflammation, elevated soluble α2 integrin chain, and changes in the bronchial wall geometry. Both subtypes of asthma showed thicker RBM than control, but collagen deposition and epithelial α1 and α2 integrins staining were similar. Type-I collagen accumulation and RBM thickness were inversely related to the epithelial expression of the α2 integrin chain. Expression of α2β1 integrin on T-cells and eosinophils was not altered in asthma. Collagen I deposits were, however, more abundant in patients with lower α2β1 integrin on blood and airway CD8+ T-cells. Thicker airway walls in CT were associated with lower α2 integrin chain on blood CD4+ T-cells and airway eosinophils. Our data suggest that α2β1 integrin on inflammatory and epithelial cells may protect against airway remodeling advancement in asthma. [ABSTRACT FROM AUTHOR]