Severe Asthma Phenotypes Research Articles

Azithromycin in uncontrolled asthma

Asthma is a highly prevalent chronic airway disease affecting more than 300 million people worldwide. Despite treatment with inhaled corticosteroids and long-acting bronchodilators, asthma is uncontrolled in a substantial number of patients who remain symptomatic and are at risk of asthma exacerbations. These asthma attacks are often triggered by viral respiratory infections and might lead to emergency room visits, hospitalisations, and rarely, death; they result in a huge personal and societal burden. 1 Beran D Zar HJ Perrin C Menezes AM Burney P Burden of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-income countries. Lancet Respir Med. 2015; 3: 159-170 Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar Although targeted add-on therapy with monoclonal antibodies such as anti-IgE (omalizumab) and anti-IL5 (mepolizumab and reslizumab) has been shown to be efficacious in specific phenotypes of severe asthma, 2 Castro M Zangrilli J Wechsler ME et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015; 3: 355-366 Summary Full Text Full Text PDF PubMed Scopus (832) Google Scholar , 3 Ortega HG Liu MC Pavord ID et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371: 1198-1207 Crossref PubMed Scopus (1510) Google Scholar the high costs preclude widespread use in many parts of the world. Therefore, affordable, effective, and safe add-on therapies in patients with poorly controlled asthma are needed. Previous studies have shown a beneficial effect of macrolide antibiotics such as azithromycin on asthma symptoms, but their effect on asthma exacerbations has been inconclusive due to a lack of large long-term trials. 4 Kew KM Undela K Kotortsi I Ferrara G Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015; 9 (CD002997.) PubMed Google Scholar , 5 Reiter J Demirel N Mendy A et al. Macrolides for the long-term management of asthma—a meta-analysis of randomized clinical trials. Allergy. 2013; 68: 1040-1049 Crossref PubMed Scopus (69) Google Scholar Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trialAdults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma. Full-Text PDF

Severe Asthma Phenotypes — How Should They Guide Evaluation and Treatment?

Although patients with "severe" asthma tend to be characterized by ongoing symptoms and airway inflammation despite treatment with high doses of inhaled and systemic corticosteroids, there is increasing recognition of marked phenotypic heterogeneity within affected patients. Although "precision medicine" approaches for patients with severe asthma are needed, there are many hurdles that must be overcome in daily practice. The National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) has been at the forefront of phenotype discovery in severe asthma for the past decade. SARP, along with other international groups, has described clinical severe asthma phenotypes in both adults and children that can be evaluated in the clinical setting. Although these clinical phenotypes provide a good "starting point" for addressing disease heterogeneity in severe asthma in everyday practice, more efforts are needed to understand how these phenotypes relate to underlying disease mechanisms and pharmacological treatment responses. This review highlights the clinical asthma phenotypes identified to date, their associations with underlying endotypes and potential biomarkers, and remaining knowledge gaps that must be addressed before precision medicine can become a reality for patients with severe asthma.

Point-of-care blood eosinophil count in a severe asthma clinic setting

BackgroundOne of the main severe asthma phenotypes is severe eosinophilic or eosinophilic refractory asthma for which novel biologic agents are emerging as therapeutic options. In this context, blood eosinophil counts are one of the most reliable biomarkers. ObjectiveTo evaluate the performance of a point-of-care peripheral blood counter in a patients with severe asthma. MethodsThe blood eosinophil counts of 76 patients with severe asthma were evaluated by point-of-care and standard analyzers. ResultsA significant correlation between blood eosinophils assessed by the 2 devices was found (R2 = 0.854, P < .001); similar correlations were found also for white blood cells, neutrophils, and lymphocytes. The point-of-care device had the ability to predict blood eosinophil cutoffs used to select patients for biologic treatments for severe eosinophilic asthma and the ELEN index, a composite score useful to predict sputum eosinophilia. ConclusionThe results of our study contribute to the validation of a point-of-care device to assess blood eosinophils and open the possibility of using this device for the management of severe asthma management.

Age is associated with asthma phenotypes.

The relationship between age and asthma phenotypes is important as population is ageing, asthma is becoming common in older ages and recently developed treatments for asthma are guided by phenotypes. The aim of this study is to evaluate whether age is associated with specific asthma phenotypes. This is a cross-sectional study. We included subjects with asthma of varied degrees of severity. Subjects underwent spirometry, skin prick test to aeroallergens, answered the Asthma Control Questionnaire and had blood samples collected. We performed binary logistic regression analysis to evaluate whether age is associated with asthma phenotypes. We enrolled 868 subjects. In comparison with subjects ≤ 40 years, older subjects had high odds of irreversible airway obstruction (from 41 to 64 years, OR: 1.83 (95% CI: 1.32-2.54); ≥65 years, OR: 3.45 (2.12-5.60)) and severe asthma phenotypes (from 41 to 64 years, OR: 3.23 (2.26-4.62); ≥65 years, OR: 4.55 (2.39-8.67)). Older subjects had low odds of atopic (from 41 to 64 years, OR: 0.56 (0.39-0.79); ≥65 years, OR: 0.47 (0.27-0.84)) and eosinophilic phenotypes (from 41 to 64 years, OR: 0.63 (0.46-0.84); ≥65 years, OR: 0.39 (0.24-0.64)). Older subjects with asthma have low odds of atopic and eosinophilic phenotypes, whereas they present high odds of irreversible airway obstruction and severe asthma.

Saturated Fatty Acid Increases Lung Macrophages and Augments House Dust Mite-Induced Airway Inflammation in Mice Fed with High-Fat Diet

Obesity is one of the phenotypes of severe asthma, which is considered to be a heterogeneous syndrome; however, its interaction with airway inflammation is not fully understood. The aim of this study was to clarify the role of saturated fatty acids in augmenting airway inflammation induced by house dust mite (HDM) in obesity. Subjects were Balb/c mice fed a high-fat diet (HFD) for 10 weeks, followed by sensitization and exposure to HDM. Subjects were also administered palmitic acid (PA) for 4 weeks with concurrent sensitization and exposure to HDM. Airway inflammation was assessed by quantifying the amount of inflammatory cells in bronchoalveolar lavage (BAL) and airway resistance was measured. In vitro, lipopolysaccharide (LPS)-primed macrophages were stimulated by PA. The amount of monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) was examined in the supernatant. Compared to normal chow mice, HFD mice underwent significant increases in body weight; increases in number of lung macrophages, including circulating monocytes and alveolar macrophages; and increases in bronchoalveolar lavage fluid (BALF) total cell count, including neutrophils but not eosinophils, after HDM sensitization and exposure. In vitro, PA induced MCP-1 and augmented LPS-primed production of IL-1β and TNF-α in macrophages. Among HDM mice that were administered PA, there was an increase BALF total cell count, including neutrophils but not eosinophils, compared to vehicle mice. In conclusion, saturated fatty acid increased the number of lung macrophages and augmented HDM-induced neutrophilic airway inflammation in a HFD mouse model.

Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid-Refractory Asthma in Children

Little is known about inflammatory pathways of severe recurrent wheeze in preschool children and severe asthma in children. The aim of the Severe Asthma Molecular Phenotype cohort was to characterize phenotypes of severe recurrent wheeze and severe asthma during childhood in terms of triggers (allergic or not), involved cells (eosinophil or neutrophil), and corticoid responsiveness. Children with moderate-to-severe asthma and preschool children with moderate-to-severe recurrent wheeze were enrolled prospectively. They underwent standardized clinical and blood workup, and bronchoalveolar lavage (BAL) evaluation. Cluster analysis was applied to 350 children with 34 variables. Three clusters were identified: cluster 1, Neutrophilic steroid-refractory recurrent wheeze phenotype, with 138 children uncontrolled despite high-dose inhaled corticosteroids (ICS) (92%, P < .001), with more history of pneumonia (31%, P<.001), more gastroesophageal reflux disease (37%, P < .001), and the highest blood neutrophil count (mean 4.524 cells/mm3, P= .05); cluster 2, Severe recurrent wheeze with sensitization to a single aeroallergen (12%, P= .002), with 104 children controlled with high-dose ICS (63%, P < .001); cluster 3, Eosinophilic steroid-refractory asthma phenotype, with 108 children uncontrolled despite high-dose ICS (76%, P < .001) with more allergic rhinitis, atopic dermatitis, and food allergies (82%, 40%, 31%, P < .001, respectively). They also had a higher blood eosinophil count and a higher percentage of BAL eosinophil (506/mm3, 2.6%, P < .001 respectively). Inflammation pathway of asthma and recurrent wheeze are related to eosinophil cells in older children and neutrophil cells in younger children. These results could improve personalized treatments.

Co-morbidities in severe asthma: Clinical impact and management.

Patients with severe asthma represent a minority of the total asthma population, but carry a majority of the morbidity and healthcare costs. Achieving better asthma control in this group of patients is therefore of key importance. Systematic assessment of patients with possible severe asthma to identify treatment barriers and triggers of asthma symptoms, including co-morbidities, improves asthma control and reduces healthcare costs and is recommended by international guidelines on management of severe asthma. This review provides the clinician with an overview of the prevalence and clinical impact of the most common co-morbidities in severe asthma, including chronic rhinosinusitis, nasal polyposis, allergic rhinitis, dysfunctional breathing, vocal cord dysfunction, anxiety and depression, obesity, obstructive sleep apnoea syndrome (OSAS), gastroesophageal reflux disease (GERD), bronchiectasis, allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatous with polyangiitis (EGPA). Furthermore, the review offers a summary of recommended diagnostic and management approaches for each co-morbidity. Finally, the review links co-morbid conditions to specific phenotypes of severe asthma, in order to guide the clinician on which co-morbidities to look for in specific patients.

Lyn regulates mucus secretion and MUC5AC via the STAT6 signaling pathway during allergic airway inflammation

Hypersecretion of mucus is an important component of airway remodeling and contributes to the mucus plugs and airflow obstruction associated with severe asthma phenotypes. Lyn has been shown to down-regulate allergen-induced airway inflammation. However, the role of Lyn in mucin gene expression remains unresolved. In this study, we first demonstrate that Lyn overexpression decreased the mucus hypersecretion and levels of the muc5ac transcript in mice exposed to ovalbumin (OVA). Lyn overexpression also decreased the infiltration of inflammatory cells and the levels of IL-13 and IL-4 in OVA-challenged airways. Whereas Lyn knockdown increased the IL-4 or IL-13-induced MUC5AC transcript and protein levels in the human bronchial epithelial cell line, 16HBE, Lyn overexpression decreased IL-4- or IL-13-induced MUC5AC transcript and protein levels. Overexpression of Lyn also decreased the expression and phosphorylation of STAT6 in OVA-exposed mice, whereas Lyn knockdown increased STAT6 and MUC5AC levels in 16HBE cells. Finally, chromatin immunoprecipitation analysis confirmed that Lyn overexpression decreased the binding of STAT6 to the promoter region of Muc5ac in mice exposed to OVA. Collectively, these findings demonstrated that Lyn overexpression ameliorated airway mucus hypersecretion by down-regulating STAT6 and its binding to the MUC5AC promoter.

Dupilumab for the treatment of asthma

ABSTRACTIntroduction: Dupilumab (REGN668/SAR231893), produced by a collaboration between Regeneron and Sanofi, is a monoclonal antibody currently in phase III for moderate-to-severe asthma. Dupilumab is directed against the α-subunit of the interleukin (IL)-4 receptor and blocks the IL-4 and IL-13 signal transduction.Areas covered: Pathophysiological role of IL-4 and IL-13 in asthma; mechanism of action of dupilumab; pharmacology of IL-4 receptor; phase I and phase II studies with dupilumab; regulatory affairs.Expert opinion: Patients with severe asthma who are not sufficiently controlled with standard-of-care represent the target asthma population for dupilumab. If confirmed, efficacy of dupilumab in both eosinophilic and non-eosinophilic severe asthma phenotype might represent an advantage over approved biologics for asthma, including omalizumab, mepolizumab, and reslizumab. Head-to-head studies to compare dupilumab versus other biologics with different mechanism of action are required. Pediatric studies with dupilumab are currently lacking and should be undertaken to assess efficacy and safety of this drug in children with severe asthma. The lack of preclinical data and published results of the completed four phase I studies precludes a complete assessment of the pharmacological profile of dupilumab. Dupilumab seems to be generally well tolerated, but large studies are required to establish its long-term safety and tolerability.

Phenotype-Driven Therapeutics in Severe Asthma.

Inhaled corticosteroids are the mainstay of asthma treatment using a step-up approach with incremental dosing and additional controller medications in order to achieve symptom control and prevent exacerbations. While most patients respond well to this treatment approach, some patients remain refractory despite high doses of inhaled corticosteroids and a long-acting β-agonist. The problem lies in the heterogeneity of severe asthma, which is further supported by the emergence of severe asthma phenotypes. This heterogeneity contributes to the variability in treatment response. Randomized controlled trials involving add-on therapies in poorly controlled asthma have challenged the idea of a "one size fits all" approach targeting specific phenotypes in their subject selection. This review discusses severe asthma phenotypes from unbiased clustering approaches and the most recent scientific evidence on novel treatments to provide a guide in personalizing severe asthma treatment.

Two inflammatory phenotypes of nasal polyps and comorbid asthma

BackgroundNasal polyps and comorbid asthma (NPCA) is a common united airway disease. However, the inflammatory phenotyes of NPCA are not clear. ObjectiveTo identify inflammatory phenotypes of NPCA. MethodsA total of 106 patients diagnosed with NPCA were recruited from rhinologic clinics. A combined method of biopsies from nasal polyps and fractional exhaled nitric oxide (FeNO) was used to explore inflammatory phenotyes of NPCA. Patients were evaluated with respect to clinical, functional, and inflammatory parameters. Clinical outcomes after medical treatment were also assessed. ResultsTwo distinct inflammatory phenotypes (eosinophilic [64.15%] and noneosinophilic phenotypes [35.85%]) were identified. Inflammatory patterns of upper and lower airways were consistent in NPCA. Patients with eosinophilic NPCA had a higher nasal polyps recurrence rate than did patients with noneosinophilic NPCA, a more severe asthma phenotype (P < .001), higher exhaled nitric oxide levels (P < .001), higher IgE levels (P < .001), higher Lund-Mackay scores (P < .05), and more blood eosinophilia (P < .001). In addition, eosinophilic NPCA was associated with worse pulmonary function and responded well to an 8-week course of medical treatment based on computed tomographic findings and the ratio of forced expiratory volume in 1 second to forced vital capacity. The total IgE concentration was a marker for eosinophilic NPCA (optimal cutoff, >55.5 kU/L; sensitivity, 86.2%; specificity, 85.4%). ConclusionPatients with NPCA had 2 inflammatory phenotypes with distinct clinical profiles. Total IgE is a marker of eosinophilic NPCA.

Therapeutic modality of plasmacytoid dendritic cells in a murine model of &lt;em&gt;Aspergillus fumigatus&lt;/em&gt; sensitized and infected asthma

Aspergillus fumigatus (Af) is a representative pathogen for severe asthma with fungal sensitization (SAFS), which has been coined to define a particular phenotype of severe asthma despite the use of high-dose inhaled corticosteroids and long-acting bronchodilators. Since current therapies cannot adequately control SAFS, a new therapeutic modality is required. Focusing on the immunoregulatory profile of plasmacytoid dendritic cells (pDCs), the purpose of the present study was to investigate the effects of intranasal transfer of pDCs to a murine model of Af sensitized and infected asthma mimicking SAFS on airway inflammation and cytokine profiles. Splenic pDCs were obtained from Af sensitized and infected donor mice. Thereafter, these pDCs were intranasally transferred into the airway of Af sensitized and infected recipient mice. pDCs inhibited both eosinophilic and neutrophilic airway inflammation. Analysis of cytokine profiles in lung tissue revealed that pDCs significantly inhibited proinflammatory cytokines, MIP-2, IL-5 and IL-17, and significantly increased an immunoregulatory cytokine, IL-10. In contrast, pDCs did not significantly modulate IFN-γ, a critical cytokine for antifungal immunity, suggesting the absence of immunosuppressive effects. Transfer of pDCs into the airway could be an effective and safe therapeutic modality for SAFS.

Aspirin-exacerbated respiratory disease: an update.

The pathophysiology of aspirin-exacerbated respiratory disease (AERD) is not fully understood and diagnostic methods and so far, treatments for AERD have not been standardized. We summarize recent research into the pathological mechanisms of AERD, diagnostic methods, and treatments for AERD patients. In AERD pathophysiology, not only the reduced expression of E prostanoid 2 but also the dysfunction of its pathway could be involved. Moreover, eosinophils of AERD patients could be directly activated by aspirin to produce prostaglandin D2. Platelet activations are well known to be involved in AERD; however, plasma markers do not change during aspirin challenge tests. Additionally, novel genetic polymorphisms, such as P2RY12 and dipeptidyl peptidase 10 gene, and epigenetic predispositions of AERD were found. In AERD diagnosis, bronchial and nasal aspirin challenges have been applied in addition to oral challenge. Serum periostin has been suggested as a potential biomarker for AERD. Apart from standard pharmacological treatment and aspirin desensitization, biologics, including omalizumab and mepolizumab, as well as CRTH2 antagonists have been suggested as promising therapies for AERD treatment. AERD is usually associated with severe asthma phenotypes. AERD pathophysiology mainly involves the dysregulation of eicosanoid metabolisms, activations of effector cells, which could be influenced by genetic/epigenetic factors. Understanding the pathophysiology of AERD is key to improve the diagnostic methods and proper management of AERD patients.

Reslizumab in the treatment of patients with severe eosinophilic asthma phenotype

It is known that patients with severe asthma often fail to achieve disease control. Excessive airways eosinophilic inflammation is one of the key causes of severe uncontrolled asthma in this case. The occurrence of eosinophilic phenotype of inflammation is quite high in severe uncontrolled asthma. Thus, about 55% of patients have eosinophil level in induced sputum ≥ 3%. Eosinophilic phenotype of asthma is associated with greater severity of symptoms, presence of atopy, late onset of the disease, and lack of response to inhaled glucocorticosteroids. Numerous studies confirmed the relationship between elevated eosinophils in the airways and more frequent and severe asthma exacerbations, as well as reduced lung function, increased administration of steroids and other medications, and more frequent use of healthcare services. Severe eosinophilic asthma is characterized mainly by late onset of the disease, persistent eosinophilia in the airways and peripheral blood. It is associated with frequent exacerbations, chronic or intermittent need to the use of systemic corticosteroids to achieve better control of the disease, and unfavorable prognosis of the natural course. Predominantly eosinophilic type of airway inflammation is a characteristic manifestation of T2 endotype of asthma, that is implemented due to the domination of Th2-lymphocyte response (allergic asthma) and/or due to high activity of type 2 innate lymphoid cells (ILC2) involved in the development of both non-allergic and allergic asthma. Th2 and ILC2 cells increase IL-5 level, which plays an important role in the formation of uncontrolled eosinophilic inflammation in the airways in patients suffering from T2 endotype of severe asthma, by stimulating eosinophil precursor maturation in the bone marrow, mobilization of eosinophils and precursors from the bone marrow, accumulation of eosinophils in the blood, eosinophilic infiltration of lung tissue, and eosinophil migration in the area of inflammation. The novel medication reslizumab (Cinqair) is the first anti-IL-5 immunological biologic drug registered in Russia for the treatment of severe asthma with eosinophilic airway inflammation. As a humanized monoclonal antibody (IgG4k) with high affinity for IL-5, reslizumab specifically binds to IL-5 and inhibits its interaction with IL-5 receptor on the cell surface, thus disrupting the underlying pathophysiology of bronchial inflammation in asthma, including maturation and survival of eosinophils, inflammation and remodeling of the airways. Clinical effects of reslizumab are manifested as decreased asthma exacerbation rate, improved lung function, and disease control.

A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED.

Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. Using transcriptomic profiling of airway tissues, we sought to define the molecular phenotypes of severe asthma. The transcriptome derived from bronchial biopsies and epithelial brushings of 107 subjects with moderate to severe asthma were annotated by gene set variation analysis using 42 gene signatures relevant to asthma, inflammation, and immune function. Topological data analysis of clinical and histologic data was performed to derive clusters, and the nearest shrunken centroid algorithm was used for signature refinement. Nine gene set variation analysis signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper cell type 2 cytokines and lack of corticosteroid response (group 1 and group 3). Group 1 had the highest submucosal eosinophils, as well as high fractional exhaled nitric oxide levels, exacerbation rates, and oral corticosteroid use, whereas group 3 patients showed the highest levels of sputum eosinophils and had a high body mass index. In contrast, group 2 and group 4 patients had an 86% and 64% probability, respectively, of having noneosinophilic inflammation. Using machine learning tools, we describe an inference scheme using the currently available inflammatory biomarkers sputum eosinophilia and fractional exhaled nitric oxide levels, along with oral corticosteroid use, that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. This analysis demonstrates the usefulness of a transcriptomics-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target T-helper cell type 2-mediated inflammation and/or corticosteroid insensitivity.

Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma

Introduction: Endoplasmic reticulum (ER) stress has been considered to be an important regulator of airway inflammation in the pathogenesis of bronchial asthma, but the mechanism of ER stress involved in neutrophilic asthma remain not fully understood. Methods: Tunicamycin is a mixture of homologous nucleoside antibiotics, which is used to induce ER stress. In the present study, Tunicamycin was administered to mouse bronchial epithelial cells and a neutrophilic asthma model (OVALPS-OVA mice), and ER stress indicators and inflammatory cytokines were measured by Western blotting and Elisa. Results: Tunicamycin not only induced ER stress in mouse bronchial epithelial cells, but also increased expression of inflammation indicators such as IL-6, IL-8, and TNF-α via PERK-ATF4-CHOP signaling. Additionally, the phosphorylation of PERK and the expression levels of ATF4 and CHOP proteins and inflammatory cytokines (IL-6, IL-8 and TNF-α) were elevated in the lung tissue of OVALPS-OVA mice. Administering tunicamycin further increased protein expression levels of ER stress indicators and inflammatory cytokines, and resulted in more severe asthma phenotypes in OVALPS-OVA mice, suggesting that PERK-ATF4-CHOP signaling is associated with airway inflammation in neutrophil-dominant asthma. Conclusions: These data support the emerging notion that regulation of ER stress could be strongly associated with the development of neutrophilic asthma.

Obesity increases the prevalence and the incidence of asthma and worsens asthma severity

We aimed to explore the association between obesity and asthma prevalence, incidence and severity. The study included 32,644 adults, 52.6% female, from a representative sample of the 4th Portuguese National Health Survey. The following asthma definitions were used: ever asthma (ever medical doctor asthma diagnosis), current asthma (asthma within the last 12 months), current persistent asthma (required asthma medication within the last 12 months), current severe asthma (attending an emergency department because of asthma within the last 12 months), and incident asthma (asthma diagnosis within the last 12 months). Body mass index was calculated based on self-reported weight and height and categorised according to WHO classification. Logistic regression models adjusted for confounders were performed. Prevalence of ever asthma was 5.3%, current asthma 3.5%, current persistent asthma 3.0%, current severe asthma 1.4%, and incident asthma 0.2%. Prevalence of obesity was 16%, overweight 37.6%, normal weight 44.6% and underweight 0.2%. Being overweight, obesity class I and II, and obesity class III were associated with an OR (95% CI) with ever asthma 1.22 (1.21-1.24), 1.39 (1.36-1.41), 3.24 (3.08-3.40) respectively; current asthma 1.16 (1.14-1.18), 1.86 (1.82-1.90), 4.73 (4.49-4.98) respectively; current persistent asthma 1.08 (1.06-1.10), 2.06 (2.01-2.10), 5.24 (4.96-5.53), and current severe asthma 1.36 (1.32-1.40), 1.50 (1.45-1.55) and 3.70 (3.46-3.95), respectively. Considering the incidence of asthma, obesity more than quadrupled the odds (OR=4.46, 95% CI 4.30, 4.62). Obesity is associated in a dose dependent way with an increase of prevalent and incident asthma, and it seems to increase the odds of a more persistent and severe asthma phenotype independently of socio-demographic determinants, physical activity, and dietary patterns. Our results provide rational for future lifestyle intervention studies for weight reduction in the obesity-asthma phenotype.

Profile of difficult to treat asthma patients referred for systematic assessment

AimWe determined the proportion of asthma patients under specialist care who remain difficult-to-treat and might benefit from systematic assessment. We additionally report the characteristics and indications for referral in 90 patients who received systematic assessment for difficult asthma. MethodsWe conducted a three-month prospective audit of our hospital’s general asthma clinic. We then analyzed consecutive patients over 18 months referred on for systematic assessment of difficult asthma. ResultsOver 3 months, 22/166 patients (13.3%) in the general asthma clinic were considered likely to benefit from systematic assessment of difficult asthma. These patients had higher inhaled steroid requirements (890 ± 604 mg), lower lung function (FEV1: 65 ± 18%), and more often received GINA step 5 treatment (22.7%). However, 7/22 (32%) of suitable patients were not referred for assessment, mainly due to patient factors.Over 18 months, 90 patients received systematic assessment for difficult asthma, on account of poor symptom control (62%), frequent exacerbations (44%), poor lung function (42%), patient factors (29%), and diagnostic uncertainty (26%). There was a high disease burden with a mean (±SD) asthma control test score and asthma quality of life questionnaire score of 14 ± 5 and 4.26 ± 1.45 respectively. 80% fulfilled criteria for severe asthma. The majority were either atopic (66.7%) or eosinophilic (54.4%); only 15.6% were neither. Patients had a median of three extra-pulmonary comorbidities, of which most were previously unrecognised. ConclusionOne-in-eight asthma patients already under specialist care were suitable for systematic assessment of difficult asthma, but a third of these were not referred due to patient factors. Diagnostic uncertainty and patient factors were important indications for systematic assessment. Most patients who underwent systematic assessment exhibited severe asthma phenotypes potentially responsive to targeted treatment, but also had multiple comorbidities. Our results highlight the importance of management strategies to address patient factors, severe asthma biology, and concurrent contributory conditions.

Airway Inflammatory Biomarker: Could It Tailor the Right Medications for the Right Asthmatic Patient?

Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active drugs. To solve this paradox, we need objective airway biomarkers to tailor the proper medications to the proper patient. Biomarkers should have one or more of the following characteristics:1) A biomarker that could differentiate poor symptoms perceivers from over perceivers, 2) A biomarker that could predict disease activity and hence disease outcome, 3) A biomarker that could clarify responders from non-responders asthma phenotypes, and finally 4) A biomarker that could characterize different clinical asthma phenotypes. In conclusion, we have conducted a review of literature trying to apply those four parameters to different airway inflammatory biomarkers. We found that FeNO fulfilled the four proposed clinical parameters of airway inflammatory biomarkers whereas; serum periostin was the single best systemic biomarker of airway luminal and tissue eosinophilia in severe uncontrolled TH2 asthma phenotype. Thus, this may be considered a trial towards tailoring the proper medication to the proper patient. However, application of biomarkers in clinical practice requires easier and cheaper techniques together with standardized methods for sample collection and analysis.

MARKERS OF ATOPIC REACTIVITY IN THE PUPILS WITH SEVERE BRONCHIAL ASTHMA

The aim of the work was to increase the effectiveness of treatment of the severe asthma phenotype in school-age children, taking into account the diagnostic value of atopic reactivity indicators. The study involved 30 pupils with severe asthma and 30 children with moderate-heavy version of it. Amid severe asthma increases risk of higher concentrations of IL-4 and IL-5 in the serum, and almost in every second child was observed the increased concentrations of Ig E (more than 545,3 IU/mL, odds ratio was 1,9 (95 % CI 1,1-3,4). In the group of patients with severe asthma were significantly more frequent cases of the skin hypersensitivity to household allergens with respect to the members of the second group. There were separated the indices of clinical and epidemiological risk and diagnostic value of some markers of atopic reactivity for verification of the severe asthma phenotype. It was established that the development of severe asthma in children marked tendency to reduce the metabolic activity of eosinophilic granulocytes in blood (in terms of intracellular content of cationic proteins and peroxidase) and phagocytic ability of these effector cells of allergic inflammation. For the phenotype of severe asthma the risk of high concentration of IL-4 and IL-5 in serum increased in 3,1 times, but this paraclinical test is rather suitable for verification of this phenotype (SP – 84,6% (95 % Sp 75,9–91,1)) than for its detection (Se – 36,4 % (95 % CI 26,9–46,6)).