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Pharmacotherapy of severe asthma.

ABSTRACT: Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.

SUBMITTER: Firszt R

PROVIDER: S-EPMC4390052 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Project description:RationaleSevere asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity.ObjectivesTo compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant parameters between normal subjects and subjects with asthma to clarify their pathobiologic importance.MethodsEndobronchial biopsies, epithelial brushings, and bronchoalveolar lavage were obtained from subjects with asthma and normal subjects from the Severe Asthma Research Program (N = 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MC(Tot)) and the MC(TC) subset (MCs positive for both tryptase and chymase) using immunostaining and quantitative real-time polymerase chain reaction. Lavage was analyzed for tryptase and prostaglandin D2 (PGD2) by ELISA.Measurements and main resultsSubmucosal MC(Tot) (tryptase-positive by immunostaining) numbers were highest in "mild asthma/no inhaled corticosteroid (ICS) therapy" subjects and decreased with greater asthma severity (P = 0.002). In contrast, MC(TC) (chymase-positive by immunostaining) were the predominant (MC(TC)/MC(Tot) > 50%) MC phenotype in SA (overall P = 0.005). Epithelial MC(Tot) were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MC(TC). Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P = 0.008 and P = 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P = 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MC(TC)/MC(Tot) predicted SA.ConclusionsSevere asthma is associated with a predominance of MC(TC) in the airway submucosa and epithelium. Activation of those MC(TC) may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.

Project description:BackgroundThe UK Severe Asthma Registry (UKSAR) is the world's largest national severe asthma registry collecting standardised data on referrals to UK specialist services. Novel biologic therapies have transformed the management of type 2(T2)-high severe asthma but have highlighted unmet need in patients with persisting symptoms despite suppression of T2-cytokine pathways with corticosteroids.MethodsDemographic, clinical and treatments characteristics for patients meeting European Respiratory Society / American Thoracic Society severe asthma criteria were examined for 2225 patients attending 15 specialist severe asthma centres. We assessed differences in biomarker low patients (fractional exhaled nitric oxide (FeNO) <25?ppb, blood eosinophils <150/?L) compared with a biomarker high population (FeNO ?25?ppb, blood eosinophils ?150/µL).ResultsAge (mean 49.6 (14.3) y), age of asthma onset (24.2 (19.1) y) and female predominance (62.4%) were consistent with prior severe asthma cohorts. Poor symptom control (Asthma Control Questionnaire-6: 2.9 (1.4)) with high exacerbation rate (4 (IQR: 2, 7)) were common despite high-dose treatment (51.7% on maintenance oral corticosteroids (mOCS)). 68.9% were prescribed biologic therapies including mepolizumab (50.3%), benralizumab (26.1%) and omalizumab (22.6%). T2-low patients had higher body mass index (32.1 vs 30.2, p<0.001), depression/anxiety prevalence (12.3% vs 7.6%, p=0.04) and mOCS use (57.9% vs 42.1%, p<0.001). Many T2-low asthmatics had evidence of a historically elevated blood eosinophil count (0.35 (0.13, 0.60)).ConclusionsThe UKSAR describes the characteristics of a large cohort of asthmatics referred to UK specialist severe asthma services. It offers the prospect of providing novel insights across a range of research areas and highlights substantial unmet need with poor asthma control, impaired lung function and high exacerbation rates. T2-high phenotypes predominate with significant differences apparent from T2-low patients. However, T2-low patients frequently have prior blood eosinophilia consistent with possible excessive corticosteroid exposure.

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Pharmacotherapy of severe asthma.

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