Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and ...leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs. MC localization within the ASM is accompanied with the hypertrophy and hyperplasia of the layer, and smooth muscle dysfunction that is mainly observed in forms of bronchial hyperresponsiveness, and variable airflow obstruction. Owing to the expression of a wide range of surface receptors and releasing various cytoplasmic mediators, MCs orchestrate the pathologic events of the disease. MC-released preformed mediators including chymase, tryptase, and histamine and de novo synthesized mediators such as PGD2, LTC4, and LTE4 in addition of cytokines mainly TGFβ1, TSLP, IL-33, IL-4, and IL-13 participate in pathogenesis of asthma. The release of MC mediators and MC/airway cell interactions during remodeling phase of asthma results in persistent cellular and structural changes in the airway wall mainly epithelial cell shedding, goblet cell hyperplasia, hypertrophy of ASM bundles, fibrosis in subepithelial region, abnormal deposition of extracellular matrix (ECM), increased tissue vascularity, and basement membrane thickening. We will review the current knowledge regarding the participation of MCs in each stage of asthma pathophysiology including the releasing mediators and their mechanism of action, expression of receptors by which they respond to stimuli, and finally the pharmaceutical products designed based on the strategy of blocking MC activation and mediator release.
It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease ...subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called “asthma endotypes.” An “endotype” is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.
Inflammation is a key pathology in asthma. In the central airways local inflammation leads to irreversible remodeling and airway dysfunction. Complex inflammatory changes also occur in the nose, ...sinuses, and small airways. In particular, rhinitis and asthma are linked by a common pathogenic process with common inflammatory cells, mediators, and cytokines. Cross-communication between the airways and bone marrow through inflammatory mediators in the circulation leads to systemic propagation of airway inflammation. Treatment of asthma has traditionally focused on relieving bronchospasm with β2 -agonists, which do not affect inflammation. Treatment of eosinophilic inflammation in the central airways with inhaled corticosteroids reduces local inflammation and improves pulmonary function but does not improve the systemic manifestations of asthma. If asthma is a systemic disease, the underlying systemic pathology should be targeted by identifying common disease mediators, mechanisms, or both that are triggered only during active disease. Of currently available therapies, leukotriene receptor antagonists block the action of cysteinyl leukotrienes and thus improve both asthma and rhinitis and other conditions systemically linked with asthma. Other potential treatments include receptor-blocking molecules and synthesis inhibitors related to eicosanoid inflammation. Treatment of asthma as a systemic disease requires clinical trials that evaluate the effects of new treatments on both lung function and the wider systemic pathology.
Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous ...spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best‐defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non‐type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point‐of‐care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
Abstract Background Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the ...effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD. Methods In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 μg, 2.5/5 μg, tiotropium 5 μg or placebo for 12 weeks, via the Respimat® inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1 ) area under the curve from 0 to 3 h (AUC0–3 ) response and trough FEV1 response. Results In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 μg improved SGRQ total score by 4.89 (95% confidence interval CI −6.90, −2.88) and 4.56 (95% CI −6.50, −2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI −4.47, −0.51; p < 0.05) and 1.72 (95% CI −3.63, 0.19) units versus tiotropium 5 μg. Tiotropium + olodaterol 2.5/5 μg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0–3 response compared to placebo and tiotropium 5 μg. Tiotropium + olodaterol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 μg in OTEMTO 2. Adverse-event incidence was similar between treatment groups. Conclusion Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 μg. Trial registration ClinicalTrials.gov: NCT01964352 and NCT02006732.
End-stage chronic obstructive pulmonary disease (COPD) is associated with an accumulation of pulmonary lymphoid follicles. IL-17A is implicated in COPD and pulmonary lymphoid neogenesis in response ...to microbial stimuli. We hypothesized that IL-17A is increased in peripheral lung tissue during end-stage COPD and also directly contributes to cigarette smoke-induced lymphoid neogenesis.
To characterize the tissue expression and functional role of IL-17A in end-stage COPD.
Automated immune detection of IL-17A and IL-17F was performed in lung tissue specimens collected from patients with Global Initiative for Chronic Obstructive Lung Disease stage I-IV COPD, and smoking and never-smoking control subjects. In parallel, Il17a(-/-) mice and wild-type control animals were exposed to cigarette smoke for 24 weeks, and pulmonary lymphoid neogenesis was assessed.
Tissue expression of IL-17A and IL-17F was increased in COPD and correlated with lung function decline. IL-17A was significantly elevated in severe to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease III/IV) compared with both smokers and never-smokers without COPD. Although CD3(+) T cells expressed IL-17A in very severe COPD, most IL-17A(+) cells were identified as tryptase-positive mast cells. Attenuated lymphoid neogenesis and reduced expression of the B-cell attracting chemokine C-X-C motif ligand (CXCL) 12 was observed in cigarette smoke-exposed Il17a(-/-) mice. CXCL12 was also highly expressed in lymphoid follicles in COPD lungs, and the pulmonary expression was significantly elevated in end-stage COPD.
IL-17A in the peripheral lung of patients with severe to very severe COPD may contribute to disease progression and development of lymphoid follicles via activation of CXCL12.
Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in ...low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids.
The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV
) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions.
Change from baseline in trough FEV
at Week 24 was 66 mL (95% confidence interval CI: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 95% CI: 0.06, 0.68, p = 0.018; vs salmeterol: 0.45 95% CI: 0.15, 0.76, p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% p < 0.01) and salmeterol (by 26-41% p < 0.001). Safety profiles were similar between treatments.
Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.
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