Accelerated elastin degradation by age-disease interaction: a common feature in age-related diseases.

Aging is a major driving force for many diseases but the relationship between chronological age, the aging process and age-related diseases is not fully understood. Fragmentation and loss of ultra-long-lived elastin are key features in aging and several age-related diseases leading to increased mortality. By comparing the relationship between age and elastin turnover with healthy volunteers, we show that accelerated elastin turnover by age-disease interaction is a common feature of age-related diseases.

The Role of Smoking in Asthma and Chronic Obstructive Pulmonary Disease Overlap.

Exposure to cigarette smoke has a key role in the development, adverse health outcomes, and impaired response to some therapies among individuals with features of asthma and chronic obstructive pulmonary disease overlap (ACO). To aid the identification of clinical subtypes, the description of ever smokers with features of asthma and COPD should include data on smoking status, cumulative smoking history, and the phenotype of asthma and smoking-related chronic airway disease. Pathogenic mechanisms in smoking-related ACO involve poorly understood, complex interactions between smoking-induced and asthma-induced airway inflammation, corticosteroid insensitivity, and tissue remodeling. Evidence for the clinical effectiveness of interventions for adults with smoking-related ACO is limited. Management currently involves the identification and targeting of treatable traits such as current smoking, type 2 high eosinophilic inflammation, symptomatic airflow obstruction, and extrapulmonary comorbidities.

Cigarette Smoking and Asthma.

Globally, around half the adult asthma population are current or former cigarette smokers. Cigarette smoking and asthma interact to induce an "asthma-smoking phenotype(s)," which has important implications for diagnosis, pathogenic mechanisms, and management. The lack of progress in understanding the effects of smoking on adults with asthma is due in part to their exclusion from most investigative studies and large clinical trials. In this review, we summarize the adverse clinical outcomes associated with cigarette smoking in asthma, highlight challenges in diagnosing asthma among cigarette smokers with chronic respiratory symptoms, particularly in older individuals with a long-standing smoking history, and review pathogenic mechanisms involving smoking- and asthma-related airway inflammation, tissue remodeling, corticosteroid insensitivity, and low-grade systemic inflammation. We discuss the key components of management including the importance of smoking cessation strategies, evidence for the effectiveness of the Global Initiative for Asthma recommendations on treatment in cigarette smokers, and the role of treatable traits such as type 2 eosinophilic airway inflammation. Lastly, we provide an algorithm to aid clinicians to manage current and former smokers with asthma. In the future, controlled and pragmatic trials in real-world populations should include cigarette smokers with asthma to provide an evidence base for treatment recommendations.

Factors Associated with Frequent Exacerbations in the UK Severe Asthma Registry.

BACKGROUND: Frequent exacerbations are an important cause of morbidity in patients with severe asthma. OBJECTIVE: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed in patients treated with and without maintenance oral corticosteroids (OCS). METHODS: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities and physiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year. RESULTS: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire-6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively). CONCLUSIONS: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status.

Phenotypic and functional translation of IL33 genetics in asthma.

BACKGROUND: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.

Recent Developments In Bronchial Thermoplasty For Severe Asthma.

PURPOSE: Bronchial thermoplasty is approved in many countries worldwide as a non-pharmacological treatment for severe asthma. This review summarizes recent publications on the selection of patients with severe asthma for bronchial thermoplasty, predictors of a beneficial response and developments in the procedure and discusses specific issues about bronchial thermoplasty including effectiveness in clinical practice, mechanism of action, cost-effectiveness, and place in management. RESULTS: Bronchial thermoplasty is a treatment option for patients with severe asthma after assessment and management of causes of difficult-to-control asthma, such as nonadherence, poor inhaler technique, comorbidities, under treatment, and other behavioral factors. Patients treated with bronchial thermoplasty in clinical practice have worse baseline characteristics and comparable clinical outcomes to clinical trial data. Bronchial thermoplasty causes a reduction in airway smooth muscle mass although it is uncertain whether this effect explains its efficacy since other mechanisms of action may be relevant, such as alterations in airway epithelial, gland, and/or nerve function; improvements in small airway function; or a placebo effect. The cost-effectiveness of bronchial thermoplasty is greater in countries where the costs of hospitalization and emergency department are high. The place of bronchial thermoplasty in the management of severe asthma is not certain, although some experts propose that bronchial thermoplasty should be considered for patients with severe asthma associated with non-type 2 inflammation or who fail to respond favorably to biologic therapies targeting type 2 inflammation. CONCLUSION: Bronchial thermoplasty is a modestly effective treatment for severe asthma after assessment and management of causes of difficult-to-control asthma. Asthma morbidity increases during and shortly after treatment. Follow-up studies provide reassurance on the long-term safety of the procedure. Uncertainties remain about predictors of response, mechanism(s) of action, and place in management of severe asthma.

Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.

BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.

Insights into frequent asthma exacerbations from a primary care perspective and the implications of UK National Review of Asthma Deaths recommendations.

The United Kingdom National Review of Asthma Deaths (NRAD) recommends that patients who require ≥3 courses of oral corticosteroids (OCS) for exacerbations in the past year or those on British Thoracic Society (BTS) Step 4/5 treatment must be referred to a specialist asthma service. The aim of the study was to identify the proportion of asthma patients in primary care that fulfil NRAD criteria for specialist referral and factors associated with frequent exacerbations. A total of 2639 adult asthma patients from 10 primary care practices in Glasgow, UK were retrospectively studied between 2014 and 2015. Frequent exacerbators and short-acting ß2-agonist (SABA) over-users were identified if they received ≥2 confirmed OCS courses for asthma and ≥13 SABA inhalers in the past year, respectively. Community dispensing data were used to assess treatment adherence defined as taking ≥75% of prescribed inhaled corticosteroid (ICS) dose. The study population included 185 (7%) frequent exacerbators, 137 (5%) SABA over-users, and 319 (12%) patients on BTS Step 4/5 treatment. Among frequent exacerbators, 41% required BTS Step 4/5 treatment, 46% had suboptimal ICS adherence, 42% had not attended an asthma review in the past year and 42% had no previous input from a specialist asthma service. Older age, female gender, BTS Step 4/5, SABA over-use and co-existing COPD diagnosis increased the risk of frequent exacerbations independently. Fourteen per 100 asthma patients would fulfil the NRAD criteria for specialist referral. Better collaboration between primary and secondary care asthma services is needed to improve chronic asthma care.

Challenges in the management of asthma associated with smoking-induced airway diseases.

INTRODUCTION: Smoking-induced airway diseases such as chronic bronchitis, emphysema, and small airway dysfunction contribute to the chronic respiratory symptoms experienced by adults with asthma, including those with spirometric chronic obstructive pulmonary disease (COPD), termed asthma-COPD overlap (ACO). Drug treatment of symptomatic smokers with asthma or ACO is uncertain due to their exclusion from most clinical trials. AREAS COVERED: This review summarizes evidence for the efficacy of small molecule drugs used in the clinic to treat current and former smokers with a diagnostic label of asthma or ACO. Other therapeutic interventions are reviewed, including smoking cessation and biologics. EXPERT OPINION: Clinical trials and observational studies suggest that smoking cessation and approved drugs used to treat non-smokers with asthma produce clinical benefits in smokers with asthma or ACO, although the overall quality of evidence is low. The efficacy of some treatments for asthma is altered in current smokers, including reduced responsiveness to short-term inhaled corticosteroids and possibly improved responsiveness to leukotriene receptor antagonists. Preliminary findings suggest that low-dose theophylline, statins, and biologics, such as omalizumab, mepolizumab, and dupilumab, may improve clinical outcomes in smokers with asthma or ACO. Improved phenotyping and endotyping of asthma and smoking-induced airway diseases should lead to better targeted therapies.

Bronchial thermoplasty as a treatment for severe asthma: controversies, progress and uncertainties.

INTRODUCTION: Bronchial thermoplasty is a licensed non-pharmacological treatment for severe asthma. Area covered: This article considers evidence for the efficacy and safety of bronchial thermoplasty from clinical trials and observational studies in clinical practice. Its place in the management of severe asthma, predictors of response and mechanisms of action are reviewed. Expert commentary: Bronchial thermoplasty improves quality of life and reduces exacerbations in moderate to severe asthma. Morbidity from asthma is increased during treatment. Overall, patients treated in clinical practice have worse baseline characteristics and comparable clinical outcomes to trial data. Follow-up studies provide reassurance on long-term safety. Despite some progress, future research needs to investigate uncertainties about predictors of response, mechanism of action and place in management of asthma.

Targeting oxidant-dependent mechanisms for the treatment of respiratory diseases and their comorbidities.

Oxidative stress is implicated in the pathogenesis of respiratory diseases, such as COPD and its comorbidities, asthma, idiopathic pulmonary fibrosis and radiation pneumonitis. Antioxidants drugs, such as small molecule thiols, nuclear erythroid-2 related factor 2 activators and catalytic enzyme mimetics have been developed to target oxidant-dependent mechanisms. The therapeutic effects of antioxidants have been generally disappointing. A small number of antioxidants are approved for clinical use, such as the small molecule thiol N-acetyl-l-cysteine for chronic obstructive pulmonary disease, and in the United States, the superoxide dismutase mimetic AEOL 10150 for severe radiation pneumonitis. The future use of antioxidants for the treatment of chronic respiratory diseases may require a precision medicine approach to identify responsive patients.

Asthma and smoking-induced airway disease without spirometric COPD.

Due to the high prevalence rates of cigarette smoking and asthma, current and ex-smokers frequently develop chronic airway disease without spirometric evidence of chronic obstructive pulmonary disease (COPD), either alone or associated with asthma. This review considers the classification, clinical outcomes, inflammatory and imaging variables, phenotypes, and management of current and ex-smokers with airway disease without COPD, focusing on overlaps in those with and without asthma. These individuals have more respiratory symptoms, worse quality of life, increased exacerbation rates, reduced lung function and more comorbidities than never-smokers with asthma or healthy never-smokers. As well as clinical features, airway inflammatory and structural changes in smoking-induced airway disease without COPD overlap with those found in smokers with asthma. Cigarette smoking is associated with worse clinical outcomes in some phenotypes of asthma. Management involves public health measures to control exposure to tobacco smoke, personal advice on smoking cessation and the use of appropriate targeted therapies, although evidence is limited on their effectiveness. Understanding the mechanisms, natural history and management of current and ex-smokers with asthma and smoking-induced airway disease without COPD is a priority for future research.