To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.
Cross-sectional observational study.
The primary care Optimum Patient Care Research Database and the British ...Thoracic Society Difficult Asthma Registry.
Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)-severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).
Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.
748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.
Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.
Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important ...clinical challenge.
Suppression of fractional exhaled nitric oxide (Fe
) with directly observed ICS therapy over 7 days can identify nonadherence to ICS treatment in difficult-to-control asthma. We examined the feasibility and utility of Fe
suppression testing in routine clinical care within UK severe asthma centers using remote monitoring technologies.
A web-based interface with integrated remote monitoring technology was developed to deliver Fe
suppression testing. We examined the utility of Fe
suppression testing to demonstrate ICS responsiveness and clinical benefit on electronically monitored treatment with standard high-dose ICS and long-acting β
-agonist treatment.
Clinical response was assessed using the Asthma Control Questionnaire-5, spirometry, and biomarker measurements (Fe
and peripheral blood eosinophil count). Of 250 subjects, 201 completed the test with 130 positive suppression tests. Compared with a negative suppression test, a positive test identified a Fe
-low population when adherent with ICS/long-acting β
-agonist (median, 26 ppb interquartile range, 16-36 ppb vs. 43 ppb interquartile range, 38-73 ppb) with significantly greater FEV
% (mean, 88.2 ± 16.4 vs. 74.1 ± 20.9; P < 0.01). Asthma Control Questionnaire-5 improved significantly in both groups (positive test: mean difference, -1.2; 95% confidence interval, -0.9 to -1.5; negative test: mean difference, -0.9; 95% confidence interval, -0.4 to -1.3).
Remote Fe
suppression testing is an effective means of identifying nonadherence to ICS in subjects with difficult-to-control asthma and the substantial population of subjects who derive important clinical benefits from optimized ICS/long-acting β
-agonist treatment.
BACKGROUND Systematic assessment of severe asthma can be used to confirm the diagnosis identify comorbidities, and address adherence to therapy. However, the prospective usefulness of this approach ...is yet to be established. The objective of this study was to determine whether the systematic assessment of severe asthma is associated with improved quality of life (QoL) and health-care use and, using prospective data collection, to compare relevant outcomes in patients referred with severe asthma to specialist centers across the United Kingdom. METHODS Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics, and health-care use between initial assessment and a median follow-up of 286 days. RESULTS The study population consisted of 346 patients with severe asthma. At follow-up, there were significant reductions in health-care use in terms of primary care or ED visits (66.4% vs 87.8%, P < .0001) and hospital admissions (38% vs 48%, P = .0004). Although no difference was noted in terms of those requiring maintenance oral corticosteroids, there was a reduction in steroid dose (10 mg 8-20 mg vs 15 mg 10-20 mg, P = .003), and fewer subjects required short-burst steroids (77.4% vs 90.8%, P = .01). Significant improvements were seen in QoL and control using the Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. CONCLUSIONS To our knowledge, this is the first time that a prospective study has shown that a systematic assessment at a dedicated severe asthma center is associated with improved QoL and asthma control and a reduction in health-care use and oral steroid burden.
Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to ...temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70°C) for 10 s to mimic thermoplasty.
we developed a mathematical model of airway heat distribution post-thermoplasty.
we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.
airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C.
simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm.
at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured
Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1-1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0-10; p=0.03) and epithelial integrity increased (14%, IQR 6-29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated
and
modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.
Severe refractory asthma is a heterogeneous disease. We sought to determine statistical clusters from the British Thoracic Society Severe refractory Asthma Registry and to examine cluster-specific ...outcomes and stability.
Factor analysis and statistical cluster modelling was undertaken to determine the number of clusters and their membership (N = 349). Cluster-specific outcomes were assessed after a median follow-up of 3 years. A classifier was programmed to determine cluster stability and was validated in an independent cohort of new patients recruited to the registry (n = 245).
Five clusters were identified. Cluster 1 (34%) were atopic with early onset disease, cluster 2 (21%) were obese with late onset disease, cluster 3 (15%) had the least severe disease, cluster 4 (15%) were the eosinophilic with late onset disease and cluster 5 (15%) had significant fixed airflow obstruction. At follow-up, the proportion of subjects treated with oral corticosteroids increased in all groups with an increase in body mass index. Exacerbation frequency decreased significantly in clusters 1, 2 and 4 and was associated with a significant fall in the peripheral blood eosinophil count in clusters 2 and 4. Stability of cluster membership at follow-up was 52% for the whole group with stability being best in cluster 2 (71%) and worst in cluster 4 (25%). In an independent validation cohort, the classifier identified the same 5 clusters with similar patient distribution and characteristics.
Statistical cluster analysis can identify distinct phenotypes with specific outcomes. Cluster membership can be determined using a classifier, but when treatment is optimised, cluster stability is poor.
The Asthma Control Questionnaire (ACQ) is used to assess asthma symptom control. The relationship between the questionnaire items and symptom control has not been fully studied in severe asthmatic ...patients, and its validity for making comparisons between subgroups of patients is unknown.
Data was obtained from patients in the United Kingdom Severe Asthma Registry whose symptom control was assessed using the five-item ACQ (ACQ5) (n = 2,951). Confirmatory factor analysis determined whether a latent factor for asthma symptom control, as measured by the ACQ5, was consistent with the data. Measurement invariance was examined in relation to ethnicity, sex and age; this included testing for approximate measurement invariance using Bayesian Structural Equation Modelling (BSEM). The fitted models were used to estimate the internal consistency reliability of the ACQ5. Invariance of factor means across subgroups was assessed.
A one-factor construct with residual correlations for the ACQ5 was an excellent fit to the data in all subgroups (Root Mean Square Error Approximation 0.03 90%CI 0.02,0.05, p-close fit 0.93, Comparative Fit Index 1.00, Tucker Lewis Index 1.00}. Expected item responses were consistent for Caucasian and non-Caucasian patients with the same absolute level of symptom control. There was some evidence that females and younger adults reported wakening more frequently during the night than males and older adults respectively with the same absolute level of symptom control (p<0.001). However approximate measurement invariance was tenable and any failure to observe strong measurement invariance had minimal impact when comparing mean levels of asthma symptom control between patients of different sexes or ages. Average levels of asthma symptom control were lower for non-Caucasians (p = 0.001), females (p<0.01)and increased with age (p<0.01). Reliability of the instrument was high (over 88%) in all subgroups studied.
The ACQ5 is informative in comparing levels of symptom control between severe asthmatic patients of different ethnicities, sexes and ages. It is important that analyses are replicated in other severe asthma registries to determine whether measurement invariance is observed.
Background Clinical outcomes are worse in current smokers and exsmokers with mild-to-moderate asthma compared with never smokers, but little is known about the influence of smoking status in patients ...with severe asthma. Objectives We sought to examine the association of current or previous cigarette smoking with clinical and inflammatory variables in patients with severe asthma. Methods We compared patients' demographics, disease characteristics, and biomarkers of inflammation in current smokers (n = 69 9%), exsmokers (n = 210 28%), and never smokers (n = 461 62%) with severe asthma (n = 760) recruited to the British Thoracic Society Severe Asthma Registry. Results Current smokers had poorer asthma control, more unscheduled health care visits, more rescue courses of oral steroids, and higher anxiety and depression scale scores than exsmokers or never smokers. Current smokers had a reduced proportion of sputum eosinophils compared with never smokers (1% and 4%, respectively) and lower fraction of expired nitric oxide (50 mL/s; 14 ppb and 35 ppb, respectively). Exsmokers compared with never smokers had an increased proportion of sputum neutrophils (59% and 43%, respectively) but a similar proportion of sputum eosinophils (3%) and fraction of expired nitric oxide (50 mL/s; 35 ppb). Both current smokers and exsmokers had reduced serum specific IgE levels to several common environmental allergens. Conclusion Current smokers with severe asthma exhibit worse clinical and health care outcomes compared with exsmokers and never smokers with severe asthma. Their inflammatory profiles in sputum and blood differ.
Bronchial thermoplasty is a bronchoscopic procedure to reduce the mass of airway smooth muscle and attenuate bronchoconstriction. We examined the effect of bronchial thermoplasty on the control of ...moderate or severe persistent asthma.
We randomly assigned 112 subjects who had been treated with inhaled corticosteroids and long-acting beta2-adrenergic agonists (LABA) and in whom asthma control was impaired when the LABA were withdrawn to either bronchial thermoplasty or a control group. The primary outcome was the frequency of mild exacerbations, calculated during three scheduled 2-week periods of abstinence from LABA at 3, 6, and 12 months. Airflow, airway responsiveness, asthma symptoms, the number of symptom-free days, use of rescue medication, and scores on the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ) were also assessed.
The mean rate of mild exacerbations, as compared with baseline, was reduced in the bronchial-thermoplasty group but was unchanged in the control group (change in frequency per subject per week, -0.16+/-0.37 vs. 0.04+/-0.29; P=0.005). At 12 months, there were significantly greater improvements in the bronchial-thermoplasty group than in the control group in the morning peak expiratory flow (39.3+/-48.7 vs. 8.5+/-44.2 liters per minute), scores on the AQLQ (1.3+/-1.0 vs. 0.6+/-1.1) and ACQ (reduction, 1.2+/-1.0 vs. 0.5+/-1.0), the percentage of symptom-free days (40.6+/-39.7 vs. 17.0+/-37.9), and symptom scores (reduction, 1.9+/-2.1 vs. 0.7+/-2.5) while fewer puffs of rescue medication were required. Values for airway responsiveness and forced expiratory volume in 1 second did not differ significantly between the two groups. Adverse events immediately after treatment were more common in the bronchial-thermoplasty group than in the control group but were similar during the period from 6 weeks to 12 months after treatment.
Bronchial thermoplasty in subjects with moderate or severe asthma results in an improvement in asthma control. (ClinicalTrials.gov number, NCT00214526 ClinicalTrials.gov.).
Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. ...This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance.
In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids).
In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments.
Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study.
EU clinical trials register (2017-003679-75), 6 October 2017.
The study was designed to assess the effect of cigarette smoking on the therapeutic response to oral corticosteroids in chronic stable asthma. We performed a randomized, placebo-controlled, crossover ...study with prednisolone (40 mg daily) or placebo for 2 weeks in smokers with asthma, ex-smokers with asthma, and never-smokers with asthma. All subjects had reversibility in FEV1 after nebulized albuterol of 15% or more and a mean postbronchodilator FEV1% predicted of more than 80%. Efficacy was assessed using FEV1, daily PEF, and an asthma control score. There was a significant improvement after oral prednisolone compared with placebo in FEV1, ml (mean difference, 237; 95% confidence intervals, 43, 231; p = 0.019), morning PEF L/m (mean difference, 36.8; 95% confidence intervals (CI), 11, 62; p = 0.006), and asthma control score (mean difference, -0.72; 95% CI, -1.2, -0.3; p = 0.004) in never-smokers with asthma but no change in smokers with asthma (mean differences of 47, 6.5, and -0.05 with p values of 0.605, 0.47, and 0.865, respectively). Ex-smokers with asthma had a significant improvement in morning and night PEF (mean difference, 29.1; CI, 2.3, 56; p = 0.04 and 52.4; CI, 26, 79; p = 0.003, respectively), but not in FEV1 or asthma control score. We conclude that active smoking impairs the efficacy of short-term oral corticosteroid treatment in chronic asthma.
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