The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways ...inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type‐2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type‐2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non‐type‐2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.
Severe asthma is associated with an increased risk for exacerbations, reduced lung function, fixed airflow obstruction, and substantial morbidity and mortality. The concept of remission in severe ...asthma as a new treatment goal has recently gained attention due to the growing use of monoclonal antibody therapies, which target specific pathologic pathways of inflammation. This review evaluates the current definitions of asthma remission and unveils some of the barriers for achieving this state in the severe asthma population. Although there is no unified definition, the concept of clinical remission in asthma should be based on a sustained period of symptom control, elimination of oral corticosteroid exposure and exacerbations, and stabilization of pulmonary function. The conjugation of these criteria seems a realistic treatment target in a minority of asthmatic patients. Some unmet needs in severe asthma may affect the achievement of clinical remission. Late intervention with targeted therapies in the severe asthma population may increase the risk of corticosteroid exposure and the development of irreversible structural airway changes. Moreover, airway infection is an important component in persistent exacerbations in patients on biologic therapies. Phenotyping exacerbations may be useful to guide therapy decisions and to avoid the liberal use of oral corticosteroids. Another challenge associated with the aim of clinical remission in severe asthma is the multifaceted interaction between the disease and its associated comorbidities. Behavioural factors should be evaluated in case of persistent symptoms despite optimised treatment, and assessing biomarkers and targeting treatable traits may allow for a more objective way of reaching remission. The concept of clinical remission will benefit from an international consensus to establish unifying criteria for its assessment, and it should be addressed in the future management guidelines.
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.
The prevalence of nonadherence in difficult asthma Gamble, Jacqueline; Stevenson, Michael; McClean, Elizabeth ...
American journal of respiratory and critical care medicine,
11/2009, Letnik:
180, Številka:
9
Journal Article
Recenzirano
With the advent of new and expensive therapies for severe refractory asthma, targeting the appropriate patients is important. An important issue is identifying nonadherence with current therapies. ...The extent of nonadherence in a population with difficult asthma has not been previously reported.
To examine the prevalence of nonadherence to corticosteroid medication in a population with difficult asthma referred to a Specialist Clinic and to examine the relationship of poor adherence to asthma outcome.
General practitioner prescription refill records for the previous 6 months for inhaled combination therapy and short-acting beta-agonists were compared with initial prescriptions and expressed as a percentage. Blood plasma prednisolone and cortisol assay levels were used to examine the utility of these measures in assessing adherence to oral prednisolone. Patient demographics, hospital admissions, lung function, oral prednisolone courses, and quality of life data were analyzed to indentify the variables associated with reduced medication adherence.
A total of 182 patients were assessed. Sixty-three patients (35%) filled 50% or fewer inhaled medication prescriptions; 88% admitted poor adherence with inhaled therapy after initial denial. Twenty-one percent of patients filled more than 100% of presciptions, and 45% of subjects filled between 51 and 100% of prescriptions. Twenty-three of 51 patients (45%) prescribed oral steroids were found to be nonadherent.
A significant proportion of patients with difficult-to-control asthma remained nonadherent to corticosteroid therapy. Objective surrogate and direct measures of adherence should be performed as part of a difficult asthma assessment and are important before prescibing expensive novel biological therapies.
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.
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.
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.
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