Overuse of Oral Corticosteroids, Underuse of Inhaled Corticosteroids, and Implications for Biologic Therapy in Asthma.

BACKGROUND: Asthma patients using high cumulative doses of oral corticosteroids (OCSs) are at risk of serious adverse events and are increasingly being treated with steroid-sparing asthma biologics. However, it is unknown whether prescribing these expensive biologics is always justified. OBJECTIVES: This study aimed to (1) assess the prevalence of asthma patients using high cumulative doses of OCSs, (2) explore the role of suboptimal inhaler therapy, and (3) estimate the proportion of patients to whom asthma biologics might be prescribed unnecessarily. METHODS: All adults (n = 5,002) with at least 1 prescription of high-dose inhaled corticosteroids (≥500-1,000 mcg/day fluticasone-equivalent) and/or OCSs (GINA step 4-5) in 2010 were selected from a pharmacy database including 500,500 Dutch inhabitants, and sent questionnaires. Of 2,312 patients who returned questionnaires, 929 had asthma. We calculated the annual cumulative OCS dose and prescription fillings and checked inhaler technique in a sample of 60 patients. Patients estimated to have good adherence and inhaler proficiency who still required high doses of OCSs (≥420 mg/year) were considered candidates for initiating biologic treatment. RESULTS: 29.5% of asthma patients on GINA 4-5 therapy used high doses of OCSs, of which 78.1% were likely to have poor therapy adherence or inadequate inhaler technique. Only 21.9% were considered definitive candidates for biologic therapy. CONCLUSION: High OCS use in Dutch GINA 4-5 asthma patients was common. However, in 4 out of 5 patients adherence to inhaled corticosteroid therapy and/or inhalation technique was considered suboptimal. Since optimizing inhaler therapy may reduce the need for OCSs, this should be mandatory before prescribing expensive steroid-sparing drugs.

The prevalence of severe refractory asthma.

BACKGROUND: Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment. However, prevalence figures of severe asthma are lacking, whereas longstanding estimates vary between 5% and 10% of all asthmatic patients. Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making, drug development, and reimbursement policies by health authorities. OBJECTIVE: We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus. METHODS: Adult patients with a prescription for high-intensity treatment (high-dose inhaled corticosteroids and long-acting ß2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting ß2-agonists) were extracted from 65 Dutch pharmacy databases, representing 3% of the population (500,500 inhabitants). Questionnaires were sent to 5,002 patients, of which 2,312 were analyzed. The diagnosis of asthma and degree of asthma control were derived from questionnaires to identify patients with difficult-to-control asthma. Inhalation technique was assessed in a random sample of 60 adherent patients (prescription filling, ≥80%). Patients with difficult-to-control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. Results were mirrored to the Dutch population. RESULTS: Of asthmatic adults, 3.6% (95% CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants. CONCLUSION: The prevalence of severe refractory asthma might be lower than estimated by expert opinion. This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare diseases.

Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes.

Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (≥3%) in different adult asthma phenotypes.Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex-)smoking and never-smoking asthma patients.Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78-0.87) for blood eosinophils, 0.82 (0.77-0.87) for FeNO and 0.69 (0.63-0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients.Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma.

Severe adult-onset asthma: A distinct phenotype.

BACKGROUND: Some patients with adult-onset asthma have severe disease, whereas others have mild transient disease. It is currently unknown whether patients with severe adult-onset asthma represent a distinct clinical phenotype. OBJECTIVE: We sought to investigate whether disease severity in patients with adult-onset asthma is associated with specific phenotypic characteristics. METHODS: One hundred seventy-six patients with adult-onset asthma were recruited from 1 academic and 3 nonacademic outpatient clinics. Severe refractory asthma was defined according to international Innovative Medicines Initiative criteria, and mild-to-moderate persistent asthma was defined according to Global Initiative for Asthma criteria. Patients were characterized with respect to clinical, functional, and inflammatory parameters. Unpaired t tests and χ(2) tests were used for group comparisons; both univariate and multivariate logistic regression were used to determine factors associated with disease severity. RESULTS: Apart from the expected high symptom scores, poor quality of life, need for high-intensity treatment, low lung function, and high exacerbation rate, patients with severe adult-onset asthma were more often nonatopic (52% vs 34%, P = .02) and had more nasal symptoms and nasal polyposis (54% vs 27%, P ≤ .001), higher exhaled nitric oxide levels (38 vs 27 ppb, P = .02) and blood neutrophil counts (5.3 vs 4.0 10(9)/L, P ≤ .001) and sputum eosinophilia (11.8% vs 0.8%, P ≤ .001). Multiple logistic regression analysis showed that increased blood neutrophil (odds ratio, 10.9; P = .002) and sputum eosinophil (odds ratio, 1.5; P = .005) counts were independently associated with severe adult-onset disease. CONCLUSION: The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation. This suggests that severe adult-onset asthma has a distinct underlying mechanism compared with milder disease.

Risk of deep vein thrombosis and pulmonary embolism in asthma.

Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age- and sex-matched reference population. 648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified. In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20-63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42-1.44) per 1000 person-years, 0.33 (95% CI 0.07-0.60) in mild-to-moderate asthma and 0.18 (95% CI 0.03-0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16-9.93) and 2.82 (1.09-7.30), respectively). Asthma was not associated with deep vein thrombosis. Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used.

New-Onset Asthma in Adults: What Does the Trigger History Tell Us?

BACKGROUND: Adult-onset asthma is an important asthma phenotype and, in contrast to childhood asthma, is often associated with specific triggers of onset. It is unknown whether these triggers correspond with specific phenotypic characteristics or predict a specific asthma outcome. OBJECTIVE: To compare clinical, functional, and inflammatory characteristics between patients with different triggers of asthma onset, and relate these triggers to asthma outcome. METHODS: Two hundred adults with recently diagnosed (<1 year) asthma were prospectively followed for 5 years. The trigger of asthma onset was patient reported and defined by the question: "What, in your opinion, elicited your asthma?" Asthma remission was defined as no asthma symptoms and no asthma medication use for ≥1 year. Kruskal-Wallis and Fisher's exact test were used to compare categories containing >10 patients. RESULTS: Ten categories of triggers were identified, of which 5 contained >10 patients. Clinical and inflammatory characteristics and remission rates differed significantly between categories. "New allergic sensitization" (11%) was associated with mild atopic asthma and a relatively young age at onset; "pneumonia" (8%) with previous smoking, low IgE, and the highest remission rates (one third); "upper respiratory symptoms" (22%) with high exhaled NO and eosinophilia; "no trigger identified" (38%) did not show any specific characteristics; and "stressful life event" (7%) with high medication usage, low type 2 markers, and no disease remission. CONCLUSIONS: Patients with adult-onset asthma can be characterized by the trigger that seemingly incited their asthma. These triggers might represent underlying mechanisms and may be important to phenotype patients and predict disease outcome.

Diagnosing persistent blood eosinophilia in asthma with single blood eosinophil or exhaled nitric oxide level.

BACKGROUND: Eosinophilic asthma is characterized by persistently elevated blood eosinophils, adult-onset asthma and corticosteroid resistance. For stratified medicine purposes one single measurement of blood eosinophils or exhaled nitric oxide (FeNO) is commonly used. The aim of this study was to investigate in patients with new-onset asthma whether persistent blood eosinophilia can be predicted with one single measurement of these biomarkers. METHODS: Blood eosinophils and exhaled nitric oxide levels were measured at yearly intervals over 5 years in 114 adults with new-onset asthma on inhaled corticosteroid treatment. Two definitions of persistent blood eosinophilia were used (1); blood eosinophils at every visit ≥0.30 × 109/L, or (2) ≥0.40 × 109/L. Receiver operating characteristic analyses were performed. Diagnostic cut-off values were defined at a positive predictive value of 95% (or the highest achievable). RESULTS: Using definition 1 (blood eosinophils ≥0.30 × 109/L) the cut-off value for a single measurement of blood eosinophils was 0.47 × 109/L. For definition 2 (≥0.40 × 109/L) the cut-off value was 0.49 × 109/L. Cut-off values for persistently low blood eosinophils were 0.17 × 109/L for definition (1) and 0.21 × 109/L for definition (2), respectively. For FeNO no cut-off values with sufficient accuracy could be defined. CONCLUSION: We showed that by using high and low cut-off values, one single measurement of blood eosinophils, but not FeNO in the initial phase of new-onset asthma in adults can be used to predict persistence or absence of blood eosinophilia in asthma.

Comorbidities in Difficult-to-Control Asthma.

BACKGROUND: Difficult-to-control asthma is associated with significant medical and financial burden. Comorbidities are known to contribute to uncontrolled asthma. Better insight into the prevalence, nature, and risk factors of comorbidities may optimize treatment strategies in patients with difficult-to-control asthma and decrease disease burden. OBJECTIVES: The objectives of this study were to assess the prevalence, number, and type of comorbidities in difficult-to-control asthma compared with not-difficult-to-control asthma, and to investigate whether specific patient characteristics are associated with particular comorbidities. METHODS: A total of 5,002 adult patients with a prescription for high-dose (>1,000 µg) fluticasone or oral corticosteroids, extracted from 65 Dutch pharmacy databases, were sent questionnaires about patient characteristics. Of the 2,312 patients who returned the questionnaires, 914 were diagnosed with difficult-to-control asthma. Diagnoses of comorbidities (gastroesophageal reflux, nasal polyps, cardiovascular disease, anxiety/depression, obesity, and diabetes) were based on treatment prescriptions or questionnaires. Associations were assessed using multivariable logistic regression analyses. RESULTS: A total of 92% of patients with difficult-to-control asthma had ≥1 comorbidity. Patients with difficult-to-control asthma had more comorbidities (mean ± SD comorbidities 2.22 ± 1.27 vs 1.69 ± 1.32; P < .01), and a significantly higher prevalence of each comorbidity, compared with patients with not-difficult-to-control asthma, except for diabetes and nasal polyposis. Comorbidities were associated with specific patient characteristics, including older age, female gender, smoking history, and chronic prednisone use. CONCLUSIONS: Almost all patients with difficult-to-control asthma have comorbidities, in particular asthmatic women of older age, former smokers, and asthmatics who are prednisone dependent. Recognition of these typical characteristics can help physicians in the diagnostic workup, so that adequate preventive measures can be taken.

Clinical profile of patients with adult-onset eosinophilic asthma.

Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×109 L-1) were compared with 361 adult-onset asthma patients with low (<0.3×109 L-1) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7-8.1), 3.0 (95% CI 1.1-8.1) and 2.4 (95% CI 1.3-4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice.

Predictors of frequent exacerbations in (ex)smoking and never smoking adults with severe asthma.

BACKGROUND: Persistent eosinophilic airway inflammation is an important driver for asthma exacerbations in non-smokers with asthma. Whether eosinophilic inflammation is also a predictor of asthma exacerbations in (ex)smokers is not known. OBJECTIVE: The aim was to investigate factors associated with frequent exacerbations in never smokers and (ex)smokers with asthma. METHODS: (Ex)smoking (n = 83) and never smoking (n = 70) patients with uncontrolled asthma despite high dose asthma medication (GINA treatment step 4-5) were selected from a cohort of 571 adult-onset asthma patients. Clinical, functional and inflammatory parameters were used in multivariate logistic regression analyses to identify factors associated with frequent exacerbations (≥3 oral corticosteroid (OCS) bursts in the previous year). RESULTS: Frequent exacerbations in (ex)smokers were independently associated with ICS dose (OR 1.2, 95%CI: 1.1-1.3) and blood neutrophil count (OR 1.5, 95%CI: 1.2-2.1). In never smokers frequent exacerbations were independently associated with blood eosinophil count (OR 18.9, 95%CI: 1.8-202.1). CONCLUSION AND CLINICAL RELEVANCE: This study shows that never smoking and (ex)smoking patients with severe asthma have different predictors of frequent exacerbations: higher blood neutrophils in (ex)smokers versus higher blood eosinophils in never smokers. This suggests that different types of systemic background inflammation play a role in the aetiology of exacerbations in these patients. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register: NTR2217, NTR1846 and NTR1838.

Anxiety, depression and personality traits in severe, prednisone-dependent asthma.

BACKGROUND: Anxiety and depression are prevalent in patients with asthma, and associated with more exacerbations and increased health care utilization. Since psychiatric intervention might improve asthma control, we examined whether patients with severe, prednisone-dependent asthma are at higher risk of these disorders than patients with severe non-prednisone dependent asthma or mild-moderate asthma, and whether they exhibit different personality traits. METHODS: Sixty-seven adults with severe prednisone-dependent asthma, 47 with severe non-prednisone dependent and 73 patients with mild-moderate asthma completed the HADS depression and anxiety subscale and the NEO-FFI for personality traits. In addition, asthma duration, body mass index and FEV1 were measured. RESULTS: The prevalence of clinically significant depressive symptoms (9% vs. 0 vs. 0%; p = 0.009) and anxiety symptoms (19% vs. 6.4 vs. 5.5%; p = 0.01), was higher in patients with severe, prednisone-dependent asthma than in patients with severe non-prednisone dependent or mild-moderate asthma. Patients with prednisone-dependent asthma were respectively 3.4 (95%CI: 1.0-10.8 p = 0.04) and 3.5 (95%CI: 1.3-9.6 p = 0.01) times more likely to have significant depression symptoms and 1.6 (95%CI: 0.7-3.7, p = 0.2) and 2.5 (95%CI: 01.1-5.5, p = 0.02) times more likely to have symptoms of anxiety than patients with severe non-prednisone dependent or mild-moderate asthma. There were no differences found in personality traits between the 3 groups. CONCLUSION: Patients with severe, prednisone-dependent asthma have more often psychological distress as compared to patients with severe non-prednisone dependent or mild-moderate asthma.