Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort.

BACKGROUND: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. RESEARCH QUESTION: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? STUDY DESIGN AND METHODS: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). RESULTS: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. INTERPRETATION: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

The burden of corticosteroid overload in severe and difficult to treat asthma: how to reduce this?

PURPOSE OF REVIEW: Severe asthma is a serious condition that requires an individualized approach combining several treatment agents administered simultaneously in order to reach adequate control. Glucocorticosteroid treatment, as the cornerstone of asthma pharmacotherapy, has great disease-controlling capability, although it may induce a vast amount of severe adverse effects. This review describes our current knowledge of the monitoring and managing options of these adverse effects and possibilities to prevent them, including new therapeutic options. RECENT FINDINGS: A large amount of new drugs is emerging, which may offer a better control of glucocorticosteroid-induced adverse effects. At the same time, major achievements in our understanding of the underlying mechanisms in severe asthma and in the field of biologic agents may help to substantially reduce the need of glucocorticosteroids in the first-line treatment. SUMMARY: We discuss new insights and approaches to treatment strategy of severe asthma allowing less oral glucocorticosteroid use and hence, substantial less severe adverse effects of the treatment.

Effects of medication adherence on healthcare services use among asthma patients.

INTRODUCTION AND OBJECTIVES: Medication adherence is an important indicator of quality in healthcare, and non-adherence is associated with increased healthcare costs, hospital admissions, re-admissions, and decline in health outcomes. Despite the availability of medication to control and avoid adverse health outcomes, adherence to medications among asthma patients varies between 40% and 60%. The objective of this study is to evaluate the effects of asthma medication adherence on healthcare services. MATERIAL AND METHODS: This cross-sectional study is based on insurance claims data for Medicaid patients primarily diagnosed with asthma during 2015-2016. A regression analysis was performed to examine the relationship between control and rescue medication adherence with healthcare use (hospital admissions and re-admissions, clinic visits, and emergency department visits), as well as patient demographics (age, gender, and estimated income). RESULTS: This study found a control medication adherence of 82%. Patients with high rescue medication adherence had fewer emergency department visits (p=.0004) and inpatient admissions (p=.0303). Patients with more than 4 clinic visits had higher rescue medication adherence. Older and low-income patients had higher 30-day re-admissions. Males and low-income patients had more emergency visits. CONCLUSIONS: These results provide evidence that certain populations (older, low-income, and male) may benefit from additional education on monitoring and controlling asthma. This may reduce costlier healthcare services use in favor of less expensive physician visits and education programs.

Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma.

INTRODUCTION: Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. METHODS: Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. CONCLUSION: Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc. CLINICAL TRIALS. GOV IDENTIFIER: NCT02414854.

Asthma and chronic obstructive pulmonary disease inhalers: Techniques for proper use.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) affect millions of Americans. Inhalers are necessary to manage these diseases, but physicians and patients often struggle to use them correctly. OBJECTIVE: To simplify inhaler use for patients and physicians. METHODS: This article compares the various inhalers used to treat asthma and COPD, their techniques for use, and the steps necessary to prime the inhaler if required. The authors provide a suggested standardized technique for the use of metered-dose inhalers, dry powder inhalers, and soft-mist inhalers to provide for a more universal approach for the use of these medications and summarizes how each product is to be used per the U.S. Food and Drug Administration approved package insert. RESULTS AND CONCLUSIONS: The simplified techniques proposed in this article for the use of metered-dose inhalers, dry powder inhalers, and soft mist inhalers used to treat asthma and COPD may limit inhaler misuse and aid in proper medication delivery and treatment.

Primary Care of the Patient with Asthma.

Obstructive lung disease includes asthma and chronic obstructive pulmonary disease (COPD). Because a previous issue of Medical Clinics of North America (2012;96[4]) was devoted to COPD, this article focuses on asthma in adults, and addresses some topics about COPD not addressed previously. Asthma is a heterogeneous disease marked by variable airflow obstruction and bronchial hyperreactivity. Onset is most common in early childhood, although many people develop asthma later in life. Adult-onset asthma presents a particular challenge in the primary care clinic because of incomplete understanding of the disorder, underreporting of symptoms, underdiagnosis, inadequate treatment, and high rate of comorbidity.

Guidelines for severe uncontrolled asthma.

Since the publication, 9 years ago, of the latest SEPAR (Spanish Society of Pulmonology and Thoracic Surgery) Guidelines on Difficult-to-Control Asthma (DCA), much progress has been made in the understanding of asthmatic disease. These new data need to be reviewed, analyzed and incorporated into the guidelines according to their level of evidence and recommendation. Recently, consensus documents and clinical practice guidelines (CPG) addressing this issue have been published. In these guidelines, specific mention will be made of what the previous DCA guidelines defined as "true difficult-to-control asthma". This is asthma that remains uncontrolled after diagnosis and a systematic evaluation to rule out factors unrelated to the disease itself that lead to poor control ("false difficult-to-control asthma"), and despite an appropriate treatment strategy (Spanish Guidelines for the Management of Asthma [GEMA] steps 5 and 6): severe uncontrolled asthma. In this respect, the guidelines propose a revised definition, an attempt to classify the various manifestations of this type of asthma, a proposal for a stepwise diagnostic procedure, and phenotype-targeted treatment. A specific section has also been included on DCA in childhood, aimed at assisting healthcare professionals to improve the care of these patients.

[Diagnosis and treatment of asthma]. / Diagnosi e trattamento dell'asma bronchiale.

Asthma is an inflammatory disease of the airways. It is suggested by characteristic history of recurrent episodes of wheezing, breathlessness, chest tightness, and/or cough especially at night or in early morning. In asthmatic patients spirometry or pulmonary function tests demonstrate airflow obstruction that improves significantly, defined as both a 12% and 200 ml improvement in either FEV1 in response to inhaled bronchodilator. Measurement of airways responsiveness to methacholine in specialized pulmonary function laboratories may help to diagnose asthma. The goals for successful management of asthma are to achieve and maintain control of symptoms and to prevent asthma exacerbations.

Evidence for phenotype-driven treatment in asthmatic patients.

PURPOSE OF REVIEW: Asthma is a complex inflammatory disease and current therapy remains inadequate in many sufferers. There is phenotypic heterogeneity in its clinical expression as a consequence of gene-environment interactions and heterogeneity in response to therapy. This review summarizes the current state of knowledge on phenotype-driven treatment of asthma. RECENT FINDINGS: Evidence is accumulating that even standard therapies such as inhaled corticosteroids benefit some groups of asthmatic patients more than others. Macrolide antibiotics and antifungal agents are examples of drugs that have established indications outside the field of airways disease but which may benefit a subset of patients with asthma. Finally, new and expensive biological therapies for asthma are emerging that may be highly efficacious, but only for a selected group of patients. SUMMARY: The emergence of novel therapies, in particular highly specific treatments, bring the promise of improving healthcare in asthma but present the challenge of choosing the right therapy for the right patient. Phenotype-driven treatment of asthma is emerging as a potential reality and will pave the way for personalized healthcare.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

Total control of asthma: an evaluation in patients of a tertiary hospital.

BACKGROUND: Asthma control is an important goal of international asthma guidelines, but in most reports total control is reached in a small proportion of cases. OBJECTIVE: To know the degree of asthma control, the percentage of ER visits and hospitalizations in the last month and in the last year, and the type of pharmacologic treatment for asthma in a tertiary hospital. PATIENTS AND METHOD: This is an observational study in asthmatic patients from 12 to 60 years old, with more than one year of treatment, who answered the questionnaire of Asthma Control Test (ACT). RESULTS: A total of 204 patients were included, 116 women and 88 men, with an average age of 24 years. We observed that 19 patients (9.3%) were in total control of asthma: scored 25 ACT points, 88 patients (43.1%) scored 20-24 points (non total control) and 97 patients (47.5%) less than 20 points (asthma not controlled). According to the asthma severity index, 125 patients had intermittent symptoms (61.3%), and persistent symptoms were present in 79 patients. In the previous month 8.3% of patients had ER visits and 2.9% were hospitalized; in the previous year the ER visits and hospitalizations percentages were 33.3% and 14.2%, respectively. Inhaled steroids were used by 12.2% of the patients, long-action beta2 agonists by 9.8% and daily short action beta2 agonists by 28%. CONCLUSIONS: Total control of asthma was observed in less than 10% of our patients-sample; the majority of them had intermittent asthma; the pattern of medication was inadequate, with misuse of inhaled steroids and an elevated use of inhaled rescue medications.

A Danish population-based cohort study of newly diagnosed asthmatic children's care pathway - adherence to guidelines.

BACKGROUND: Asthma is the most common chronic disease in childhood. Large variations exist concerning the number of children being treated by general practitioners and by specialists. Consequently, health related costs due to this disease vary as care by specialists is more expensive compared with care by general practitioners. Little is known of the consequences of these variations concerning the quality of care. The aim of the study was to analyse associations between care providers and adherence to guidelines concerning frequency of contacts with the health service due to asthma. METHODS: A cohort study was performed of 36,940 incident asthmatic children's (aged 6-14) contacts with the health service using the unique personal registration number to link data from five national registries. The prevalence ratios were calculated for associations between provider (general practitioner, primary care specialist, hospital specialist or both GP and specialist) and adherence with guidelines concerning three indicators of quality of care pathway: 1) diagnostic examination of lung function at start of medical treatment 2) follow-up the first six months and 3) follow-up the next six months. The associations were adjusted for sex, age, socioeconomic status, county, and severity of disease. RESULTS: Most children (70.3%) had only been seen by their GP. About 80% of the children were treated with inhaled steroids, 70% were treated with inhaled steroids as well as inhaled beta2agonists and 13% were treated with inhaled beta2agonists only. A total of 12,650 children (34.2%) had no registered asthma-related contacts with the health service except when redeeming prescriptions. Care was in accordance with guidelines in all three indicators of quality in 7% of the cases (GPs only: 3%, primary care specialists only: 16%, hospital specialists: 28%, and both GP and specialists: 13%). Primary care specialists had a 5.01, hospital specialists a 8.81 and both GP and specialists a 4.32 times higher propensity to provide a clinical pathway according to guidelines compared to GPs alone. CONCLUSION: The majority of the children were seen in general practice. Hospital specialists provided care in accordance with guidelines nine times more often compared with GPs, but still only one quarter of these children had pathways in accordance with guidelines. It is relevant to study further if these lacks of adherence to guidelines have implications for the asthmatic children or if guidelines are too demanding concerning frequency of follow-up or if asthmatic children should be stratified to different care pathways.

Treatment with inhaled corticosteroids in asthma is too often discontinued.

PURPOSE: To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. METHODS: From the PHARMO database, asthma-patients (age < 35 years) with a first dispensing for ICS in 1999-2002 and > or = 2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and 1 year before. RESULTS: The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at 1 year. Similar persistence-rates were observed when stratified for age (children/adolescents: 0-18 years and adults: 19-34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. CONCLUSION: New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency.