Biologics in severe asthma: the overlap endotype - opportunities and challenges.

INTRODUCTION: Patients with severe asthma experience a significant burden of symptoms, disease exacerbations and medication side-effects. Severe asthma interferes with the patients' quality of life and has high health-care costs. New targeted biologic therapies have improved the management of severe asthma by significantly reducing exacerbations and maintenance corticosteroid use, and also improving lung function and patient quality of life. AREAS COVERED: Not all severe asthmatics are eligible for such therapies. Those with allergic and eosinophilic asthma, usually referred to as 'T2-high' asthma benefit from anti-IgE and anti-IL-5/5 R antibodies respectively, whereas some asthmatics are eligible for both: 'overlap' endotype. In this review, we present briefly the monoclonal antibodies that have been approved in the management of severe asthma and we focus on the 'overlap' endotype. EXPERT OPINION: Since these therapies are costly, it is extremely important to choose the right treatment for the right patient especially in the 'overlapping' one. The decision is mainly based on the judgment of the clinician and is often driven by the most easily obtainable biomarker, thus the blood eosinophil count. Comorbidities, patient's input and administration frequency may aid the decision of choosing one over another biologic.

Exploring the role of nerves in asthma; insights from the study of cough.

Cough in asthma predicts disease severity, prognosis, and is a common and troublesome symptom. Cough is the archetypal airway neuronal reflex, yet little is understood about the underlying neuronal mechanisms. It is generally assumed that symptoms arise because of airway hyper-responsiveness and/or airway inflammation, but despite using inhaled corticosteroids and bronchodilators targeting these pathologies, a large proportion of patients have persistent coughing. This review focuses on the prevalence and impact of cough in asthma and explores data from pre-clinical and clinical studies which have explored neuronal mechanisms of cough and asthma. We present evidence to suggest patients with asthma have evidence of neuronal dysfunction, which is further heightened and exaggerated by both bronchoconstriction and airway eosinophilia. Identifying patients with excessive coughing with asthma may represent a neuro-phenotype and hence developing treatment for this symptom is important for reducing the burden of disease on patients' lives and currently represents a major unmet clinical need.

Asthma and gender: The female lung.

Asthma is a common chronic disease that affects over 300 million people worldwide, resulting in a considerable socio-economic burden. Literature data suggest that asthma has a higher incidence in females, particularly at certain stages of pubertal development. Moreover, women seem to experience more asthma symptoms than men and to use more rescue medications, resulting in a reduced quality of life. Although several mechanisms have been proposed to explain these differences, there are not yet final data available in the literature on the role of gender in the pathogenesis of asthma and different behavior in females. Some study suggested a more prevalent hyper-responsiveness in women than in men. Nevertheless, in the literature definitive data on a possible different response to drugs used for asthma between males and females are not described. Understanding the mechanisms that underlie these gender differences in clinical history of asthma patients could give inspiration to new areas of research to obtain a more specific diagnostic and therapeutic approach gender-oriented.

Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN).

Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 µm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal.

Manifesto on small airway involvement and management in asthma and chronic obstructive pulmonary disease: an Interasma (Global Asthma Association - GAA) and World Allergy Organization (WAO) document endorsed by Allergic Rhinitis and its Impact on Asthma (ARIA) and Global Allergy and Asthma European Network (GA2LEN).

Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 µm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal.

Ask the experts: the benefits and challenges of pulmonary drug delivery.

The field of pulmonary drug delivery is ever progressing with technological advances in inhaler device design, the development of increasingly sophisticated techniques in targeted delivery and new opportunities in drug formulation, largely as a product of the rapidly advancing area of nanotechnology. Though pulmonary administration offers numerous advantages in terms of both local and systemic drug delivery, the translation of inhaled drugs from bench-to-bedside presents an ongoing challenge. Hannah Coaker, Assistant Commissioning Editor, spoke to six experts and discussed their motivations for becoming involved in the field, major obstacles in aerosol drug development and the evolving area of pulmonary drug delivery.

Inspiratory and expiratory aerosol deposition in the upper airway.

Aerosol deposition efficiency (DE) in the extrathoracic airways during mouth breathing is currently documented only for the inspiratory phase of respiration, and there is a need for quantification of expiratory DE. Our aim was to study both inspiratory and expiratory DE in a realistic upper airway geometry. This was done experimentally on a physical upper airway cast by scintigraphy, and numerically by computational fluid dynamic simulations using a Reynolds Averaged Navier?Stokes (RANS) method with a k-? SST turbulence model coupled with a stochastic Lagrangian approach. Experiments and simulations were carried out for particle sizes (3 and 6 µm) and flow rates (30 and 60 L/min) spanning the ranges of Stokes (Stk) and Reynolds (Re) number pertinent to therapeutic and environmental aerosols. We showed that inspiratory total deposition data obtained by scintigraphy fell onto a previously published deposition curve representative of a range of upper airway geometries. We also found that expiratory and inspiratory DE curves were almost identical. Finally, DE in different compartments of the upper airway model showed a very different distribution pattern of aerosol deposition during inspiration and expiration, with preferential deposition in oral and pharyngeal compartments, respectively. These compartmental deposition patterns were very consistent and only slightly dependent on particle size or flow rate. Total deposition for inspiration and expiration was reasonably well-mimicked by the RANS simulation method we employed, and more convincingly so in the upper range of the Stk and Re number. However, compartmental deposition patterns showed discrepancies between experiments and RANS simulations, particularly during expiration.