New therapies and management strategies in the treatment of asthma: patient-focused developments

It is increasingly recognized that large proportions of patients with asthma remain poorly controlled with daily symptoms, limitation in activities, or severe exacerbations despite traditional treatment with inhaled corticosteroids and other agents. This suggests that there is considerable scope for the refinement of traditional guidelines on the use of inhaled therapies in asthma and also a need for the development of novel therapeutic agents, particularly for the treatment of severe asthma. This review aims to discuss a range of emerging treatment approaches in asthma. Firstly, we will set the scene by highlighting the importance of achieving good asthma control in a patient-focused manner and discussing recent work that has furthered our understanding of asthma phenotypes and paved the way for patient-specific treatments. Secondly, we will review new strategies to better use the existing therapies such as inhaled corticosteroids and long-acting β2-agonists that remain the mainstay of treatment for most patients. Finally, we will review the novel therapies that are becoming available, both pharmacological and interventional, and discuss their likely place in the management of this complex disease

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

C-Type Lectin Receptors in Asthma

This review is submitted as part of PhD thesis by SH. SH incepted, wrote the manuscript. G.D.B and F.B. edited the manuscript. SH PhD studentship was funded by CIDRI (Wellcome Trust initiative, South Africa) and the University of Aberdeen College studentship. GDB is funded by the Wellcome Trust and Medical Research Council Centre for Medical Mycology at the University of Aberdeen.Peer reviewedPublisher PD

Development of allergic immunity in early life

The growth and maturity of the peripheral immune system and subsequent development of pulmonary immunity in early life is dictated by host, environmental and microbial factors. Dysregulation during the critical window of immune development in the postnatal years results in disease which impacts on lifelong lung health. Asthma is a common disease in childhood and is often preceded by wheezing illnesses during the preschool years. However, the mechanisms underlying development of wheeze and how and why only some children progress to asthma is unknown. Human studies to date have generally focused on peripheral immune development, with little assessment of local tissue pathology in young children. Moreover, mechanisms underlying the interactions between inflammation and tissue repair at mucosal surfaces in early life remain unknown. Disappointingly, mechanistic studies in mice have predominantly used adult models. This review will consider the aspects of the neonatal immune system which might contribute to the development of early life wheezing disorders and asthma, and discuss the external environmental factors which may influence this process

The role of Aspergillus fumigatus and other thermotolerant moulds in asthma

The fungal kingdom contains well over a million species, of which about 80,000 have been named and approximately 600 species cause some form of human disease. Fungal spores are ubiquitous in the airborne environment and inhaled daily often in large numbers though seldom lead to disease. Atopy is a common clinical feature of asthma highlighting the genetic and environment interactions that give rise to clinical phenotypes. Allergy towards fungi is recognised to play an important role in asthma and fungal sensitisation in asthma is associated with an increased risk of multiple hospital and ITU admissions. It is thought that fungal allergy arises from a disproportionate Th2 response to fungal allergens present in spores and hyphae. The risk of IgE sensitisation to fungi may be increased by the capacity of some thermotolerant fungi (typified by Aspergillus fumigatus), to colonise the airways, with an extreme though unusual form exemplified by the condition allergic bronchopulmonary aspergillosis (ABPA). This relationship however is imperfectly understood and lesser displays of fungal allergy in severe asthma are increasingly recognised. The aim was to characterise the relationship between fungal colonisation as defined by a positive sputum culture, fungal sensitisation and the clinical features of mainly moderate-severe asthma. Secondly, this information would guide a placebo controlled trial targeting airway colonisation with Voriconazole. Over 25 species of filamentous fungi were cultured from asthmatics sputum with the flora dominated by Aspergillus fumigatus. There was a correlation between IgE sensitisation to A. fumigatus and evidence of lung damage defined by fixed airflow obstruction and bronchiectasis. There was a demonstrable association between lung damage and fungal colonisation. A three-month randomised trial of oral Voriconazole in patients with asthma and Aspergillus sensitisation failed to improve asthma control or reduce exacerbations. The place of Voriconazole in patients with fungal associated asthma remains to be established