Extracellular vesicles and asthma: A review of the literature

Asthma is a chronic, recurrent and incurable allergy‐related respiratory disease characterized by inflammation, bronchial hyperresponsiveness and narrowing of the airways. Extracellular vesicles (EVs) are a universal feature of cellular function and can be detected in different bodily fluids. Recent evidence has shown the possibility of using EVs in understanding the pathogenesis of asthma, including their potential as diagnostic and therapeutic tools. Studies have reported that EVs released from key cells involved in asthma can induce priming and activation of other asthma‐associated cells. A literature review was conducted on all current research regarding the role and function of EVs in the pathogenesis of asthma via the PRISMA statement method. An electronic search was performed using EMBASE and PubMed through to November 2018. The EMBASE search returned 76 papers, while the PubMed search returned 211 papers. Following duplicate removal, titles and abstracts were screened for eligibility with a total of 34 studies included in the final qualitative analysis. The review found evidence of association between the presence of EVs and physiological changes characteristic of asthma, suggesting that EVs are involved in the pathogenesis, with the weight of evidence presently favouring deleterious effects of EVs in asthma. Numerous studies highlighted differences in exosomal contents between EVs of healthy and asthmatic individuals, which could be employed as potential diagnostic markers. In some circumstances, EVs were also found to be suppressive to disease, but more often promote inflammation and airway remodelling. In conclusion, EVs hold immense potential in understanding the pathophysiology of asthma, and as diagnostic and therapeutic markers. While more research is needed for definitive conclusions and their application in medical practice, the literature presented in this review should encourage further research and discovery within the field of EVs and asthma.     

Switching between biologics in severe asthma patients. When the first choice is not proven to be the best

During the last decades, new treatments targeting disease mechanisms referred as biologics have been introduced in the therapy of asthma and currently, five monoclonal antibodies have been approved. Although these therapeutic agents have been formulated to target specific asthma endotypes, it is often difficult for the treating physician to identify which patient is the best candidate for each one of these specific treatments especially in the clinical scenario of a patient in whom clinical characteristics overlap between different endotypes, allowing the selection of more than one biologic agent. As no head-to-head comparisons between these biologics have been attempted, there is no evidence on the superiority of one biologic agent over the other. Furthermore, a physician's first therapeutic decision, no matter how carefully has been made, may often result in suboptimal clinical response and drug discontinuation, indicating the need for switching to a different biologic. In this short review, we discuss the available evidence regarding the switching between biologics in patients with severe asthma and we propose a simple algorithm on switching possibilities in case that the physicians’ initial choice is proven not to be the best.     

Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies

Asthma is a common heterogeneous disease with a complex pathophysiology that carries a significant mortality rate and high morbidity. Current therapies based on inhaled corticosteroids and long‐acting β‐agonists remain effective in a large proportion of patients with asthma, but ~10% (considered to have ‘severe asthma’) do not respond to these treatments even at high doses or with the use of oral corticosteroids. Analytical clustering methods have revealed phenotypes that include dependence on high‐dose corticosteroid treatment, severe airflow obstruction and recurrent exacerbations associated with an allergic background and late onset of disease. One severe phenotype is eosinophilic inflammation‐predominant asthma, with late‐onset disease, rhinosinusitis, aspirin sensitivity and exacerbations. Blood and sputum eosinophilia have been used to distinguish patients with high Th2 inflammation and to predict therapeutic response to treatments targeted towards Th2‐associated cytokines. New therapies in the form of humanized antibodies against Th2 targets, such as anti‐IgE, anti‐IL4Rα, anti‐IL‐5 and anti‐IL‐13 antibodies, have shown encouraging results in terms of reduction in exacerbations and improvement in airflow in patients with a ‘Th2‐high’ expression profile and blood eosinophilia. Research efforts are now focusing on elucidating the phenotypes underlying the non‐Th2‐high (or Th2‐low) group, which constitutes ~50% of severe asthma cases. There is an increasing need to use biomarkers to indicate the group of patients who will respond to a specifically targeted treatment. The use of improved tools to measure activity of disease, a better definition of severe asthma and the delineation of inflammatory pathways with omics analyses using computational tools, will lead to better‐defined phenotypes for specific therapies.     

Inhaled Cryptococcus neoformans elicits allergic airway inflammation independent of Nuclear Factor Kappa B signalling in lung epithelial cells

Pulmonary challenge with the ubiquitous fungus Cryptococcus neoformans results in allergic airway inflammation (AAI) characterized by robust recruitment of eosinophils and T cells producing type 2 cytokines to the lungs. Previous studies have demonstrated a critical role for Nuclear Factor Kappa B (NF‐κB) activation within lung epithelial cells (LECs) in driving AAI in response to protein allergens, yet the role of LEC‐intrinsic NF‐κB in promoting AAI following exposure to C. neoformans is poorly understood. To investigate the role of LEC‐intrinsic NF‐κB in promoting AAI following C. neoformans challenge, we used IKK^?LEC mice, which lack canonical NF‐κB activation specifically within LECs. IKK^?LEC and littermate control mice were intranasally challenged with 10⁶ CFU of C. neoformans strain 52D, and lung tissues were collected at 7, 14 and 21 days post infection to assess the development of AAI. Notably, the absence of epithelial NF‐κB signalling did not affect the magnitude or kinetics of lung eosinophilia when compared with the response in wild‐type control mice. The total numbers of lung T cells producing the type 2 cytokines interleukin‐5 and interleukin‐13 were also unchanged in IKK^?LEC mice. Furthermore, IKK^?LEC mice showed no defect in the recruitment of protective interferon‐γ‐producing CD4 T cells to the lungs, fungal clearance, or host survival compared with control mice. Immunofluorescence imaging surprisingly revealed no evidence of nuclear localization of NF‐κB in LECs in response to C. neoformans challenge, indicating that NF‐κB is not activated within these cells. Taken together, these data strongly suggest that NF‐κB signalling within LECs does not promote AAI observed in response to C. neoformans.