Clinical management of severe therapy-resistant asthma

Abstract

Severe therapy-resistant asthma is an area where there has been recent advances in understanding that is percolating into improvements in management. Areas covered: This review covers the recent definition and approach to the diagnosis of severe asthma and its differentiation from difficult-to-treat asthma. The recent advances in phenotyping severe asthma and in ensuing changes in management approaches together with the introduction of new therapies are covered from a review of the recent literature. Expert commentary: After ascertaining the diagnosis of severe asthma, patients need to be treated adequately with existing therapies. The management approach to severe asthma now comprises of a phenotyping step for the definition of either an allergic or eosinophilic severe asthma for which targeted therapies are currently available. This will lead to a precision medicine approach to the management of severe asthma.

Bronchial Thermoplasty in Severe Asthma: Best Practice Recommendations from an Expert Panel

“…When asthma control is not achieved within GINA step 4, GINA step 5 advises add-on treatment including LAMA (long-acting muscarinic antagonists) -for instance, tiotropium and biologics (e.g., antiIgE and anti-interleukin-5 [anti-IL-5]) -and low-dose OCS. 1 Driven by improved phenotyping, these add-on treatments are now increasingly prescribed to patients with distinct asthma phenotypes [20,25,26]. For example, anti-IgE can be considered for patients with a predominant allergic phenotype, and anti-IL-5 for patients with a predominant eosinophilic phenotype.…”

Effect of the BMPR-II-SMAD3/MRTF complex on proliferation and migration of ASMCs and the mechanism in asthma

“…Airway inflammation promotes ASMC contraction and proliferation, whereas ASM remodelling aggravates airway inflammation by secreting a series of cytokines, forming a vicious cycle [25]. Current therapeutic drugs comprise corticosteroids and bronchodilators [26]. However, there are still patients who experience severe refractory asthma and develop resistance to these therapies [27].…”

Corticosteroids

“…These patients are distinct from those who are non-compliant with their treatment or subjects without access to the correct therapies. The reduced GC function in refractory asthma may be multifactorial, and each stage of GR activation, namely, GR expression, ligand binding, nuclear translocation and/or binding to the GRE and other transcription factors, has been proposed as a mechanism [9,15,64,65]. It is possible that redox-sensitive activation of the AP pathway may drive relative steroid refractoriness in peripheral blood mononuclear cells (PBMCs) from severe steroid-refractory asthmatics [23].…”

“…Nitrosative stress may also impact upon corticosteroid responsiveness, and peroxynitrite formation causes nitration of specific tyrosine (Y) residues which results in the loss of enzymatic activity (Y146) and degradation (Y253) of HDAC2 [62]. However, reduced HDAC2 expression and/or activity is not seen in all patients with therapy-refractory asthma possibly reflecting the heterogeneity of severe asthma phenotype [64,65].…”

“…The transcriptome of bronchial epithelial cells of mild/moderate asthmatics has identified a gene profile that predicts ICS responsivenessnamely, an IL-13-induced gene signature. The expression of this signature is variable in asthma and is inversely correlated with Th17 cells which are linked with steroid insensitivity and with IL-6 a marker of neutrophilic asthma which is also associated with more severe disease [9,15,64,65].…”