Non-allergic severe asthma encompasses non-allergic severe eosinophilic asthma (type 2) and non-eosinophilic severe asthma (non-type 2). According to GINA 2019, for patients in step 5, high dose inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) are recommended. Add-on therapy with tiotropium or anti-IgE, anti IL5/5R or anti IL4, should also be considered. A revision of evidence of anti-IL5, anti-IL5R and anti-IL4R monoclonal antibodies show that they are efficacious in allergic and non-allergic severe eosinophilic asthma. Studies with azithromycin (AZT) have evaluated its effect on the prevention of exacerbations in severe asthma. The effects of AZT vary according to phenotypes (eosinophilic/non-eosinophilic). Chronic treatment with AZT reduces oral corticosteroids (OCS) use in eosinophilic asthma and antibiotic use in non-eosinophilic asthma.
The interaction between epithelial cells and sub-epithelial mesenchymal cells has been studied. The function of both is controlled by an environmental trigger inducing epigenetic changes, which is implicated in the regulation of the airwall remodelling. The epithelial cell secretes proteins which control the mesenchymal cell physiology, that in turn, release chemo-attractants for immune cells. There are no significant differences between allergic and non-allergic asthma in the epithelium-mesenchymal interaction.
Several questions are addressed by the European Lung Foundation (ELF) on severe exacerbations; what would be an accurate definition, what are the trigger factors related to the initiation and severity of the exacerbations, and what is the best strategy to manage or prevent them. The new ERS/ATS severe asthma guidelines suggest; 1- Using anti-IL5 and anti-IL5R in severe uncontrolled eosinophilic asthma, 2- Using a blood eosinophil cut-point of >150/μL to guide anti-IL5 initiation in adults. 3- Considering eosinophil (>260/μL) and FeNO (>19.5 ppb) cut-offs for identifying adults and adolescents likely to respond to IgE therapy. 4- Use of inhaled tiotropium for adolescents and adults. 5- Using a trial of chronic macrolide therapy to reduce asthma exacerbations. 6- Using anti-IL4/13 for adult patients with severe eosinophilic asthma and those with corticosteroid-dependent asthma.
Finally, the use of bronchial thermoplasty (BT) has been reviewed. BT is the only current asthma therapy which reverts remodelling. It leads to a decrease in the airway smooth muscle cells and in the reticular basement membrane. Bronchial thermoplasty also decreases the nerve endings in the mucosa and submucosa, hyperinflation and air trapping, and ventilation heterogeneity. In addition, BT increases bronchial epithelial cell proliferation. Potential candidates are patients who are either unsuitable for bio-drugs, those who do not want to undergo biologics indefinitely, non-responders to these drugs, or patients with overlapping asthma and COPD. However, how to identify responders remains unclear.