Current concepts of severe asthma

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…This observation was insightful, drawing attention to both Th2 and non-Th2/non-type 2 mechanisms affecting lung function, which did not respond to standard inhaled CS therapy. While disease severity in these CS-unresponsive subjects was not discussed in the study, it is well known that 5%-10% of asthma patients suffering from SA do not respond adequately to CS therapy (2,8). These subjects experience frequent exacerbations and poor disease control, and they typically bear 50% of healthcare burden for all asthma (8,(34)(35)(36).…”

“…Infections by viruses (rhinovirus being the most common) and bacteria have been observed in patients with SA and can trigger asthma exacerbations (7). Several bacterial species have also been associated with severe disease (8). Once generated in lung-draining lymph nodes, Th1 cells need to be recruited to the site of infection, and the best known chemoattractant for Th1 cells is CXCL10 (9), initially cloned as an IFN-γ-induced molecule from monocytes (10).…”

Severe asthma: phenotyping to endotyping or vice versa?

“…A Th2 pattern and eosinophilia may be present in mild, moderate and severe asthma, but the underlying mechanisms could be potentially very different, particularly if the subjects respond differently to treatment [28][29][30]. One of the limitations of the KUO et al [19] study is that the clustering of differentially expressed genes was conducted by pre-selecting genes in eosinophilic versus noneosinophilic sputum from both severe and moderate asthmatics on the assumption that the mechanisms of eosinophilia could be the same.…”

“…Possibly, it is the association with factors and cytokines working with and potentiating the Th2 profile that makes the difference between clusters with overlapping gene expression. Th1 and other factors may potentiate IL-4, IL-5, and IL-13, thus promoting asthma severity and steroid resistance [28,29]. This would make it possible for Th2 cytokines in severe asthma to be synergised with other cytokines and mediators, which would affect other target cells such as mast cells, eosinophils, epithelial cells and smooth muscle and result in poor lung function, disease severity, and, more importantly, treatment resistance, a feature not seen in milder disease.…”

Do insights from mice imply that combined Th2 and Th17 therapies would benefit select severe asthma patients?

“…However, there remains a considerable percentage of individuals with an asthma diagnosis for whom these conventional therapeutic approaches are ineffective. These patients are considered to have severe disease (1), and severe asthma disproportionately accounts for the socioeconomic impacts of asthma. It has become an important objective for researchers to identify the contributors to severe asthma and to develop approaches to target these events.…”