Steroid-Resistant Asthma: Exploring New Therapeutic Possibilities

Although disease-modifying biologics are being used as add-on therapies in individuals with severe asthma, corticosteroids remain the mainstay of asthma treatment. The majority of patients with asthma respond to these agents, but some patients do not show an adequate response.

“There are effective treatments for people with mild to moderate asthma. However, anywhere between 5% to 25% of people with asthma have more severe disease and do not respond to current treatments,” according to Philip M. Hansbro, PhD, professor and chair of immunology and microbiology at the University of Newcastle in New South Wales, Australia.^1,2 “As a result, [this kind of treatment-resistant disease] accounts for  50% [to] 80% of healthcare costs for asthma³ and are the major issue in asthma management,” he told Pulmonology Advisor.

Such patients are considered to have severe, steroid-resistant asthma, which is associated with more frequent exacerbations, greater likelihood of hospitalizations, and worse quality of life compared with other patients with asthma. In clinical practice, they are often “treated with high-dose steroids and bronchodilators, but they do not respond well” to these therapies, says Dr Hansbro.

The development of effective treatments in this patient population is impeded by the lack of clarity regarding potential underlying mechanisms, as well as the variety of heterogeneous endotypes of severe, steroid-resistant asthma. Although the condition is often linked with non-eosinophilic asthma endotypes^4,5 such as neutrophilic asthma, other findings suggest the involvement of persistent eosinophilic inflammation in severe disease.⁶ “This heterogeneity of disease and likely involvement of different underlying immunological, inflammatory, and molecular mechanisms in different subtypes of severe, steroid-resistant asthma has hampered the development of effective therapies,” Dr Hansbro and colleagues wrote in a review recently published in Immunological Reviews.⁷

Previous research has linked steroid sensitivity in asthma with impaired glucocorticoid receptor (GR) expression and activity — for example, reduced GR binding affinity to glucocorticoids and increased expression of proinflammatory transcription factors — while other results implicate different mechanisms including steroid resistance of macrophages.^8,9

In their recent paper, Dr Hansbro, et al, stated that the development of effective therapies in these patients “may be achieved by applying new strategies to increase our understanding of the mechanisms that underpin the pathogenesis of steroid insensitivity, and identifying, and therapeutically targeting, the factors that underpin disease.”

They describe their use of animal models to investigate such mechanisms, which may include infection and infection-induced responses, according to a growing body of evidence. Selected highlights of their observations from these experimental studies and other relevant findings are summarized below.

• In both Chlamydia and Haemophilus-associated allergic-airway disease (AAD), inflammation and airway hyper-responsiveness are resistant to intranasal dexamethasone
• Severe, steroid-resistant AAD that is induced by infection “is not only associated with increased neutrophilic inflammation and type 1 and/ or type 17 immunity but also with increased TLR2, TLR4, IL-6, IL-1β, caspase-1, and NLRP3 responses,” all of which have been linked to severe, steroid-resistant disease in humans.
• These bacterial infections induce steroid-resistant, neutrophil-dominated forms of the disease, while respiratory syncytial virus (RSV) and influenza infections induce steroid-resistant, eosinophilic-dominated disease types.
• The macrolide antibiotic clarithromycin suppressed severe, steroid-resistant AAD induced by Chlamydia and Haemophilus “by targeting the predominant immune responses that drive disease in either model, and … that these immunomodulatory effects were independent of the antimicrobial effects of the drug,” they reported. This supports a potential role for macrolide therapy in treating adults and children with infection-associated, steroid-resistant asthma. 
• The following processes may have key roles in the pathogenesis of severe, steroid-resistant asthma, with implications for novel treatment targets: increased phosphoinositide-3-kinase (PI3K), toll-like receptor (TLR) signaling, and NLRP3 inflammasome responses, and altered microRNA (miRNA), cytokine, and immune factor expression.

In addition, emerging research demonstrates that obesity and air pollution could underlie this condition. Obesity, a major risk factor for asthma, may lead to severe asthma via alterations in macrophage function, TLRs, the NLRP3 inflammasome, and endoplasmic reticulum (ER) stress, in part due to increased consumption of high-fat foods. An excess of fatty acids activates the unfolded protein response and thus inflammatory pathways including JNK/AP-1 and IKK/ NF-κB.¹⁰