Small Airways Disease (SAD) in Severe Asthma as a Novel Endpoint and Distinct Target for Biological Therapy. Small Airways Disease (SAD) in Severe Asthma as a Novel Endpoint and Distinct Target for Biological Therapy (SASAB Study)

Severe asthma is now widely accepted to be a heterogeneous syndrome consisting of multiple phenotypes identified by specific biomarkers and targeted by tailored biological therapies. However, much remains unclear regarding the best approaches to manage these patients, or concerning the pathophysiological mechanisms underlying the disease.

Small airway (SA) are defined as those airways with an internal diameter <2 mm. In patients affected by asthma, it has been reported that SA are the predominant site of airflow resistance. Peripheral airways are thickened in asthma due to chronic inflammation in the epithelium, submucosa and muscle area. It has been suggested that the outer wall is more inflamed than the inner wall, with a higher number of lymphocytes, eosinophils, and neutrophils associated to an increased expression of interleukin-4 (IL-4), interleukin-5 (IL-5) and eotaxin. Moreover, it is well documented that SA inflammation and dysfunction contribute significantly to the clinical impact of asthma and that 50-60% of asthmatics have a SA involvement across all disease severities. An important question is whether SA disease in asthma is variable among distinct asthma phenotypes and whether it occurs in all patients. Cluster analyses have been recently used to identify specific asthma phenotypes, but markers of SA function have not been investigated. However, evidence is accumulating to support that SA dysfunction and inflammation may contribute to distinct asthma phenotypes. Recent findings indicate that SA are significantly affected in severe asthma and that their involvement is associated with worse disease outcomes. It has been reported that patients with asthma and a history of frequent exacerbations per year had a significant SA involvement. Furthermore, peripheral airways significantly contribute not only to the level of asthma control, but also to patients' quality of life and perception of symptoms. At last more thickened SA and higher numbers of eosinophils are detectable in subjects with fatal asthma.

The assessment of SA represents a big challenge and requires qualified expertise and sophisticated techniques including body plethysmography, single and multiple breath nitrogen washout, impulse oscillometry (IOS), fraction exhaled NO at multiflow, sputum induction and high-resolution chest CT (HRCT). Such procedures can either provide functional information on the degree/extent of ventilation heterogeneity and air trapping or facilitate the understanding of the inflammatory and remodeling processes.

In addition, a number of clinical trials have in recent years demonstrated the efficacy of biologics in severe asthma. Omalizumab, a humanized anti-Imunoglobulin E monoclonal antibody (mAb) has been well recognized as an important option for treating allergic asthma as an add- on therapy for uncontrolled disease.

Three anti-IL-5 therapies are currently available for the treatment of severe asthma, including Mepolizumab, Reslizumab, and Benralizumab.

The newest biologic agent to be approved is Dupilumab that is a human mAb that targets the subunit of the IL-4 receptor.

Biologics represent an innovative strategy for the treatment of severe asthma. In most patients with SAD these drugs control inflammation, improve lung function, ameliorate clinical symptoms, reduce exacerbations and have a marked steroid-sparing effect. However, there is still a significant proportion of non-responders and a lack of validated predictive biomarkers in such subpopulation. In regard to this, very limited findings are available about the effect of biologics therapy on SA.