Severe asthma: how can we differentiate phenotypes?

Difficult-to-treat asthma, severe asthma or refractory asthma are all terms defining a fraction of asthmatics (5-10%) whose asthma cannot be controlled with a combination of high-dose inhaled corticoids together with long-acting b2 agonists.One major step before claiming that a patient has difficult-to-treat asthma is to ensure that asthma is the correct diagnosis. This involves taking a history of symptoms suggestive of asthma together with objective evidence of variable airflow limitation and/or airway hyperresponsiveness, calling for an intensive initial investigation taking in associated comorbid conditions and multiple re-evaluations over a period of at least 6 months.The pathophysiology of severe/refractory asthma is likely to be different from that of the mild to moderate form. The immune mechanisms underlying the inflammatory process are not purely Th2. The contribution of allergic mechanisms is usually less prominent than in mild to moderate asthma, and other environmental factors such as air pollution, including tobacco smoke and viruses, may be determinant. Involvement of small airways causing air trapping appears to be crucial in making asthma refractory to classic treatment.Several phenotypes have been identified on the basis of demographic, functional, pathological and clinical characteristics, which may sometimes overlap.A cluster analysis has identified two clusters specific to refractory asthma: an early onset symptom-predominant asthma and a late onset inflammation-predominant form.Teasing out mechanisms underlying different phenotypes is essential in finding a new treatment target to improve asthma control in these patients.