Around 5-10% of patients with asthma do not respond adequately to inhaled steroids and long-acting bronchodilators and become difficult-to-treat; they remain symptomatic, have recurrent... Show moreAround 5-10% of patients with asthma do not respond adequately to inhaled steroids and long-acting bronchodilators and become difficult-to-treat; they remain symptomatic, have recurrent exacerbations or persistent airflow limitation. This thesis focuses on the mechanisms that may explain why these patients become difficult-to-treat and investigate biomarkers that can predict the development of specific asthma phenotypes. The different studies describe the possible role of alpha- antitrypsin in the development of persistent airflow limitation, the relationship between severity of asthma and the degree of peripheral airway inflammation and dysfunction, the clinical and inflammatory characteristics of obese patients with difficult-to-treat asthma, risk factors of lung function decline and the consistency of the eosinophilic phenotype Show less