Immunopathological and Structural Alterations in Difficult to Control Asthma

Sammanfattning: Asthma is a chronic respiratory disorder affecting an estimated 300 million people worldwide. Most patients with asthma can be controlled with bronchodilators and low to moderate dose inhaled corticosteroids. However, an estimated 5-10% of the population presents a more troublesome disease, often referred to as severe asthma. The aim of present thesis was to study the relationship between histopathological alterations and clinical control in patients with different severities of asthma. To study this, a detailed immunohistochemical analysis was performed on lung biopsies obtained from moderate asthmatics (n = 24 in Paper I), severe asthmatics (n = 25 in Paper II), and uncontrolled severe asthmatics undergoing bronchial thermoplasty treatment (n = 15 and n = 20 in Paper III and IV, respectively). In Paper I, we show that allergic airway inflammation extends to the peripheral airways specifically in patients that are poorly controlled. This suggests that targeting peripheral airway inflammation, for example with extrafine-particle formulations of inhaled corticosteroids, may benefit patients that remain symptomatic despite standard inhaled corticosteroid treatment. In Paper II, we found that symptomatic severe asthma is associated with lower number of eosinophils and no apparent signs of chronic inflammation as compared with stable severe asthma. However, we detected stretches of bronchoepithelial metaplasia in the former patient category suggesting that external assaults, possible episodic pathogen infections, may play an important role in this form of asthma. In Paper III, we show that bronchial thermoplasty markedly improves several elements of clinical control in patients with uncontrolled severe asthma. The clinical improvements were associated with a down-regulation of structures involved in airway narrowing and hyperreactivity, including airway smooth muscle, neuroendocrine epithelial cells, and nerve fibres. In Paper IV, we show that bronchial thermoplasty treatment likewise has long-lasting immunological effects as evident by a reduction of key bronchial immune cells including mast cell populations and T helper cells. These changes may to some extent explain the clinical benefits associated with bronchial thermoplasty, although this remains to be investigated. In summary, the results in this thesis provide new histopathological data that are associated with clinical control in asthma.