Severe asthma: a consequence of over exuberant repair?

There is an increasing recognition that asthma, especially severe asthma, is a complex condition [1]. It comprises of several dimensions in particular clinical expression of disease, disordered airway physiology and tissue injury and repair. The latter is manifest as airway inflammation and remodelling. Each dimension itself is complex with substantial heterogeneity. The clinical expression includes typical symptoms of breathlessness, wheeze and cough punctuated with episodes of disease worsening known as exacerbations. Individuals with asthma have varying degrees of each symptom and in some these occur in isolation. Similarly, variable airflow obstruction, airway hyperresponsiveness (AHR) and persistent airflow obstruction can be present to a greater of lesser extent between individuals. This heterogeneity also extends to inflammation and repair. With respect to inflammation over the last 20 years non-invasive assessment of asthma using sputum induction has led to the identification of new inflammatory phenotypes namely eosinophilic, neutrophilic and paucigranulocytic asthma [2]. Airway remodelling, which is a common feature of asthma occurs across severity and can be present even in childhood [3]. Understanding the interplay between these complex dimensions of disease is important as it will shed light on the pathogenesis of asthma and impact upon targeted therapy. Our need to define this heterogeneity is most important in severe disease as patients with severe disease present a clinically unmet need with the greatest morbidity and mortality. In this issue of Clinical & Experimental Allergy Macedo et al. [4] have compared features of airway inflammation, remodelling and dysfunction in a group of severe asthmatics compared with those with moderate disease. As with previous studies, they found that there was tremendous variability in the intensity and pattern of inflammation and remodelling both within and between severity groups [5, 6]. The pattern of inflammation in tissue and differential cell counts from sputum and bronchoalveolar lavage (BAL) did not differ between groups. However, they did identify marked differences in remodelling with increased airway smooth muscle mass and reticular basement membrane thickening in those patients with severe disease suggesting that severe asthma is a consequence of over exuberant repair. These changes in airway structure were associated with disordered airway physiology with a significant inverse correlation between post-bronchodilator forced expiratory volume in 1 s and AHR with subbasement membrane thickening. Increased airway smooth muscle mass is a consistent feature of asthma [5–7]. Benayoun et al. [5] in a comprehensive examination of airway remodelling across asthma severities with healthy controls and subjects with chronic obstructive pulmonary disease found that the strongest predictors of persistent airflow obstruction were subepithelial fibroblast number and airway smooth muscle hypertrophy. Similarly, Kaminska et al. [7] demonstrated that smooth muscle area was greater in biopsies from severe asthmatics with persistent airflow obstruction compared with those without. Taken together these studies suggest that ongoing remodelling particularly in severe disease contributes to the development of airflow obstruction. In contrast the relationship between airway remodelling and AHR is much more tenuous [6] with some reports suggesting that remodelling may protect against AHR [8]. Advances in the assessment of airway geometry by computerized tomography (CT) imaging have also confirmed that the airways in asthma, particularly in severe disease, are remodelled with qualitative [9] and quantitative [7, 10–12] evidence of bronchial wall thickening. On a par with airway remodelling the relationship between airway geometry and lung function is also complex with some studies reporting a strong association [10–12] whereas others have not [7]. Although these crosssectional studies generally support a relationship between airway remodelling and dysfunction the natural history Correspondence: Prof. C. E. Brightling, Department of Infection, Inflammation and Immunity, Institute for Lung Health, University of Leicester, Glenfield Hospital, LE3 9QP Leicester, UK. E-mail: ceb17@le.ac.uk Cite this as: C. E. Brightling, D. Desai and S. Siddiqui, Clinical & Experimental Allergy, 2009 (39) 1630–1632. doi: 10.1111/j.1365-2222.2009.03356.x Clinical & Experimental Allergy, 39, 1630–1632