Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

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Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation — into ‘T helper 2 (TH2)-high’ and ‘TH2-low’ subtypes (endotypes) — has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.

long-term treatment instituted, without any objective diagnostic measurements ever being made. Is there any other chronic disease for which objective diagnostic tests are readily available of which this can be said? Although the Commissioners differed in their views on the strength of evidence for diagnosis and management guided by biomarkers, particularly in children, there was a consensus that the incorporation of biomarkers into the diagnosis could only enhance the capacity to diagnose asthma responsive to ICS and lead to a paradigm shift from the current approach to diagnose the umbrella term asthma, to the diagnosis of asthma phenotypes that respond to specific treatments. New drug development Until recently we have not seen the developments in new drug discovery enjoyed by other specialty areas (table 2) 19. This area perhaps exposes the limitations of our current view of 'asthma' and airway disease most obviously. New asthma treatments are largely variants on the old; a browner inhaler, with more potent topical effects, despite increasing concerns about topical immunosuppression 103. When new treatments become available, they are widely prescribed to all comers despite being largely ineffective (Sodium Cromoglycate, Ketotifen) or effective only in subgroups of patients (Omalizumab, Mepolizumab). There has been, until recently, no concept of targeted treatment. Progress in new drug discovery has been slow, with relatively few molecules progressing from the laboratory to the clinic and a depressingly high rate of failure at the later stages of clinical development (table 2) 19. Mepolizumab, a humanised monoclonal antibody that was developed to inhibit eosinophilic airway inflammation by blocking interleukin (IL)-5, is a good example. Mepolizumab was found to be safe and effective at blocking IL-5 and reducing eosinophilic airway inflammation when tested with in vitro systems and in vivo models 104,105. A subsequent clinical trial was designed based around incorporating Mepolizumab into a step-up guideline-based paradigm 106. Within this paradigm, Mepolizumab was investigated in patients who remained symptomatic on current ICS therapy and the clinical trial focused on lung function and asthma symptoms as traditional outcome measures. Despite adequate power, this trial was unexpectedly negative. This led to much soul-searching and the near-abandonment of the drug 107. Investigators who were experienced with non-invasive measures of airway inflammation identified two important problems with this initial clinical trial: first, the heterogeneity of airway inflammation in severe asthma meant that a significant number of the trial participants would not have had eosinophilic airway inflammation and therefore would not be expected to respond; and second, the

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calciumactivated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.gene expression microarray ͉ serpinB2 ͉ CLCA1 ͉ FKBP51