Ironically, the effectiveness of ICS as a treatment for most patients with asthma, especially young adults with allergic asthma, may have retarded recognition that the term “asthma” encompasses a heterogeneous collection of disorders, many of which are poorly responsive to corticosteroid treatment. The existence of different forms or subtypes of asthma has actually long been recognized, as implied by the use of modifying terms such as “extrinsic,” “intrinsic,” “aspirin-sensitive,” “adult-onset,” “steroid-dependent,” “exacerbation-prone,” “seasonal,” “postviral,” and “obesity-related” to describe asthma in particular patients. More rigorous description of asthma phenotypes, based on cluster analysis of multiple clinical, physiologic, and laboratory features, including analysis of blood and sputum inflammatory cell assessments, has identified as many as five different asthma phenotypes. The key question raised by this approach is whether the phenotypes respond differently to available asthma treatments.
Persuasive evidence of the existence of different asthma phenotypes requiring different approaches to therapy is the demonstration of differences in the pattern of gene expression in the airway epithelium of asthmatic and healthy subjects. Compared with healthy controls, half of the asthmatic participants overexpressed genes for periostin, CLCA1, and serpinB2, genes known to be up-regulated in airway epithelial cells by IL-13, a signature cytokine of T2 lymphocytes. The other half of the asthmatic participants did not. These findings suggest that fundamentally different pathophysiologic mechanisms exist even among patients with mild asthma. The participants with overexpression of genes up-regulated by IL-13 are referred to as having a “T2-high molecular phenotype” of asthma. The other subjects, who did not overexpress these genes, are described as having a “non-T2”or “T2-low” molecular phenotype. The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes. The response to ICS treatment of these two groups was quite different. Six weeks of treatment with an ICS improved forced expiratory volume in 1 second (FEV1) only in the T2-high subjects. The implications of these findings are far reaching because they indicate that perhaps as many as half of patients with mild to moderate asthma do not respond to ICS therapy. The proportion of non-ICS responders among patients with severe “steroid-resistant” asthma could be much higher.
Current research focuses on further exploring molecular phenotypes in asthma and in finding effective treatments for each group. An investigational IL-13 receptor antagonist, lebrikizumab, for example, has been shown to be more effective in asthmatic subjects with elevated serum levels of periostin (one of the genes up-regulated in the “T2-high molecular phenotype”).
To examine whether tiotropium might be an alternative to ICS therapy for “T2-low” asthma, a NIH–sponsored multicenter trial is embarking on a prospective, double-blind, placebo-controlled trial of ICS versus tiotropium in asthmatic subjects characterized as T2-high or non-T2-high by analysis of their induced sputum samples for eosinophil number and for expression of T2-dependent genes (https://clinicaltrials.gov/ct2/ show/NCT02066298).