Complex phenotypes in asthma: Current definitions
Introduction
Asthma has long been recognized as a heterogeneous disease. Previously, the relative importance of identifying the specific subgroups has been modest, as there were few treatment options for asthma, and little to suggest one subgroup responded to any one of these treatments better than another. However, the convergence of recent pathobiologic studies, corticosteroid (CS) response studies and emergence of targeted immunologic agents has resurrected the concept that asthma is not a single disease, rather one consisting of clinically recognizable phenotypes. This concept has been further solidified by the recent matching of the clinical phenotypes with targeted biologic therapies. These studies should form the basis for more rigorously defining the biologic endotypes of “asthma” and eventually eliminating the umbrella term of asthma completely.
Section snippets
Asthma and the phenotype concept (Fig. 1)
The term “asthma” clinically defines a group of patients with broad general respiratory symptoms in the setting of a reversible or hyperactive airway. In fact, there are many similarities between the term asthma and “arthritis”, which similarly clinically and nonspecifically defines a swollen joint. Yet, patients are no longer treated for “arthritis”, rather for the “type” of arthritis they have, be it osteo or rheumatoid or something else. While the rheumatologic world now identifies these as
The transition to asthma endotypes
Perhaps the three most important factors driving the identification of endotypes as opposed to phenotypes are: 1) the identification of asthma phenotypes through statistical clustering approaches, 2) the application of 'omics approaches to asthma and 3) the appreciation that specific targeted (and even non-targeted) immune therapies are more effective in relation to certain biologic characteristics.
For many years, clinically biased approaches identified features which seemed to identify certain
Potential asthma endotypes (Table 1)
Th2-“like” asthma. No single endotype of asthma has yet been fully characterized. However, the convergence of factors described above has led to the wide appreciation that some version of a Th2-“like” endotype (or endotypes) exists. This was made clear in follow-up studies which utilized the Th2 biomarker periostin, this time in serum, to identify a subgroup of moderate to severe asthmatics with lung eosinophilia and, importantly, who responded specifically to therapy with a monoclonal antibody
Conclusions
Definitions of asthma phenotypes are steadily evolving. Whereas earlier definitions relied primarily in singular and often clinical characteristics, the emergence of statistical clustering approaches, Th2 biomarkers and targeted therapies are identifying molecular pathways which contribute to more distinct molecular phenotypes, and to some degree even endotypes. Ongoing integration of large clinical, molecular and therapeutic databases could eventually identify several distinct diseases which
References (52)
Asthma: defining of the persistent adult phenotypes
Lancet
(2006)Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease
Lancet
(2008)- et al.
Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome
The Journal of Allergy and Clinical Immunology
(2011) - et al.
Non-eosinophilic corticosteroid unresponsive asthma
Lancet
(1999) - et al.
Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation
The Journal of Allergy and Clinical Immunology
(2004) - et al.
Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma
The Journal of Allergy and Clinical Immunology
(2001) - et al.
Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma
Chest
(2004) - et al.
Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial
Lancet
(2002) - et al.
Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial
Lancet
(2012) - et al.
Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response
Lancet
(2000)