One way to classify asthma involves identifying the phenotypes of asthma – that is the clusters of properties observed in different types of asthma. Although phenotypes are usually clinically relevant, in terms of presentation, triggers, and treatment response, they do not necessarily relate to or give any insight into the underlying disease processes.1
The term endotype is used to describe a subtype of a condition, which is defined by a distinct functional or pathophysiological mechanism. It has been suggested that asthma is made up of several endotypes, and although currently the underlying mechanisms of many of the proposed endotypes are poorly understood, their definition will enable the identification of novel therapeutic targets and biomarkers that meet formal diagnostic and prognostic criteria. Asthma phenotypes can be present in more than one endotype, and endotypes can contain more than one phenotype (see Table 1). Defining endotypes may help predict the response to treatment and thus facilitate improved management decisions with currently available treatments.
To investigate whether some asthma endotypes can already be identified, Lötvall et al selected 7 parameters – clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology, and treatment response – to define each endotype. It was proposed that each endotype should fulfill at least 5 of the 7 parameters, examples of which are:
- aspirin-sensitive asthma,
- allergic bronchopulmonary mycosis,
- allergic asthma (adults),
- asthma-predictive indices-positive preschool wheezer,
- severe late-onset hypereosinophilic asthma, and
- cross-country skiers’ asthma.2
Th2-driven asthma
Mechanistic studies conducted in asthma of similar severities have identified two types of immunological responses or ‘immunophenotypes’: low eosinophils and high eosinophils. The best studied endotype so far is the association with T-helper type 2 (Th2) cell eosinophilic airway inflammation.
While non-eosinophilic asthma has a very low level of Th2-associated transcription factors, this level is very high in high-eosinophils asthma – which can thus be considered as ’Th2-driven’. It is generally considered that Th2-driven inflammation defines a major subtype of asthma. This subtype is likely to respond to agents targeting Th2 related processes – i.e. inhibitors of cytokines produced by Th2 cells (i.e. interleukins IL-4, IL-5 and IL-13) as well as CRTH2-antagonists. However evidence also suggests that there is a subtype of asthma with low Th2 which is not likely to respond to these therapies3 (see Table 2).
The challenge for diagnostics is to identify patients exhibiting the Th2-driven endotype, and this is the starting point for the search for new biomarkers. One biomarker that has recently been selected based on differential gene expression analysis, and which seems to be strongly associated with the Th2 endotype, is periostin.4
Classification of patients with asthma by endotype will facilitate future research to establish genetic associations, identify biomarker for disease endotypes, and test novel therapeutic targets and endotype-specific treatments. The use of endotypes in clinical research could identify patient groups that will benefit most from new and existing treatments, substantially improving future asthma care.
Key message
- Asthma can be identified and classified by its phenotype – that is by its observable characteristics including asthma symptoms or related personality traits. More recently, asthma has been classified by its endotype – this is more closely associated to the underlying mechanisms.
- This mechanistic approach offers unexpected therapeutic opportunities for patients with specific endotypes. The identification of asthma endotypes, including Th2 driven asthma, along with the targeting of responders, has the potential to improve treatment efficacy substantially and eventually lead to a cure for asthma.
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References:
1. Anderson GP. Lancet. 2008 Sep 20;372(9643):1107-19. 2. Lötvall J, et al. J Allergy Clin Immunol. 2011 Feb;127(2):355-60. 3. Woodruff PG, et al. Am J Respir Crit Care Med. 2009 Sep 1;180(5):388-95. 4. Lauer S and Renz H. JIFCC. 2013; Vol. 24, n. 3 – 4. 5. Wenzel S, et al. Lancet. 2007 Oct 20;370(9596):1422-31. 6. Corren J, et al. N Engl J Med. 2011 Sep 22;365(12):1088-98. 7. Leckie MJ, et al. Lancet. 2000 Dec 23-30;356(9248):2144-8. 8. Haldar P, et al. N Engl J Med. 2009 Mar 5;360(10):973-84. 9. Singh D, et al. ERS Annual Congress, Barcelona 2010. MIMS Ireland Copyright®