National Center for Biotechnology Information (NCBI) public domain databases, Pubmed, and OMIM (On-line mendelian inheritance in man) were searched by combining the key term “asthma” sequentially with each of the following descriptors: “phenotype”, “subtype”, “factor analysis”, “principal component analysis”, “cluster”, “clade”, “classification”, “pattern recognition”, “severe”, “severity”, “refractory”, “complex disease”, “heterogeneity”, “variant”, “inflammation”, “sputum”, “biopsy”,
ReviewEndotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease
Introduction
In recent years, the morbidity and mortality of asthma have decreased, probably as a result of improved management. Some evidence suggests that the relentless rise in disease incidence and prevalence is now also reaching a plateau.1 However, although contemporary treatment approaches are indisputably effective, many patients have substantial residual disease and some, with very severe asthma, respond suboptimally even to high-dose oral steroids (figure 1).2, 3, 4, 5, 6 Furthermore, asthma—the most common serious chronic lung disease afflicting around 150 million people worldwide—remains both unpreventable and incurable.7 Despite decades of intensive research, little progress in identification of new treatments has been made since the introduction of inhaled β2 adrenoceptor selective agonists (1969) and inhaled glucocorticosteroids (1974).
This Review aims to advance the argument that the way in which we think about the pathogenesis of asthma is flawed (or incomplete), which in turn is preventing the discovery of better treatments, preventions, and cures. Clear evidence now suggests that asthma is a heterogeneous and genetically complex disease (>100 genes have already been implicated) that cannot be explained by one mechanism alone. To order this heterogeneity and the volume and complexity of clinical and basic research data, the new notion of disease endotypes (panel 1), identifying definable subpopulations of asthma with discrete pathogenic pathways, is introduced and a conceptual framework to model endotypes is presented.
This Review is structured into four sections: weaknesses of the current T-helper-2 (Th2)-inflammation hypothesis; asthma heterogeneity in terms of ontogeny, clinical phenotypes, and molecular patterns; asthma endotypes; and novel mechanisms, with particular emphasis on alternative macrophage specification programmes and the role of innate immunity as determinants of more severe and steroid-refractory asthma endotypes. By understanding asthma endotypes, and their molecular determinants, effective therapies, and possibly cures, can be developed that are highly effective in targeted patient subgroups.
Section snippets
Limitations of the Th2-inflammation hypothesis
Since the mid-1990s, asthma research has been propelled forward by innovations stemming from the Th2-inflammation hypothesis, providing a molecular framework for understanding the well known associations of atopy or IgE and eosinophilic lung inflammation with asthma. A helper T-cell population induced by interleukin 4 is able to produce a panel of cytokines—such as interleukin 4 or 13 (causing B-cell IgE production, mucus secretion, and fibrosis), interleukin 5 (causing eosinophilic
Heterogeneity of clinical asthma and treatment responses
Asthma continues to elude specific definition and can therefore currently only be characterised in functional terms (panel 2). Although evidence has suggested the pronounced heterogeneity of asthma for decades, little interest has focused on understanding its basis. Most asthma trials and research protocols have used inclusion criteria—typically predicted forced expiratory volume in 1 second (FEV1), degree of reversibility, inflammation, eosinophilia, and often IgE, because they can be measured
An asthma endotype model
In view of the manifest problems with the Th2-inflammation model and the pronounced heterogeneity of asthma, how is the disease to be modelled and how will new treatments be found? Gibson's four inflammatory patterns provide one simple and useful model.52 A more extensive rational approach is to assess components of disease that could be considered in the definition of endotypes. The asthma endotype model shown in figure 3 maps inter-relations between clinical determinants that are known to be
Novel disease mechanisms
Asthma has a heritable component that is estimated to be between 36% and 94%. More than 100 plausible candidate genes have been suggested, but each has a very low attributable risk (<5%), with often poor replication125 or lack of plausible biology or functional single nucleotide polymorphisms. Of this very large information set, two broad new notions are emerging: auto-innate immunity driven by tissue damage and Th2-like responses that occur without T cells (figure 4).
Until recently, innate
Summary and implications
This Review has developed the argument that the Th2-inflammation hypothesis, although useful, is not adequate to understand the substantial heterogeneity of asthma. The first iteration of an open-frame asthma endotype model has been presented and discussed in the context of entirely novel disease pathways, many of which are independent of adaptive immunity. The role of innate immunity, which is intrinsically insensitive to steroids and can be driven by tissue damage, has been emphasised. There
Search strategy and selection criteria
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