Elsevier

The Lancet

Volume 372, Issue 9643, 20–26 September 2008, Pages 1107-1119
The Lancet

Review
Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease

https://doi.org/10.1016/S0140-6736(08)61452-XGet rights and content

Summary

Clinical asthma is very widely assumed to be the net result of excessive inflammation driven by aberrant T-helper-2 (Th2) immunity that leads to inflamed, remodelled airways and then functional derangement that, in turn, causes symptoms. This notion of disease is actually poorly supported by data, and there are substantial discrepancies and very poor correlation between inflammation, damage, functional impairment, and degree of symptoms. Furthermore, this problem is compounded by the poor understanding of the heterogeneity of clinical disease. Failure to recognise and discover the underlying mechanisms of these major variants or endotypes of asthma is, arguably, the major intellectual limitation to progress at present. Fortunately, both clinical research and animal models are very well suited to dissecting the cellular and molecular basis of disease endotypes. This approach is already suggesting entirely novel pathways to disease—eg, alternative macrophage specification, steroid refractory innate immunity, the interleukin-17–regulatory T-cell axis, epidermal growth factor receptor co-amplification, and Th2-mimicking but non-T-cell, interleukins 18 and 33 dependent processes that can offer unexpected therapeutic opportunities for specific patient endotypes.

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

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”,

References (150)

  • S Illi et al.

    Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study

    Lancet

    (2006)
  • DS Postma

    Gender differences in asthma development and progression

    Gend Med

    (2007)
  • S Zanconato et al.

    Leukotrienes and 8-isoprostane in exhaled breath condensate of children with stable and unstable asthma

    J Allergy Clin Immunol

    (2004)
  • L Balaci et al.

    IRAK-M is involved in the pathogenesis of early-onset persistent asthma

    Am J Hum Genet

    (2007)
  • P Haldar et al.

    Noneosinophilic asthma: a distinct clinical and pathologic phenotype

    J Allergy Clin Immunol

    (2007)
  • S Dragonieri et al.

    An electronic nose in the discrimination of patients with asthma and controls

    J Allergy Clin Immunol

    (2007)
  • PD Phelan et al.

    The Melbourne Asthma Study: 1964-1999

    J Allergy Clin Immunol

    (2002)
  • C Lemiere et al.

    Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes

    J Allergy Clin Immunol

    (2006)
  • ID Pavord et al.

    Non-eosinophilic corticosteroid unresponsive asthma

    Lancet

    (1999)
  • K Nakashima et al.

    Association of the RIP2 gene with childhood atopic asthma

    Allergol Int

    (2006)
  • PJ Barnes

    New therapies for asthma

    Trends Mol Med

    (2006)
  • SJ Szefler et al.

    Significant variability in response to inhaled corticosteroids for persistent asthma

    J Allergy Clin Immunol

    (2002)
  • H Bisgaard et al.

    Determinants of lung function and airway hyperresponsiveness in asthmatic children

    Respir Med

    (2007)
  • H Aoki et al.

    Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma

    Biochem Biophys Res Commun

    (2008)
  • K Liu et al.

    Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection

    J Biol Chem

    (2008)
  • HR Anderson et al.

    50 years of asthma: UK trends from 1955 to 2004

    Thorax

    (2007)
  • ED Bateman et al.

    Rate of response of individual asthma control measures varies and may overestimate asthma control: an analysis of the goal study

    J Asthma

    (2007)
  • AK Tee et al.

    Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma

    Cochrane Database Syst Rev

    (2007)
  • FM Ducharme et al.

    Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma

    Cochrane Database Syst Rev

    (2006)
  • S Walker et al.

    Anti-IgE for chronic asthma in adults and children

    Cochrane Database Syst Rev

    (2006)
  • C MacDonald et al.

    A systematic review and meta-analysis of interventions used to reduce exposure to house dust and their effect on the development and severity of asthma

    Environ Health Perspect

    (2007)
  • AJ Coyle et al.

    Interleukin-4 is required for the induction of lung Th2 mucosal immunity

    Am J Respir Cell Mol Biol

    (1995)
  • AF Holloway et al.

    Changes in chromatin accessibility across the GM-CSF promoter upon T cell activation are dependent on nuclear factor kappaB proteins

    J Exp Med

    (2003)
  • JJ Smit et al.

    The balance between plasmacytoid DC versus conventional DC determines pulmonary immunity to virus infections

    PLoS ONE

    (2008)
  • LS van Rijt et al.

    In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma

    J Exp Med

    (2005)
  • J Travers et al.

    External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?

    Thorax

    (2007)
  • HM Brown et al.

    Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma

    BMJ

    (1972)
  • JL Brown et al.

    Lower airways inflammation in allergic rhinitics: a comparison with asthmatics and normal controls

    Clin Exp Allergy

    (2007)
  • GJ Braunstahl et al.

    Segmental bronchoprovocation in allergic rhinitis patients affects mast cell and basophil numbers in nasal and bronchial mucosa

    Am J Respir Crit Care Med

    (2001)
  • GJ Braunstahl et al.

    Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways

    Clin Exp Allergy

    (2003)
  • CE Lopuhaa et al.

    Allergen-induced bronchial inflammation in house dust mite-allergic patients with or without asthma

    Clin Exp Allergy

    (2002)
  • MJ Alvarez et al.

    Comparison of allergen-induced changes in bronchial hyperresponsiveness and airway inflammation between mildly allergic asthma patients and allergic rhinitis patients

    Allergy

    (2000)
  • MJ Alvarez et al.

    Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing

    Allergy

    (2000)
  • AJ Woolcock et al.

    What is the relationship between airway hyperresponsiveness and atopy?

    Am J Respir Crit Care Med

    (2000)
  • AJ Wardlaw et al.

    New insights into the relationship between airway inflammation and asthma

    Clin Sci (Lond)

    (2002)
  • CE Brightling et al.

    Mast-cell infiltration of airway smooth muscle in asthma

    N Engl J Med

    (2002)
  • SH Cho et al.

    Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma

    Am J Respir Crit Care Med

    (2005)
  • E Dehlink et al.

    Immunosuppressive therapy does not prevent the occurrence of Immunoglobulin E-mediated allergies in children and adolescents with organ transplants

    Pediatrics

    (2006)
  • GP Anderson

    Interactions between corticosteroids and beta-adrenergic agonists in asthma disease induction, progression, and exacerbation

    Am J Respir Crit Care Med

    (2000)
  • H Miyaura et al.

    Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids

    J Immunol

    (2002)
  • Cited by (812)

    View all citing articles on Scopus
    View full text