Eosinophilic asthma

The presence of eosinophils in these latter organs is associated with disease.
The presence of eosinophils in these latter organs is associated with disease.

Professor Ian Pavord describes the characteristics of eosinophilic asthma and the treatment implications of differentiating between eosinophilic and non-eosinophilic asthma

Key learning points

  • It is clinically important to distinguish between eosinophilic and non-eosinophilic asthma as they have different management and outcomes.
  • Early-onset allergic asthma is associated with allergy to aero-allergens and is characterised by eosinophilic airway inflammation, and can be controlled with inhaled corticosteroids (ICS).
  • Adult-onset asthma is a highly eosinophilic, non-atopic form requiring high-dose ICS with periodic oral corticosteroids.
  • Specific inhibitors of type 2 inflammation are emerging as an adjunctive treatment to steroids.

Introduction

The term ‘eosinophilic asthma’ was first used in 1999 when two research groups independently identified a subset of patients with asthma who had no pathological evidence of eosinophilic airway inflammation in comparison to those with eosinophil predominant inflammation.1,2 These reports concluded that it was clinically important to distinguish eosinophilic and non-eosinophilic asthma because patients with eosinophilic asthma had a higher risk of severe asthma attacks2 and tended to respond better to ICS.1

Studies since then have confirmed the clinical value of identification of eosinophilic asthma by showing that management guided by objective measures of eosinophilic asthma result in better outcomes,3,4 and by the clear demonstration that a response to ICS5 and anti-IL-5 treatment6-8 is confined to patients with eosinophilic asthma.

There are two common patterns of disease within the broad category of eosinophilic asthma.

1. Early-onset allergic asthma

This is the commonest phenotype, early-onset allergic asthma, and starts in childhood, is associated with allergy to aero-allergens and is characterised by eosinophilic airway inflammation, which can be episodic. Most patients have allergic rhinitis as concomitant disease and suffer from mild-to-moderate asthma, although the disease can become severe in a minority of patients. The allergy to house dust mite, pollens or animal dander can be documented by skin prick testing or serum radioallergosorbent test (RAST), demonstrating the presence of allergen-specific immunoglobulin E (IgE). The eosinophilic airway inflammation is evidenced by an increased percentage of eosinophils in induced sputum or airway biopsies in research settings, or by an increased blood eosinophil count and/or exhaled nitric oxide in clinical practice.

The pathogenesis of early-onset allergic eosinophilic asthma has been extensively studied. In susceptible individuals, exposure to aero-allergens such as house dust mite leads to thymic stromal lymphopoietin (TSLP), IL‑25 and IL‑33-driven induction of Th2 CD4+ T-lymphocytes by antigen-presenting dendritic cells. These type 2 T helper cells (Th2 cells) produce the type 2 cytokines IL-4, IL-5 and IL-13; IL-4 induces switching of B lymphocytes to IgE production; IL-5 stimulates eosinophil development in the bone marrow and increased eosinophil survival in the bronchial mucosa, leading to blood and airway eosinophilia; and IL-13 stimulates goblet cell metaplasia and bronchial hyper-reactivity.

The reasons why type 2 immune responses initiated during childhood become persistent are not well understood. It may be that aberrant immune programmes become established and fixed during a crucial time window in early life when the immune system is particularly plastic. Th2 cells and the ensuing eosinophilic airway inflammation are sensitive to therapy with ICS, and early-onset allergic asthma can be well controlled in the majority of patients, provided that the adherence to ICS treatment is optimal, and the inhalation technique is correct.

2. Adult-onset asthma

The second phenotype of severe asthma identified consistently by clinical and other classification techniques9  is a highly eosinophilic, non-atopic, adult onset form of the disease. Characteristic features include:

Onset as an adult and commonly following a viral respiratory tract infection.

Prominent upper airway symptoms with marked rhinosinusitis, often complicated by the formation of nasal polyps and typically occurring before the onset of asthma.

Lower respiratory tract symptoms in the form of recurrent exacerbations, which may be initially interpreted by the patient and healthcare advisors as chest infections.

Variable but most commonly low serum IgE and the absence of allergen-specific IgE.

Marked eosinophilic upper and lower airway inflammation despite the use of potent topical corticosteroids. This is usually associated with a peripheral blood eosinophilia.

Variable airflow obstruction and airway hyper-responsiveness are often not prominent, although apparently fixed airflow obstruction can be seen.

A marked and often complete response to systemic treatment with corticosteroids and anti-IL-5, although the former are often required in high dose and cause significant side-effects.

The common occurrence of aspirin sensitivity, where ingestion of aspirin and other inhibitors of cyclooxygenase cause acute worsening of rhinosinusitis and bronchospasm via a mechanism involving cysteinyl-leukotrienes.

The clinical course of this form of asthma is sufficiently stereotypical suggesting a common underlying cause and mechanism. There is particular interest in the possibility that eosinophilic airway inflammation is mediated by type 2 cytokine production by type 2 innate lymphoid cells (ILC2s).10 IL-4 production by ILC2s is variable, so an important role for ILC2s would explain why atopy is not present and IgE levels are generally low. ILC2s have been identified in human nasal polyp tissue11 and are present in increased numbers in sputum from patients with severe eosinophilic asthma.

Many patients with this form of eosinophilic asthma require treatment with high dose ICS with periodic oral corticosteroids to cover exacerbations. Up to 30% require regular oral corticosteroids to achieve any form of control.12 These treatments have potential local side-effects (including dysphonia and candidiasis) and oral corticosteroids are associated with systemic side-effects (including cataracts, osteoporosis and adrenal suppression), particularly when used in high doses over prolonged periods of time.13 The advent of more specific inhibitors of type 2 inflammation over the past 10–15 years has raised hope that these new drugs will provide similar benefits as corticosteroids to patients with severe eosinophilic asthma without the same side-effect profile.14 This hope has, to a large extent, been realised, although specific inhibitors of type 2 inflammation have a more limited range of effects on airway function and asthma control but have a large effect on the risk of asthma attacks. Their emerging role is as an adjunctive treatment to steroids in patients who are at risk of attacks. They are likely to be particularly applicable in patients with severe non-atopic eosinophilic asthma.

 

This article was initiated and funded by Teva Respiratory. Teva have had no influence over content and the aforementioned trails. Topics and content have been selected and written by independent experts.


References
  1. Pavord ID, Brightling CE, et al. The Lancet 1999;353:2213-2214.
  2. Wenzel SE, Schwartz LB, et al. American Journal of  Respiratory and Critical Care Medicine 1999;160:1001-1008.
  3. Green RH, Brightling CE, et al. The Lancet 2002;360:1715-21.
  4. Powell H, Murphy VE, et al. The Lancet 2011;378:983-890.
  5. Green R, Brightling C, et al. Thorax 2002;57:875-879.
  6. Haldar P, Brightling CE, et al. New England Journal of Medicine 2009;360:973-984.
  7. Pavord ID, Korn S, et al. The Lancet 2012;380:651-659.
  8. Nair P, Pizzichini MM, et al. New England Journal of Medicine 2009;360:985-993.
  9. Haldar P, Pavord ID, et al. American Journal of Respiratory and Critical Care Medicine 2008;178:218-24.
  10. Brusselle GG, Maes T, et al. Nature Medicine 2013;19:977-979.
  11. Mjosberg JM, Trifari S, et al. Nature Immunology 2011;12:1055-1062.
  12. Heaney LG, Brightling CE, et al. Thorax 2010;65:787-794.
  13. Sweeney J, Patterson CC, et al. Thorax 2016;71:339-346.
  14. Hilvering B, Xue L, et al. Therapeutic Advances in Respiratory Disease 2015;9:135-145.

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