Severe and Difficult-to-Treat Asthma in Adults

Published - Written by Carla Rothaus

What are some of the features of the inflammatory phenotypes that underlie severe asthma?

Considerable progress in understanding and treating severe asthma has been made in the past 5 years. Advances include formulation of a standardized definition and evidence-based treatment guidelines, compilation of substantial evidence about phenotypic patterns and biomarkers, and the availability or near-approval of novel targeted treatments. Read the new Review Article.

Clinical Pearls

Q: How prevalent is severe asthma among adults?

A: Patients with severe asthma make up only 3% to 10% of the population of adults with asthma, but their care is estimated to account for more than 60% of the costs associated with asthma, which are primarily for medications. Health care costs per patient for severe asthma are higher than those for type 2 diabetes, stroke, or chronic obstructive pulmonary disease (COPD).

Q: How is severe asthma defined?

A: Severe asthma is a subset of difficult-to-control asthma; the term is used to describe patients with asthma that remains uncontrolled despite treatment with high-dose inhaled glucocorticoids combined with a long-acting β2-agonist (LABA), a leukotriene modifier, or theophylline for the previous year or treatment with systemic glucocorticoids for at least half the previous year. The term is also used to describe asthma that requires such treatment in order to remain well controlled; it excludes patients in whom asthma is vastly improved with optimization of adherence, inhaler technique, and treatment of coexisting conditions.


Morning Report Questions

Q: What are some of the features of the inflammatory phenotypes that underlie severe asthma?

A: Type 2 inflammation in the airway is characterized by the presence of cytokines (interleukin-4, interleukin-5, and interleukin-13) that were originally recognized as being produced by type 2 helper T (Th2) cells. These cytokines are also produced by innate lymphoid cells (which do not express B- or T-cell receptors) in response to infectious agents and pollutants and other “nonallergic” stimuli. Since interleukin-4 and interleukin-5 promote the production of IgE and eosinophils, respectively, this inflammation is frequently characterized by eosinophils and may be accompanied by atopy. In mild-to-moderate asthma, type 2 inflammation is common and generally promptly resolves after treatment with glucocorticoids. However, in the context of severe asthma, this phenotype is characterized by persistent evidence of active type 2 inflammation despite high-dose therapy with inhaled glucocorticoids. Less well characterized are patients with severe asthma who have neutrophilic inflammation (variably defined as exceeding 40 to 60% neutrophils) in induced sputum samples; some have no evidence of eosinophilic inflammation during treatment with glucocorticoids. Although neutrophils in the sputum may sometimes relate to glucocorticoid use, the clinical characteristics of patients with neutrophilic predominance differ from those with type 2 inflammation, suggesting different pathobiologic pathways. Some patients with severe asthma have evidence of persistent neutrophilic and eosinophilic inflammation in sputum. This overlapping phenotypic cluster appears to have the greatest disease burden and airflow limitation and involves the greatest use of health care resources. Some patients do not have notable cellular inflammation in their airways; their airflow limitation is presumably due to other mechanisms. Overall, this phenotype is not as common as the others, so its finding (e.g., in some obese patients) should prompt reconsideration of the diagnosis of asthma.

Q: What are some of the approved and investigational therapies for severe asthma?

A: Interleukin-5 plays a central role in promoting eosinophilic inflammation. Anti–interleukin-5 monoclonal antibodies are now available for the treatment of patients with severe eosinophilic asthma and recurrent exacerbations. Mepolizumab and reslizumab, both of which bind to interleukin-5, have been approved by several regulatory agencies in the United States and Europe. Benralizumab, which binds to the interleukin-5 receptor, producing eosinophil apoptosis, is nearing Food and Drug Administration (FDA) approval. Blockade of interleukin-13 has the potential to alter airway inflammation and smooth-muscle reactivity, but one of two anti–interleukin-13 monoclonal antibodies, lebrikizumab, failed to provide consistent improvement in patients with type 2 inflammation. The other, tralokinumab, continues in development. Dupilumab is another compound that has been tested for use in patients with severe asthma but has not yet been approved by the FDA for asthma. Dupilumab is a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor that blocks both interleukin-4 and interleukin-13 signaling.

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