Customizing Treatment in Severe Refractory Asthma: The Role of Endotyping

Asthma is one of the most common illnesses, affecting 18.9 million US adults and 17.1 US children.¹ The Global Initiative for Asthma (GINA)’s 2012 Guidelines² provides a stepwise plan for treatment of asthma, based on disease severity.

The guidelines emphasize the use of short-acting reliever medication, and incorporating combination low-dose inhaled corticosteroids with inhaled long-acting β2-agonist (LABA) in later disease stages. In severe disease, additional controllers (eg, leukotriene modifiers, theophylline, oral corticosteroids, and anti-immunoglobulin E [IgE] humanized monoclonal antibody treatment) are recommended.²

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An estimated 5% to 10% of patients are refractory to available treatments and regarded as having severe or refractory-resistant asthma.³ They remain a “substantial part of the asthma burden,” requiring “targeted novel treatments.”⁴

A recent article by Chung⁴ explores novel therapies for treatment-resistant asthma patients. The author focuses on the “clinical heterogeneity of asthma,” stating that “asthma cannot be regarded as one disease, but as an umbrella term that embraces a collection of several different phenotypes… mediated by different pathways.”⁴

The idea of a “one-treatment-fits-all” approach cannot be applied in patients with severe asthma, so a highly targeted treatment protocol, tailored to the unique phenotype of the patient, will yield higher success rates in symptom reduction and easing disease burden.⁴

Asthma Phenotyping and Endotyping

Asthma research has identified several distinct pathophysiological characteristics that cluster together to form recognized phenotypes—chronic airflow obstruction, eosinophilic and neutrophilic asthma, corticosteroid insensitivity, and recurrent exacerbations.

The addition of pathophysiological mechanisms into the phenotypic characterization is called “endotyping.”⁵ Endotyping has the potential to enable more targeted interventions, based on the specific pathophysiological mechanisms involved. (See Table 1.)

Eosinophilic Asthma

Sputum eosinophilia is found in 36% of asthma patients not taking inhaled corticosteroids and 17% of patients being treated with inhaled corticosteroids.⁶ Measurement of sputum eosinophils might be used to guide treatment.

Refractory patients with high sputum eosinophilia, steroid dependency, and recurrent exacerbations have been found to respond to specific anti-interleukin-5 monoclonal antibody treatment, resulting in fewer exacerbations.⁴

The T-2 Helper Endotypes

The “expression of mRNA in airway epithelial cell brushings of the interleukin-13-inducible genes” determines whether an individual with mild to moderate asthma is in a T-helper-2-high (TH2H) or T-helper-2-low (TH2L) group.