Customizing Treatment in Severe Refractory Asthma: The Role of Endotyping

The type of asthma that characterizes the TH2H patients includes increased bronchial hyperresponsiveness, increased serum IgE concentrations, increased blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression.⁷ Patients receiving corticosteroid treatment show improvement in FEV1, while those with TH2L generally do not respond.⁴

Neutrophilic Asthma

Neutrophilic asthma predominates in patients with severe refractory disease.^8,9 Patients with severe asthma and mixed neutrophilia/eosinophilia have worse lung function and increased frequency of daily wheezing, as compared to patients with non-severe asthma. This disease mechanism does not seem to be driven by TH2 cells, and is therefore not responsive to steroids.

RELATED CHART: Asthma Treatments — Inhalations

Making treatment decisions based on neutrophil counts in induced sputum is inaccurate because, unlike eosinophils, neutrophils are normal constituents of sputum and no cutoff point has been established. However, it is known that this profile frequently responds well to macrolide antibiotics. Further research is needed to identify more targeted treatments.⁴

Chronic Airflow Obstruction

Chronic airflow obstruction, associated with air trapping, is characteristic of severe asthma¹⁰ and has been linked to airway remodeling and inflammation. Increased airway wall thickness is associated with pathologic changes and constitutes an increase in airway smooth muscle mass and fibrosis. These patients showed a good bronchodilator response to an antibody to the TH2 cytokine interleukin 13.¹¹

Asthma Exacerbations

Severe asthma exacerbations are typically treated with systemic corticosteroids. Patients with frequent exacerbations are also more likely to have comorbid conditions, such as severe sinus disease, gastroesophageal reflux, recurrent respiratory infections, and obstructive sleep apnea.

In cases of exacerbations characterized by sputum eosinophilia, the anti-interleukin-5 agent (mepolizumab) can reduce exacerbations by as much as 50%.¹²

Endophenotypes and potential treatments are summarized in the Table 1 below.

TABLE 1. Endophenotypes and Potential Treatments

Features of   Severe Asthma	Phenotype	Biomarkers	Specifically-targeted  Treatments
Allergic Asthma	High nitric oxide concentration in exhaled breath	High serum IgE, atopy, high blood eosinophils	Anti-IgE (omalizumab)
Eosinophilic Asthma	Recurrent exacerbations, corticosteroid-dependent	Sputum eosinophils	Anti-interleukin-4 receptor-alpha (dupilumab)
Neutrophilic asthma	Poorer lung function, higher frequency of daily wheezing, less responsiveness to corticosteroids	Sputum neutrophils	Macrolide antibiotics (azithromycin)
Recurrent airflow obstruction	Airway remodeling, low FEV1, fibrosis	High serum periostin (a marker of TH2 activation)	Anti-interleukin 13 (lebrikizumab)
Recurrent exacerbations	Necessity of systemic corticosteroids; frequent   comorbid conditions, such as severe sinus disease, gastroesophageal reflux,   recurrent respiratory infections, and obstructive sleep apnea	Sputum eosinophils	Anti-interleukin 5 (mepulizumab)