SAN DIEGO -- The recognition that asthma is a heterogeneous disease, and the identification of individual asthma phenotypes and endotypes, is poised to usher in the era of personalized medicine, but significant challenges remain.
Personalized pharmacotherapy, as well as other individual treatment approaches, hold the promise of better asthma control for patients with severe, drug-refractory disease.
The identification of new asthma biomarkers will be key to identifying patients with severe asthma who will respond to specific therapies.
Blood eosinophil count, serum IgE and serum periostin levels, nitric oxide in exhaled breath (Fe NO), and sputum eosinophil count are all markers of type 2 (Th2) inflammation and eosinophilia, but their usefulness in the clinical setting has not yet been fully realized.
With the emergence of biologic agents in the armamentarium of asthma treatments, the search for noninvasive molecular biomarkers that can better inform treatment decisions has become more urgent.
Some of the most widely recognized asthma phenotypes include:
- Allergy phenotype: Symptoms frequently begin in childhood and have an allergic component and seasonal variation related to allergen exposure. Total IgE levels tend to be higher than in nonallergic asthma. It is estimated that around 90% of children and 50% of adults have allergic asthma, and the prevalence is increasing. Among adults in the U.S., allergic asthma prevalence increased from , while non-allergic asthma prevalence remained stable.
- Obesity phenotype: In adults, this phenotype i, little evidence of allergy, frequent symptoms, non-eosinophilic inflammation, and female predominance. Several studies have suggested that weight loss improves asthma outcomes in people with obesity-related disease, but they are not conclusive.
- Exercise-induced asthma: Characterized by a narrowing of the airways during exercise. Asthma symptoms typically occur after brief exercise and can last for 30 to 90 minutes without treatment. short-acting beta-agonists taken 15 minutes before exercise, leukotriene receptor antagonists, or inhaled corticosteroids.
- Asthma-COPD overlap: Several asthma-chronic obstructive pulmonary disease (COPD) overlap syndromes (ACOS) have been identified, including asthma in smokers and neutrophilic ACOS.
- Asthma in the elderly: Frequently seen with multiple comorbidities and phenotypes, including obesity.
Molecular studies have so far revealed to two distinct asthma biologic mechanism endotypes: Th2-high (Th2-positive) and Th2-low asthma, based on expression levels of genes encoding interleukin (IL)-13, IL-5, and IL-4, cytokine expression, and responsiveness to inhaled glucocorticosteroid.
Patients with Th2 asthma are more responsive to corticosteroid therapies and the available biologics with efficacy in the treatment of severe, drug-refractory asthma, including the IgE inhibitor omalizumab (Xolair); the anti-IL-5 therapies mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra); and the IL-4 and IL-13-blocking agent dupilumab (Dupixent).
"The biologics are likely to change the algorithms of treatment for severe asthma," said Klaus Rabe, MD, PhD, of LungenClinic Grosshansdorf in Grosshansdorf, Germany, who was lead researcher for a recently published study of .
He said ongoing research aimed at identifying new asthma biomarkers may help clinicians determine which patients with severe disease will benefit from treatment with a biologic. Head-to-head studies of the biologics are also needed, he said, to determine their relative efficacy.
"The decision clinicians make now about which biologic to use are not yet based on the data, but the data will come," he told 51˶.
The mechanisms of non-inflammation driven severe asthma (T2-low) are not well understood, and the therapeutic options for patients with difficult-to-treat T2-low asthma are limited.
These patients generally have discordant disease with neutrophilic or paucigranulocytic airway inflammation with little evidence of eosinophilic inflammation. But some patients with neutrophilic asthma also present with evidence of eosinophilic asthma.
"There have been attempts to identify treatments targeting this group of patients, but they have not been successful," Helen Reddel, PhD, of the University of Sydney, told 51˶. "The problem is that the pathways are also involved in infection control. So you have to be very cautious with medications that can potentially affect your ability to respond to infections. But there is a lot of basic work going on."