Study Identifies Exacerbation-Prone Phenotype Clusters in Asthma, COPD

When examining common factors for disease exacerbation shared by asthma and chronic obstructive pulmonary disease (COPD), researchers found 5 distinct clusters that went beyond disease labels.

Asthma and COPD are among the complex chronic inflammatory airway diseases that have various pathophysiological conditions and clinical symptoms. A new concept, called "treatable traits," takes patient characteristics and features into consideration, instead of diagnostic labels, to identify the optimal treatment for patients.

"Despite the fact that asthma and COPD share common mechanisms, the mainstream approach to treating chronic inflammatory airway diseases has been to name a diagnosis first, then to follow the clinical guidelines that correspond to that diagnosis," the authors explained. "This approach, also known as one-size-fits-all medicine, has been reported to have limitations in providing appropriate treatment for a variety of conditions that vary from patient to patient."

To clarify the exacerbation-prone phenotypes beyond disease labels, researchers conducted cluster analyses of patients with 1 or more exacerbations within the previous year despite being treated by a pulmonologist.

The study was published in PLoS ONE, and included 117 patients with asthma, 48 patients with COPD, and an additional 37 patients with asthma-COPD overlap (ACO).

All patients had received treatment at the University of Tsukuba Hospital in Japan and/or its affiliated hospitals. The study authors defined exacerbation as the need for intravenous infusion of steroids, either an increased dose or at least 3 days of oral administration of steroids, or antibiotic use due to worsening symptoms within the previous year.

To also understand the role of the IL4RA gene polymorphism rs8832—which is related to type 2 inflammation—in these phenotypes, a control group of 1529 adults without asthma or COPD were included in multinomial logistic analyses. The genetic influence of rs8832 was also evaluated in 130 patients with asthma with allergic rhinitis but without history of exacerbation.

The authors identified 5 clusters that were considered “good cluster quality” according to cohesion and separation silhouette indices (0.214).

The identified clusters were:

• High eosinophil counts (cluster 1)
• Smokers with impaired lung function (cluster 2)
• Presence of gastroesophageal reflux disease (cluster 3)
• Non-allergic females (cluster 4)
• Allergic rhinitis and elevated total immunoglobulin E levels (IgE) (cluster 5)

The authors noted that clusters 1 and 3 were inconsistent with disease labels for asthma and COPD. Additionally, cluster 1 was deemed an exacerbation-prone phenotype, particularly associated with eosinophilic airway inflammation.

A significant association was found between cluster 5 and rs8832 (odds ratio [OR], 3.88; 1.34-11.26, P = .013), as well as between type 2 exacerbation-prone phenotypes and rs8832 for clusters 1 and 5 (OR, 2.73; 1.45-5.15, P = 1.9 × 10⁻³).

While genotyping for rs8832 was unsuccessful in some patients in the cluster analysis, multinomial logistic regression analyses of the G allele of rs8832 showed it was significantly associated with the highIgE allergic rhinitis group in cluster 5. A similar but not significant trend was also observed with cluster 1.

“Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases,” the authors said.

Reference

Hyodo K, Masuko H, Oshima H, et al. Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD). PLoS ONE. Published online March 21, 2022. doi:10.1371/journal.pone.0264397