T2-Low Asthma Is More Complex Than Clinicians Think

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Type 2 (T2)-high and T2-low asthma are distinguishable by unique transcriptomic networks, but characterization of T2-low asthma remains relatively poor, according to a recent study published in BMJ Open Respiratory Research.¹

Clinicians rely on T2 inflammation biomarkers to identify the different endotypes associated with T2-high and T2-low asthma. Further understanding these endotypes and their respective characteristics helps clinicians improve clinical management of patients.¹ The study identified microRNA and mRNA networks that allowed researchers to distinguish T2-high and T2-low asthma endotypes further. Yet despite the differences, some areas of overlap could broaden treatment approaches for patients with T2-low asthma, Geoffrey Chupp, MD, a pulmonologist specializing in lung diseases that affect the airway at Yale Medicine and study author, said in an interview with The American Journal of Managed Care®.

“And what I think it tells us is that there's much more, I think, overlap between the expression of T2-high and T2-low pathways in the disease than we probably see clinically,” he explained. “And it provides an opportunity to broaden how we approach asthma and T2-low patients and think of them as not necessarily T2-low completely.”

Researchers in the study analyzed microRNA and mRNA expression in whole-blood samples from 88 patients with asthma, who were classified as having T2-high (n = 59) or T2-low (n = 29) asthma based on blood eosinophil counts and/or fractional exhaled nitric oxide levels.¹ The analysis identified 2 latent components linked to the endotypes. The first was characterized by eosinophil-derived mRNAs associated with T2-high asthma, while the second was associated with both endotypes and with non-eosinophilic cell types.

T2-low asthma was enriched for taste and smooth muscle contraction pathways, which the authors noted are directly implicated in bronchoconstriction, and they suggested patients with T2-low asthma may benefit from existing therapies targeting bitter taste receptors if future studies validate their observations.¹

The signatures were also present in 2 independent validation cohorts, and most T2-high genes within the signature changed significantly after treatment with the IL-5 receptor antagonist benralizumab in patients with severe eosinophilic asthma, highlighting their potential use as biomarkers of therapeutic efficacy.¹ The authors noted limitations, including the use of bulk RNA rather than single-cell analysis and the study's cross-sectional design.¹

Chupp noted that clinical trial data have shown some patients classified as T2-low by standard biomarkers still respond to biologic therapies.

“I think it tells us that T2-low disease is more complicated than we generally think of it in the clinic,” he explained.

References

1. Ramirez M, Diaz MP, Wang N, et al. Integrated molecular networks reveal latent components distinguishing type 2-high and type 2-low asthma. BMJ Open Respir Res. 2026;13:e004003. doi:10.1136/bmjresp-2025-004003