Interleukin-6: A Phenotype-Agnostic Therapeutic Target for Mucus Plugs in Type 2 and Non-type 2 Asthma

Airway mucus plugs are prevalent in both type 2 (T2) and non-T2 asthma phenotypes, contributing to treatment resistance. Current biologics predominantly target T2 pathways. In our cross-sectional study of 321 patients with asthma, chest CT showed mucus plugs were prevalent in both T2 and non-T2 asthma (33.2% vs 20%, P = 0.034) and across all severities (mild-to-moderate: 27.0%; severe: 60.7%; P = 0.001). Patients with mucus plugs had higher rates of severe asthma (17.7% vs 4.9%, P < 0.001) and elevated serum and sputum IL-6 (P = 0.004; P < 0.001). Multivariable regression identified sputum IL-6 as an independent risk factor for mucus plugs (OR 4.84; 95%CI, 1.63–24.5; P = 0.020). In vivo and in vitro studies demonstrated that anti-IL-6/IL-6R treatment significantly reduced periodic acid-Schiff scores (2.80 ± 0.84 vs 4.60 ± 0.55, P = 0.004) and mucin 5 subtype AC/B expression via the PI3K mTOR signaling pathway. We further observed that 2 of 3 patients with mucus plugs exhibited significant resolution following tocilizumab treatment. These findings indicate that mucus plugs are a common feature across asthma inflammatory phenotypes and are associated with increased disease severity. IL-6 pathway inhibition offers a phenotype agnostic therapeutic strategy for mucus plug resolution in asthma.