D96-04 CT-Evaluated Mucus Plugging in Sputum Cellular Phenotypes of Severe Asthma

Abstract Rationale The formation and persistence of clinically-relevant mucus plugs in asthma may be influenced by distinct inflammatory processes.1 While prior studies have primarily focused on eosinophilic inflammation,2 contribution of other inflammatory pathways remains less well-defined. Here, we characterized computed tomography (CT)-evaluated mucus plugs across sputum phenotypes in biologic-naïve patients with asthma. Methods Sixty biologic-naïve patients with moderate-to-severe asthma underwent same-day full-inspiration chest CT and sputum induction. They were categorized as sputum producers (n = 52) or non-producers (n = 8), based on their ability to produce an adequate sample after three rounds of inhaled saline. In sputum producers, differential cell count was performed to define four cellular phenotypes: eosinophilic (n = 18, ≥2.3% eosinophils and/or moderate/many free-eosinophil-granules (FEGs)), neutrophilic (n = 9, ≥64.4% neutrophils with total cell count≥9.7 × 106 cells/g and/or absolute neutrophil count≥4.9 × 106 cells/g), mixed-granulocytic (n = 15, both eosinophilic and neutrophilic), and paucigranulocytic (n = 10, neither eosinophilic nor neutrophilic). To assess the effect of FEGs on mucus plugging independent of intact eosinophils, patients were stratified as: Eos-FEG-, Eos⁺FEG−, Eos−FEG⁺, and Eos+FEG+, based on eosinophil percent (Eos+≥2.3%, Eos-<2.3%) and presence (FEG+) or absence (FEG-) of FEGs. CT scans were analyzed by a single observer using VIDA|vision software (VIDA Diagnostics) to quantify mucus score,2 total plug volume, and median plug volume. Results Figure 1 summarizes CT-evaluated mucus burden across sputum phenotypes of 60 patients with moderate-to-severe asthma (36F/24M, age=56[23-73]years, FEV1=74[38-108]%pred). Mucus plugs were observed in all sputum phenotypes, with a CT mucus score≥4 in 40% (4/8) of non-producers, 30% (3/10) of paucigranulocytic, 56% (5/9) of neutrophilic, 83% (15/18) of eosinophilic, and 87% (13/15) of mixed-granulocytic patients. Mucus score (p = 0.001; Figure-1B), total plug volume (p = 0.001; Figure-1C) and median plug volume (p = 0.004; Figure-1D) significantly differed across phenotypes. Mucus score and total plug volume were higher in the eosinophilic and mixed-granulocytic groups than the paucigranulocytic group (all p < 0.05). Median plug volume was higher in the mixed-granulocytic group compared to the paucigranulocytic group (18.4[11.3-27.8]μL vs. 10.6[5.2-21.3]μL, p = 0.02). Patients with moderate (6[5-14], p = 0.03) and many (9[0-14], p = 0.003) FEGs had higher mucus scores than those without FEGs (3[0-9]). Eos+FEG+ (7[0-15], p = 0.002) and Eos-FEG+ (9[2-14], p = 0.005) groups had higher mucus scores than the Eos-FEG- group (1[0-9]) (Figure-1E). Conclusions CT-visible mucus plugs in severe asthma are observed across sputum phenotypes, are heterogenous in burden, and may be aggravated by eosinophil degranulation. Notably, mucus plugs may be present in the absence of sputum production or cellular inflammation in induced sputum. 1Liegeois et al. JCI(2025); 2Dunican et al. JCI(2018) This abstract is funded by: None