High Airway TSLP Levels in Asthma Associate With Higher Scores for Mucus Plugging and Air Trapping

Rationale: Thymic stromal lymphopoietin (TSLP) is an alarmin whose activity regulates type 2 immune responses in asthma. Tezepelumab, which inhibits TSLP, is associated with a reduction in airway mucus plugs in asthma patients1, but it is not known how airway TSLP levels relate to measures of airway mucus plugging and air trapping. Methods: Using a V-Plex immunoassay (Meso Scale Discovery, ACRO Biosystems), we measured TSLP protein levels in sputum samples from 412 participants in the Severe Asthma Research Program (SARP)-3 and from 104 health controls. Deep phenotyping of SARP-3 participants includes measures of mucus plugging and of air trapping (AT) in computed tomography (CT) lung scans and of gene expression in cells in induced sputum. Results: The upper 95th percentile value of TSLP in sputum in health (1.5pg/mL) was used to divide asthma patients into TSLP-high and -low subgroups. Compared to TSLP-low asthma patients, TSLP-high asthma was significantly associated with higher gene expression for MUC5AC and lower expression for MUC5B in sputum (Panels A and B). In addition, TSLP-high asthma was significantly associated with higher mucus plug score on CT lung images (Panel C) and sputum TSLP levels in the high mucus plug subgroup (segment score ≥4) were significantly higher than in the zero-mucus plug subgroup (Panel D). Furthermore, TSLP-high asthma associated with AT, as evidenced by higher values for LAA856% (low attenuation areas less than -856 Hounsfield units) and for the AT segment score (Panels E and F). Conclusion: Patients with TSLP-high asthma, as defined by TSLP protein levels in sputum, have higher mucus plug scores and increased air trapping. 1. Nordenmark L et al. NEJM Evid 2023. DOI: 10.1056/EVIDoa2300135