Study Uncovers Potential Drivers of Idiopathic Subglottic Stenosis

Gelbard A, Shilts MH, Hoke A, Strickland B, et al. Idiopathic Subglottic Stenosis and the Epithelial Interface of Host and Environment. J Am Coll Surg. August 2026. 

Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult White women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution have previously limited substantive mechanistic investigation into iSGS pathogenesis.

Harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, Gelbard and colleagues provide an unbiased characterization of the cell subsets present in the proximal airway scar and detail their molecular phenotypes.

Airway epithelium in patients with iSGS is depleted of basal progenitor cells and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of patients with iSGS rather than disrupted bacterial community structure. 

However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched patients with iSGS and healthy controls. Clinical outcome data from patients with iSGS suggest that surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.

These novel data support an iSGS disease model in which epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Overall, these results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.