Identification of Two Distinct Molecular Endotypes in Cough Variant Asthma Based on Sputum Transcriptomics and Clinical Pathophysiological Features

Rationale Asthmatic cough may not respond well to corticosteroids. The underlying mechanisms and heterogeneity of cough variant asthma (CVA) remain poorly understood. Objectives To explore airway immunologic mechanisms and identify molecular endotypes in CVA by analyzing sputum transcriptomics, clinical, and pathophysiological characteristics. Methods RNA sequencing and cytokine measurement were performed on sputum samples from newly diagnosed patients with CVA (n=78), classic asthma (CA, n=28), and healthy controls (HC, n=28). CVA were treated and followed up for 6 months. Results The majority of differentially expressed genes in CVA versus HC overlapped with those identified in CA versus HC. However, the type 2 immunity co-expression network in CVA was lower than that in CA. Based on sputum transcriptomics profiles, two endotypes of CVA were identified: mixed-inflammatory CVA (n=40) and pauci-inflammatory CVA (n=32). Mixed-inflammatory CVA showed higher inflammation-related gene set signatures compared to both pauci-inflammatory CVA and HC. Mixed-inflammatory CVA also showed elevated levels of eosinophils, neutrophils, Type 2, Type 1 and Type 3 cytokines in sputum compared to HC. Conversely, Pauci-inflammatory CVA had slightly elevated sputum eosinophils but no significant those gene signatures and cytokine differences compared to HC. During 6 months follow-up, pauci-inflammatory CVA showed a trend of less complete resolution in cough (56.2% versus 80.0%, p=0.0553) compared to mixed-inflammatory CVA. Kaplan–Meier analysis found significant higher cough persistence in pauci-inflammatory versus mixed-inflammatory CVA. Conclusions CVA exhibits overlapping but distinct airway transcriptomics profiles compared to CA. Two distinct molecular endotypes are identified in CVA, presenting different clinical and pathophysiological features.