Reduced aldehyde dehydrogenase 2 in respiratory tract associates with dysregulated alcohol metabolism and respiratory reactions in aspirin-exacerbated respiratory disease.

Summary

In a 600-patient AERD cohort, alcohol-induced upper and lower respiratory symptoms were common and associated with worse disease control and higher eicosanoids. Respiratory tract ALDH2 expression was reduced in AERD, downregulated by IL-4/IL-13 in vitro, and increased after IL-4Rα blockade with dupilumab. Findings support an acquired, type 2 inflammation–mediated ALDH2 deficiency causing acetaldehyde accumulation and mast cell activation during alcohol exposure.

Key Findings

• Alcohol-induced upper (79.6%) and lower (45.1%) respiratory symptoms were frequent in AERD and associated with worse sinus/asthma control and higher urinary eicosanoids.
• ALDH2 protein in nasal polyps and ALDH2 transcripts in nasal epithelial cells were lower in AERD than aspirin-tolerant controls.
• IL-4/IL-13 reduced ALDH2 expression in epithelial cultures; dupilumab increased nasal ALDH2 transcripts in vivo and improved alcohol-induced symptoms in most patients.

Clinical Implications

Counsel AERD patients regarding alcohol triggers; consider that IL-4/IL-13–targeted therapy (e.g., dupilumab) may mitigate alcohol-induced respiratory reactions and potentially normalize epithelial ALDH2. ALDH2 expression may serve as a biomarker of symptom susceptibility.

Limitations

• Observational design without randomized allocation to biologic therapy
• Potential confounding by genetic ALDH2 polymorphisms and alcohol exposure quantification not fully detailed

Future Directions

Prospective trials to test whether IL-4Rα blockade reduces alcohol-induced reactions; evaluate ALDH2 as a predictive biomarker and explore local epithelial metabolic reprogramming in AERD.