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

BACKGROUND

Patients with aspirin-exacerbated respiratory disease (AERD) frequently experience alcohol-induced respiratory reactions, the immunologic mechanism of which remains unknown. Many East Asian patients experience intense alcohol-induced skin flushing, which is due to an alcohol dehydrogenase 2 (ALDH2) polymorphism that leads to impaired alcohol metabolism and acetaldehyde buildup.

OBJECTIVE

We sought to determine whether AERD-related alcohol reactions are attributable to ALDH2 deficiency in the respiratory tract.

METHODS

AERD patients (N = 600) completed a survey to assess alcohol-induced symptoms and disease severity; urinary leukotriene E4 and prostaglandin D2 were quantified in a subgroup (n = 72). ALDH2 protein and transcript were measured in surgically excised sinus tissue and sorted sinus epithelial cells (EpCs), and in cultured respiratory EpCs before and after IL-4/IL-13 stimulation. ALDH2 expression was assessed in nasal scrapings from AERD patients before and after dupilumab and mepolizumab.

RESULTS

Alcohol-induced upper respiratory, lower respiratory, and skin-flushing symptoms were reported by, respectively, 79.6%, 45.1%, and 38.8% of AERD patients. Patients who experienced alcohol-induced respiratory reactions had faster postoperative polyp regrowth, worse baseline sinus disease and asthma control, and higher urinary eicosanoids than did those without alcohol reaction. Treatment with dupilumab or daily aspirin improved alcohol-induced symptoms for most patients. Nasal polyp ALDH2 protein and nasal EpC ALDH2 transcripts were lower in AERD patients than in aspirin-tolerant controls. In vitro stimulation with IL-4/IL-13 decreased ALDH2 expression in EpC cultures. In vivo inhibition of IL-4Rα with dupilumab increased nasal ALDH2 transcript.

CONCLUSION

Acquired ALDH2 enzyme deficiency within the respiratory tract in AERD, likely as a result of high local levels of IL-4 and IL-13, may prevent the degradation of alcohol-derived acetaldehyde, leading to mast cell activation and alcohol-induced respiratory reactions.