D2.25 - Epicutaneous responses to Bradykinin Receptor 1 and 2 agonists, Histamine, and mast cell agonists in Angiotensin Converting Enzyme Inhibitor angioedema

Angiotensin converting Enzyme inhibitors (ACEI) are cornerstone treatments for several cardiovascular diseases. The major life-threatening, treatment-limiting adverse reaction to ACEI is angioedema (AE-ACEI) occurring in up to 1%.  SNPs in the BK1R are leading GWAS signals for AE-ACEI, however there is very limited data confirming increased circulating Bradykinin (BK). We hypothesised that increased BK-receptor sensitivity and/or non-IgE mast cell degranulation may be involved. 

We conducted a pilot case-controlled study enrolling patients with a history of AE-ACEI, matched  ACEI drug-tolerant controls (MC), and healthy controls (HC) from 20 May to 23 September 2025 . No antihistamines and corticosteroids for 14 days before skin-prick testing (SPT) was allowed. SPTs were performed per ASCIA guidelines, and done in duplicate. Sterile saline, histamine, and 18 aeroallergens SPTs were performed on the volar surface of the right arm while BK (B2 agonist), Lys-des-Arg-9-bradykinin (Lda-BK, B1 agonist), Icatibant (MRGPRX2 agonist), Codeine and Morphine (both non-IgE mast-cell agonists)  SPTs were done concurrently on the volar surface of the left arm. All SPT were read after 20 minutes, planimetry was performed using the Sketch And Calc Area Calculator.

A total of 34 participants were enrolled but four were excluded from final analysis - three had dermatographism, and one chronic corticosteroid use. Overall, 18 AE-ACEI cases, nine MC, and three HC were analysed. The mean (SD) age was 52 (±14) years, and 46.7% were female. No significant differences in total serum IgE, IgE sensitisation patterns or epicutaneous responses to BK, Lda-BK, Icatibant, Codeine, Morphine, Histamine, and various aeroallergens was found between groups. Analyses were performed using either wheal diameter (mm) or wheal surface area (mm²). In the MC, ACEI use potentiated the bradykinin, codeine, and morphine wheal size, but the findings did not reach significance.

No alterations in skin test responses to BK, Lda-BK, MCGPRX2 and other non-IgE mast-cell agonists were evident between AE-ACEI cases and drug-tolerant controls. Thus, increase BK or MCGPRX2 sensitivity amongst AE-ACEI is unlikely, although mucosal sites, such as the oropharynx, most frequently involved in AE-ACEI may differ from skin and further research is required.