Isolated angioedema in the emergency department: rarely an allergic reaction

Angioedema is a common, potentially life-threatening emergency characterized by swelling of subcutaneous or submucosal tissues. While allergic reactions are common, a substantial proportion of ED angioedema presentations, particularly those without urticaria, involve non-allergic, bradykinin-mediated mechanisms. Differentiating between these pathways is critical, as standard anaphylaxis treatments like epinephrine are often ineffective for non-allergic variants. A key clinical indicator is the presence or absence of urticaria; isolated angioedema is rarely an allergy and suggests a bradykinin-driven aetiology. Common non-allergic causes include ACE inhibitors, DPP-IV (dipeptidyl peptidase IV) inhibitors, neprilysin inhibitors and C1-esterase inhibitor deficiencies. Mislabelling these conditions as "allergies" can lead to inappropriate management, unnecessary intubations, and significant patient distress. Diagnostic tools such as serum tryptase, C4 levels, and C1-inhibitor function tests are essential for accurate classification, but the results are not available at the acute moment. Effective treatment requires a targeted approach based on the underlying mechanism, including antihistamines for histamine-mediated reactions and on-demand therapies for bradykinin-mediated hereditary angioedema, such as C1-esterase inhibitor concentrate, icatibant, and the recently approved oral kallikrein inhibitor sebetralstat. This article provides a clinical framework to help emergency physicians identify the correct underlying mechanism. Ultimately, accurate diagnosis facilitates appropriate specialist referral and improves long-term patient outcomes.