The US Hereditary Angioedema Association (HAEA) Scientific Registry: Triggers and prodromes

Triggers and prodromes have been reported as preludes to hereditary angioedema (HAE) attacks.

To describe the clinical characteristics of triggers, prodromes, and their relationships to attack onset, using data from the US Hereditary Angioedema Association Scientific Registry.

Clinical data concerning trigger and prodrome types, frequency, and the likelihood of having a subsequent attack were extracted from the Scientific Registry. Data were compiled from both HAE due to C1 inhibitor deficiency (HAE-C1INH) and angioedema nonmast cell-mediated with normal C1INH (ANM-nl-C1INH) cohorts.

In the HAE-C1INH cohort, 458 of 485 patients recorded triggers, with stress the most frequent (91.5%), followed by minor trauma (83.2%) and infection (67.3%). Hormonal triggers were the most likely to always be followed by an attack. Prodromal symptoms were reported by 399 (82.3%), with the most frequent being nonitchy rash (78.7%), sense/hunch (52.6%), tiredness/fatigue (47.2%), and tightness/prickling (45.8%). A prodromal sense/hunch of an impending attack was the most likely to always be followed by an attack (47.4%). In the ANM-nl-C1INH cohort, 83 of 96 patients documented 1 or more triggers, with stress being the most common (81.25%) and menses being the most likely to always be followed by an attack (38.5%). Prodromal symptoms were reported in 83 patients, with the most common being tightness/prickling (58.3%), tiredness/fatigue (56.3%), nonitchy rash (51.0%), and a sense/hunch (45.8%). The prodrome that had the highest percentage of always being followed by an attack was a tightness/prickling sensation (62.2%).

Our analysis highlighted the importance of stress and hormonal attack triggers. The sense/hunch of an impending attack was the most reliable prodrome for HAE-C1INH vs tightness/prickling in ANM-nl-C1INH. Erythema marginatum type eruptions were common in all patients. We hypothesize that triggers and prodromes are fundamentally interconnected with attacks of HAE through activation of kinin-generating pathways.