INTRODUCTION
Hereditary Angioedema (HAE) is a rare genetic disorder, resulting from either low production or dysfunctional regulatory enzyme (C1-esterase Inhibitor, C1-INH), whose major role is to control biochemical pathways leading to endothelial permeability. 1 It is clinically expressed by recurring bouts of edema (swelling) in various organs and tissues.2-3 Recurrent and unpredicted attacks may be triggered by tissue trauma, inflammation, hormones or medications. 3 As a lifetime illness, the burden of HAE on individuals, families and health-providing systems is considerably high.4-5 Moreover, attacks involving the oropharyngeal region, if not promptly identified and treated, may become life-threatening due to asphyxiation.6
Premonitory signs or symptoms (Prodromes) have been observed as preceding attacks from the early descripitons of HAE.7Prodromes are manifested by clinically complex signals, subjective (”symptoms”) and objective (”signs”), preceding the physical attacks (Table I).8 However, their significance has not been sufficiently substantiated so far and the mechanisms of its pathophysiology are yet unknown.8 Despite this knowledge gap, recent data suggests that a large majority of HAE patients report portending perceptions before attacks and many are able to predict oncoming attacks by experiencing a prodrome.9-12. In contrast to the ample data available on HAE attacks, triggers, clinical features and their effect on health-realted quality of life (HRQoL), research of HAE prodromes is lagging, or limited to small series and observational studies. There is paucity of research on prodromes while systematic and validated instruments are not available. Another barrier for investigating prodromes and prodrome-attack associations is the lack of consensual definition of prodromes’ main attributes. 12 As a result, prodromes have not been properly investigated by a scientific, systematic and methodical manner and their relation to attacks are not sufficiently established.8
Theoretically, if applied in clinical practice, early awareness of a prodrome can alert the patients to oncoming attacks and enable to deploy therapeutic strategies to attenuate the attacks (prodrome-triggered interventions).12
To close this gap, we constructed and validated a new HAE specific instrument, capable of assessing the predictive power of prodromes as early warning signs.13 This instrument, HAE Evaluation of Prodromes and Attacks (HAE-EPA), can now be utilized to assess the critical domains and dimensions of the prodromes and attacks and investigate their associations.