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.