DISCUSSION
To our knowledge, few studies have focused on describing clinical
features of ACEi-AE attacks in a cohort of patients with a diagnosis
defined and confirmed by follow-up. Our results can be summarized as
follows: (1) overdiagnosis of ACEi-AE is frequent at baseline, with at
least a third of patients later reclassified as having histaminergic AE;
(2) in our probable ACEi-AE population, attacks occurred mostly in
elderly men, with a highly variable delay from ACEi introduction, and
preferential involvement of oral cavity and throat; (3) classical
histaminergic features (such as history of allergy and atopic
conditions, attacks with preferential evening onset and spontaneous
resolution < 24h) seemed non-rarely reported in ACEi-AE
patients; (4) ACEi-AE attacks appear refractory to histamine-mediated AE
treatments (antihistamine, corticosteroids and adrenalin) and sensitive
to bradykinin-mediated AE treatments (tranexamic acid, icatibant and
C1-INH).
Diagnosis of ACEi-AE is usually suspected in patients presenting with an
AE attack, no urticaria and exposure to ACEi. However, idiopathic
histaminergic AE, a frequent condition, can also occur in patients
treated by ACEi; and there is no definitive way to discriminate between
these 2 mechanisms at referral. This is a major issue, as it yields
important therapeutic consequences (treatment modalities of AE attacks,
unnecessary eviction of ACEi in case of misdiagnosed histaminergic
AE…). Follow-up can help better differentiate these 2 mechanisms,
as occurrence of urticaria and/or AE attacks after 6 months of ACEi
discontinuation pleads for histaminergic AE. Using follow-up data, our
study suggested that at least a third of patients referred for a
suspected ACEi-AE were actually misdiagnosed idiopathic histaminergic
AE. This highlights the relevance of performing systematic follow-up in
these patients.
In order to avoid mistakenly-included histaminergic AE, we used a strict
definition of ACEi-AE, using long-term follow-up. In this population,
most of our results supported previous data from other studies with
different designs (Table 2 ) (4,8,11–23): male predominance
(although this is not consistently reported), elderly population, highly
variable delay between ACEi introduction and first attack, preferential
involvement of oral cavity (especially lips and tongue) and throat.
Interestingly, our data suggest that patients with probable ACEi-AE can
present with classical histaminergic features. History of allergy and
atopic conditions were reported in at least 20% of patients, although
this stays within range of the prevalence of atopy in the general
population (24). AE attacks with preferential evening onset and
spontaneous resolution <24h occurred in about 25% of our
patients. Previous studies have yielded heterogeneous results regarding
the duration of untreated ACEi-AE attacks, which can be explained by the
difficulty to accurately delineate the beginning and end of an attack
(notably onset of symptom relief vs complete resolution) and the
possible inclusion of idiopathic histaminergic AE(4,17,19–21).
Nonetheless, spontaneous resolution <24h have previously been
reported (4,23). Only one work has previously studied the time of day of
ACEi-AE onset, suggesting that attacks frequently occurred outside
regular work hours (11). ACEi-AE consists in bradykinin-mediated
attacks, which are traditionally described as occurring at any time of
day and lasting at least 24h. However, this classical semiology
description mainly stems from hereditary AE patients; and these
characteristics may not all apply to other types of bradykinin-mediated
attacks (25). Overall, these data suggest that clinical features alone
seem insufficient to discriminate between ACEi-AE and histaminergic AE
at referral; and highlight an unmet need for diagnostic biomarkers.
Interestingly, our study confirmed that icatibant, a bradykinin receptor
antagonist, seems effective in ACEi-AE attacks. Data regarding the
efficiency of icatibant in this indication are conflicting, with one
randomized clinical trial favoring treatment (20) and two others
observing no difference from placebo (18) In line with other real-life
data (15–17), our results plead for using icatibant in ACEi-AE
patients, as now recommended in some expert guidelines (9).
Our study draws strength from its originality, as it uses an innovative
and strict definition of ACEi-AE and focused heavily on the follow-up of
a suspected ACEi-AE population to ascertain the diagnosis. It also has
some limitations that mainly stem from its retrospective design, missing
data and small sample size. Excluding patients with no follow-up data
may have biased the study population; however, since it is a common
practice in our department to perform at least one systematic follow-up
visit to patients referred for ACEi-AE, we believe this had only a
limited effect.