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\begin{document}

\title{Initial characteristics and follow-up of patients with a confirmed
diagnosis of angiotensin-converting enzyme inhibitors-induced angioedema}



\author[1]{Aurélien Chépy}%
\author[2]{Marie Véron}%
\author[3]{Sophie Gautier}%
\author[1]{Meryem-Maud Farhat}%
\author[1]{Ryadh Pokeerbux}%
\author[1]{Giorgia  Venturelli}%
\author[1]{Cécile Yelnik}%
\author[1]{Sylvain Dubucquoi}%
\author[1]{Céline Podevin }%
\author[1]{Manel Jendoubi}%
\author[1]{Isabelle Citerne}%
\author[3]{Jennifer Baraffe}%
\author[1]{Delphine  Staumont-Sallé}%
\author[1]{David Launay}%
\author[2]{Sébastien Sanges}%
\affil[1]{CHRU de Lille}%
\affil[2]{CHU Lille}%
\affil[3]{CHRU}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Differential diagnosis between angiotensin converting
enzyme inhibitors (ACEi) angioedema (AE) and idiopathic histaminergic AE
(ihAE) is often challenging. Follow-up data may help discriminate these
conditions but are scarcely reported. Our objective was to report on the
follow-up of patients with suspected ACEi-AE and to describe the
baseline characteristics of AE attacks in patients with a diagnosis
confirmed by follow-up. Methods: Sixty-four patients with suspected
ACEi-AE (i.e. with exposure to ACEi before first attack, no urticaria
associated and normal C1-inhibitor levels) and at least one follow-up
visit were included. Data were retrospectively collected at baseline and
during follow-up. Results: After follow-up, the diagnosis of ACEi-AE was
confirmed in only 30 patients. The remaining patients were reclassified
as ihAE (21 patients) or undetermined-mechanism AE (13 patients). In
ACEi-AE patients, attacks occurred mostly in men (61\%) with a median
age of 64 (interquartile range ?17) years old, with a highly variable
delay from ACEi introduction (23?103 months), and preferential
involvement of lips (50\%), tongue (47\%) and throat (30\%). Patients
with confirmed ACEi-AE frequently reported classical histaminergic
features, such as history of allergy and atopic conditions (20\%),
attacks with preferential evening onset (25\%) and spontaneous
resolution \textless{}24h (26\%). ACEi-AE attacks responded to icatibant
(79\%). Conclusion: A final diagnosis of ihAE is frequent in patients
with an initial suspicion of ACEi-AE; and follow-up should be
systematically performed to ascertain the diagnosis in this population.
Baseline clinical features seem insufficient to accurately discriminate
between ACEi-AE and histaminergic AE, highlighting an unmet need for
diagnostic biomarkers.%
\end{abstract}%



\sloppy


\textbf{TITLE} \textbf{PAGE}

\emph{Title:} \textbf{Initial characteristics and follow-up of patients
with a confirmed diagnosis of angiotensin-converting enzyme
inhibitors-induced angioedema}

Authorship:

Aur\selectlanguage{ngerman}élien Chepy\textsuperscript{1,2,3,4, *}, Marie
Veron\textsuperscript{4,5, *}, Sophie Gautier\textsuperscript{6},
Meryem-Maud Farhat\textsuperscript{3,4}, Ryadh
Pokeerbux\textsuperscript{3,7}, Giorgia Venturelli\textsuperscript{3},
Cécile Yelnik\textsuperscript{2,3,7,8}, Sylvain
Dubucquoi\textsuperscript{1,2,4,9}, Céline Podevin\textsuperscript{3},
Manel Jendoubi\textsuperscript{1,2,4}, Isabelle
Citerne\textsuperscript{3,4}, Jennifer Baraffe\textsuperscript{3,4},
Delphine Staumont-Sallé\textsuperscript{1,2,4,5, \$}, David
Launay\textsuperscript{1,2,3,4, \$}, Sébastien
Sanges\textsuperscript{1,2,3,4}

1. Univ. Lille, U1286 - INFINITE - Institute for Translational Research
in Inflammation, F-59000 Lille, France

2. Inserm, F-59000 Lille, France

3. CHU Lille, Département de Médecine Interne et Immunologie Clinique,
F-59000 Lille, France

4. Centre de Référence des Angi\selectlanguage{polish}œ\selectlanguage{english}d\selectlanguage{ngerman}èmes à Kinines, F-59000 Lille, France

5. CHU Lille, Département de Dermatologie, F-59000 Lille, France

6. Univ. Lille, Inserm, CHU Lille, UMR-S1172, Center for
Pharmacovigilance, F-59000 Lille, France

7. CHU Lille, Département de Médecine Polyvalente Post-Urgences, F-59000
Lille, France

8. Univ. Lille, U1167 - RIDAGE - Risk factors and molecular determinants
of aging-related diseases, F-59000 Lille, France

9. CHU Lille, Laboratoire d'Immunologie, F-59000 Lille, France

*AC and MV contributed equally to this work.

\textsuperscript{\$}DSS and DL contributed equally to this work.

Corresponding author:

Dr Sébastien SANGES

Département de Médecine Interne et Immunologie Clinique, Rue Michel
Polonovski, Hôpital Huriez, CHU Lille, F-59037 Lille Cedex, France.

Tel: + 33 (0)362943855; Fax: + 33 (0)320445459

E-mail: sebastien.sanges@univ-lille.fr

\textbf{Type of manuscript:} Original article

\textbf{Word count: 2161}

\textbf{Key Words:}

Angioedema

ACE inhibitors

Chronic urticaria

Bradykinin-mediated angioedema



\textbf{ABBREVIATION LIST}

\textbf{ACEi:}angiotensin-converting enzyme (ACE) inhibitors

\textbf{AE:} angioedema

\textbf{C1-INH:} C1 inhibitor

\textbf{EENT:} Eyes, Ears, Nose and Throat

\textbf{IgE:} immunoglobulin E

\textbf{NSAIDs:} non-steroidal anti-inflammatory drugs

\textbf{TSH:} thyroid-stimulating hormone

\textbf{STATEMENTS}

Conflicts of interest

SS reports travel grants from Shire, Sanofi-Genzyme and SOBI, outside
the submitted work. DSS reports research grants from Abbvie,
Astrazeneca, Boehringer, Amgen/Celgène, Galderma, Eli Lilly, Leo Pharma,
Novartis, Sanofi-Regeneron; board memberships from Abbvie, Astra-Zeneca,
Eli Lilly, Leo Pharma, Janssen, Novartis, Sanofi, Pfizer; and speaker
fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi; all
outside the submitted work. DL reports personal fees from Actelion,
grants and personal fees from Takeda, grants and personal fees from CSL
Behring, outside the submitted work.

AC, MV, SG, MMF, RP, GV, CY, SD, CP, MJ, IC and JB reports no conflict
of interest.

Author contributions

All individuals listed as authors met the ICMJE guidelines for
determining authorship. AC, MV, DSS, DL and SS contributed to the
conception and design of the study. AC, MV, MMF, RP, GV, CY, MJ, IC, JB,
DL and SS screened patients and collected clinical data. SD and CP
extracted biological data. AC and MV constituted the database, performed
statistical analyses and wrote the first draft of the manuscript. SS
made major revisions to the manuscript. SG provided her pharmacological
expertise. DSS provided her expertise on histaminergic AE. DL provided
his expertise on bradykinin-mediated AE. All authors read and approved
the submitted version.

Funding

No specific funding was obtained for this work.

Acknowledgments

None.

Data availability statement

The datasets used and/or analyzed during the current study are available
from the corresponding author upon reasonable request from any qualified
researcher.

Ethic statement

The study complied with the recommendations of the Helsinki declaration.
French legislation on noninterventional studies does not require ethics
committee approval for the use of de-identified data collected during
patient care. The data were de-identified and complied with the
requirements of the ``\emph{Commission Nationale de l'Informatique et
des Libertés} '' (CNIL), the organization responsible for ensuring the
ethical use of data collected for scientific purposes in France. The
CNIL approved the methods used to collect and analyze data from our
patient database (approval \#DEC20-211).

French legislation on noninterventional studies requires collecting the
non-opposition of patients but does not require written consent. As
such, non-opposition was confirmed from each patient included in the
study for the use of their de-identified medical record data.





\textbf{ABSTRACT}

\emph{Introduction:} Differential diagnosis between angiotensin
converting enzyme inhibitors (ACEi) angioedema (AE) and idiopathic
histaminergic AE (ihAE) is often challenging. Follow-up data may help
discriminate these conditions but are scarcely reported. Our objective
was to report on the follow-up of patients with suspected ACEi-AE and to
describe the baseline characteristics of AE attacks in patients with a
diagnosis confirmed by follow-up.

\emph{Methods}\textbf{:} Sixty-four patients with suspected ACEi-AE
(\emph{i.e.} with exposure to ACEi before first attack, no urticaria
associated and normal C1-inhibitor levels) and at least one follow-up
visit were included. Data were retrospectively collected at baseline and
during follow-up.

Results: After follow-up, the diagnosis of ACEi-AE was confirmed in only
30 patients. The remaining patients were reclassified as ihAE (21
patients) or undetermined-mechanism AE (13 patients). In ACEi-AE
patients, attacks occurred mostly in men (61\%) with a median age of 64
(interquartile range ±17) years old, with a highly variable delay from
ACEi introduction (23±103 months), and preferential involvement of lips
(50\%), tongue (47\%) and throat (30\%). Patients with confirmed ACEi-AE
frequently reported classical histaminergic features, such as history of
allergy and atopic conditions (20\%), attacks with preferential evening
onset (25\%) and spontaneous resolution \textless{}24h (26\%). ACEi-AE
attacks responded to icatibant (79\%).

\emph{Conclusion:} A final diagnosis of ihAE is frequent in patients
with an initial suspicion of ACEi-AE; and follow-up should be
systematically performed to ascertain the diagnosis in this population.
Baseline clinical features seem insufficient to accurately discriminate
between ACEi-AE and histaminergic AE, highlighting an unmet need for
diagnostic biomarkers.



\textbf{INTRODUCTION}

Angioedema (AE) is characterized by swelling of the deep dermis,
subcutaneous tissue, or mucous membranes. A distinction is made between
histamine-mediated AE, due to histaminoliberation (anaphylactoid
reaction, drug-induced, chronic idiopathic histaminic AE), and
bradykinin-mediated AE (1,2). Bradykinin, similarly to histamine, is a
vasodepressor that relaxes vascular smooth muscle cells, lowers blood
pressure and increases vascular permeability (3). Bradykinin-mediated AE
can be caused by C1 inhibitor (C1-INH) deficiency (either genetic or
acquired), by genetic mutations with a normal C1-INH (like factor XII or
plasminogen mutations), or by bradykinin-releasing drugs, such as
angiotensin-converting enzyme inhibitors (ACEi) (4,5).

It is estimated that 0.1 to 0.7\% of patients treated with ACEi develop
ACEi-induced angioedema (ACEi-AE) (2,5--7). Attacks usually appear
within the first 3 months of treatment, but can develop at any time
during the treatment course, even several years after its initiation
(6,8). As they are bradykinin-mediated, urticaria is deemed to never
occur during ACEi-AE attacks. So far, there is no validated set of
diagnostic criteria and no specific biomarker for ACEi-AE; and the
diagnosis can only be made with certainty on a retrospective basis, in
the absence of urticaria and relapse after at least 6 months of
treatment discontinuation (9,10).

Thus, the initial management of a patient presenting with a first AE
attack, no urticaria and ACEi treatment can be difficult, as it is not
always easy to discriminate between a first attack of an undiagnosed
idiopathic histaminergic AE and ACEi-AE. Few studies have tried to
determine the attack characteristics that are specific to ACEi-AE; and
since most of them did not follow up patients after treatment cessation,
they may have mistakenly included idiopathic histaminergic AE
(8,11--13).

The objective of this study was thus to report on the follow-up of
patients with suspected ACEi-AE and to describe the baseline
characteristics of patients and AE attacks in a population with a
definitive diagnosis of ACEi-AE, confirmed by a long-term follow-up.



\textbf{METHODS}

Study population

This was a retrospective study conducted in our national reference
center for bradykinin-mediated AE in Lille University Hospital (CREAK,
France). Eligible patients were identified by screening our consultation
database using the diagnostic code for AE. They were included if they
met all the following criteria: (1) confirmed diagnosis of AE; (2)
treatment by ACEi concomitant to at least one AE attack; (3) normal
C1-INH levels and activity; (4) baseline visit between January
1\textsuperscript{sts} 2014 and December 31\textsuperscript{st}, 2019;
(5) at least one follow-up visit at least 6 months after ACEi cessation.

Patients whose diagnosis of ACEi-AE could readily be refuted based on
baseline visit data (\emph{i.e.,} patients with urticaria before or
during AE attacks, or with AE attacks before ACEi introduction) were
excluded from the study, as there is usually no diagnostic challenge
regarding the AE mechanism and no therapeutic hesitation in this
situation.

The remaining patients were classified in 3 different groups based on
follow-up data. Patients were classified as ``\emph{undetermined AE} ''
if follow-up data did not allow to properly discriminate between ACEi-AE
and histaminergic AE (\emph{i.e.,} no recurrence of AE attacks after
ACEi cessation but with concomitant introduction of prophylactic
treatment by antihistamine and/or corticosteroids). They were classified
as ``\emph{probable histaminergic AE} '' if they met at least one of the
following criteria: (1) recurrence of AE after the
6\textsuperscript{th}month of ACEi withdrawal; (2) no recurrence of AE
despite re-exposure to ACEi; (3) occurrence of urticaria during
follow-up. They were classified as ``\emph{probable ACEi-AE} '' in any
other cases.

Data collection

Relevant data were retrospectively retrieved from medical records at
baseline visit (defined as the first consultation in our centre) and up
until the last follow-up visit. At baseline, we collected patient
characteristics (age, gender, previous medical history of relevant
conditions), treatment data (date of introduction and withdrawal of
bradykinin-releasing drugs, antihistamines, corticosteroids and/or
non-steroidal anti-inflammatory drugs (NSAIDs)), AE attack
characteristics (total number, triggering factors, prodromes,
localization, associated signs, duration, attack treatments) and
biological results (serum complement, eosinophils, immunoglobulin E
(IgE), tryptase, thyroid-stimulating hormone (TSH), anti-thyroglobulin
and anti-thyroperoxydase levels). During follow-up, we assessed ACEi
discontinuation and/or re-exposure, recurrence of AE attacks (and their
characteristics), occurrence of atopic manifestations and/or typical
lesions of urticaria and therapeutic data (treatment by
bradykinin-releasing drugs, antihistamines, corticosteroids and/or
NSAIDs).

Statistical analyses

Characteristics of the population were described using median (±
interquartile range) for quantitative variables, and number (percentage)
for qualitative variables. Comparison between ``probable histaminergic
AE'' and ``probable ACEi-AE'' groups was performed using Fisher's exact
test for qualitative variables and Mann-Whitney's test for quantitative
variables. Statistical analyses were carried out using Graph Pad Prism
v8 software. Significance was set at \emph{p} \textless{}0.05.



\textbf{RESULTS}

Classification of patients

Among the 507 patients screened (\emph{Figure 1} ), 92 were referred for
a suspected ACEi-AE, with a first visit between 2014 and 2019 and at
least one follow-up visit. Among them, 28 patients were excluded because
the diagnosis of ACEi-AE was immediately refuted (due to occurrence of
urticaria or AE attacks before ACEi introduction). This left 64 patients
with a possible ACEi-AE based on the data available at baseline visit.

These 64 patients were classified in 3 groups based on data collected
during a median follow-up of 26.5 (±35.5) months. A first group of 13
patients (20\%) was considered to have ``undetermined AE'' because
follow-up did not allow to accurately discriminate between ACEi-AE and
histaminergic AE. A second group of 21 patients (33\%) was classified as
having ``probable histaminergic AE'': 6 due to occurrence of AE attacks
after the 6\textsuperscript{th} month of ACEi cessation; 14 due to
re-exposure to ACEi with no recurrence of AE; and 16 due to episodes of
urticaria. A third group comprising the 30 remaining patients (47\%) was
thus considered to have ``probable ACEi-AE''.

Characteristics of the ``probable ACEi-AE'' cohort at baseline

Using this reliable population, we next studied the baseline
characteristics of patients, ACEi exposure, AE attacks and laboratory
tests.

\emph{Patient characteristics}

Patients with ``probable ACEi-AE'' were mostly male (61\%) with a median
age of 64 (±17) years old at baseline (\emph{Table 1} ). Among them,
6/30 (20\%) patients had previous history of allergy or atopic
conditions: atopic dermatitis in 2 cases, atopic rhinitis and
conjunctivitis in 1 case, food allergy in 2 cases, and asthma in 2
cases. None of them had previous history of autoimmune diseases.
Familial history of AE (4 patients, 13\%), of allergy or atopic
conditions (5 patients, 17\%) were also frequently reported.

\emph{Characteristics of ACEi exposure}

Patients were exposed to ACEi for a median of 23 (±103) months at
referral. ACEi were associated to another bradykinin-releasing drug in 5
patients (17\%): 4 with dipeptidyl peptidase-4 inhibitors and 1 with
angiotensin-receptor blockers.

\emph{Characteristics of AE attacks}

Patients had a median of 2 (±2) attacks at referral. The first attack
occurred a median of 2 (±20) months before referral. In at least 6/24
(25\%) patients, attacks usually happened in the evening, at night or
were noticed when waking up. Prodromes and triggering factors were
scarcely reported.

Attacks were mostly localized on the lips (15/30; 50\%), tongue (14/30;
47\%), throat (9/30; 30\%), uvula (3/30; 10\%), oral cavity (7/30;
23\%), and face (3/10; 10\%). Limbs, digestive tract and genitalia
attacks were not reported. No patient reported skin lesions of
urticaria; and only one mentioned mild pruritus during an attack. ENT
symptoms such as dyspnea (4/30; 13\%), dysphonia (7/30; 23\%) and
dysphagia (5/30; 17\%) were frequently noted.

Nine patients (30\%) reported occurrence of AE attacks that resolved
without treatment; and 8 (27\%) noted spontaneous resolutions within 24h
of AE onset. Classical treatments of histaminergic AE attacks were
nearly never reported as effective: antihistamines (1/19; 5\%),
corticosteroids (1/18; 6\%), adrenalin (0/3; 0\%). When used, patients
seemed to respond to treatments of bradykinin-mediated attacks more
consistently: tranexamic acid (7/10; 70\%), icatibant (15/19; 79\%) and
C1-INH concentrate (3/4; 75\%). No patient required airway control.

\emph{Biological characteristics}

Elevated IgE, tryptase and eosinophil levels were documented in 4, 1 and
2 cases, respectively. None had abnormal TSH levels,
anti-thyroperoxydase or anti-thyroglobulin antibodies.

\textbf{Discriminating features between ``probable ACEi-AE''
and``probable histaminergic AE'' patients at baseline}

As to better identify clinical features that could help discriminating
between the 2 AE mechanisms at referral, baseline characteristics of
probable ACEi-AE patients were compared to those of probable
histaminergic AE patients.

There was no statistically significant difference between the 2 groups.
Notably, classical histaminergic features such as evening onset and
duration \textless{} 24h were not significantly different between
probable ACEi-AE patients and probable histaminergic AE patients.



\textbf{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 \textless{} 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\ldots{}). 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 (\emph{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 \textless{}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 \emph{vs} complete resolution) and the
possible inclusion of idiopathic histaminergic AE(4,17,19--21).
Nonetheless, spontaneous resolution \textless{}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.

\textbf{CONCLUSION}

By examining follow-up data in patients with suspected ACEi-AE, our
study revealed that misdiagnosis is frequent in this population.
Patients with a diagnosis of ACEi-AE confirmed by follow-up had attacks
that could display characteristics classically associated with
histamine-mediated AE and were responsive to icatibant. These results
need to be confirmed on prospective studies performed on larger cohorts.



\textbf{REFERENCES}

1. Depetri F, Tedeschi A, Cugno M. Angioedema and emergency medicine:
From pathophysiology to diagnosis and treatment. Eur J Intern Med.
2019;59:8\selectlanguage{english}-13.

2. Stone C, Brown NJ. Angiotensin-converting Enzyme Inhibitor and Other
Drug-associated Angioedema. Immunol Allergy Clin North Am.
2017;37(3):483\selectlanguage{english}-95.

3. Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G.
Nonallergic angioedema: role of bradykinin. Allergy. 2007;62(8):842\selectlanguage{english}-56.

4. Agostoni A, Cicardi M, Cugno M, Zingale LC, Gioffre D, Nussberger J.
Angioedema due to angiotensin-converting enzyme inhibitors.
Immunopharmacology. 15 oct 1999;44(1\selectlanguage{english}-2):21\selectlanguage{english}-5.

5. Campo P, Fernandez TD, Canto G, Mayorga C. Angioedema induced by
angiotensin-converting enzyme inhibitors. Curr Opin Allergy Clin
Immunol. aout 2013;13(4):337\selectlanguage{english}-44.

6. Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme
inhibitor-induced angioedema: A review of the literature. J Clin
Hypertens Greenwich Conn. dec 2017;19(12):1377\selectlanguage{english}-82.

7. Mahmoudpour SH, Baranova EV, Souverein PC, Asselbergs FW, de~Boer A,
Maitland-van der Zee AH, et al. Determinants of angiotensin-converting
enzyme inhibitor (ACEI) intolerance and angioedema in the UK Clinical
Practice Research Datalink. Br J Clin Pharmacol. 2016;82(6):1647\selectlanguage{english}-59.

8. Banerji A, Clark S, Blanda M, LoVecchio F, Snyder B, Camargo CA.
Multicenter study of patients with angiotensin-converting enzyme
inhibitor-induced angioedema who present to the emergency department.
Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. avr
2008;100(4):327\selectlanguage{english}-32.

9. Nosbaum A, Bouillet L, Floccard B, Javaud N, Launay D, Boccon-Gibod
I, et al. Prise en charge des angi\selectlanguage{polish}œ\selectlanguage{english}d\selectlanguage{ngerman}èmes induits par les inhibiteurs de
l'enzyme de conversion de l'angiotensine~: recommandations du Centre de
référence national des angi\selectlanguage{polish}œ\selectlanguage{english}d\selectlanguage{ngerman}èmes. Rev Médecine Interne. 1 avr
2013;34(4):209\selectlanguage{english}-13.

10. Kostis WJ, Shetty M, Chowdhury YS, Kostis JB. ACE Inhibitor-Induced
Angioedema: a Review. Curr Hypertens Rep. 08 2018;20(7):55.

11. Pfaue A, Schuler PJ, Mayer B, Hoffmann TK, Greve J, Hahn J. Clinical
features of angioedema induced by renin-angiotensin-aldosterone system
inhibition: a retrospective analysis of 84 patients. J Community Hosp
Intern Med Perspect. 2019;9(6):453\selectlanguage{english}-9.

12. Sanchez-Borges M, Gonzalez-Aveledo LA. Angiotensin-converting enzyme
inhibitors and angioedema. Allergy Asthma Immunol Res. juill
2010;2(3):195\selectlanguage{english}-8.

13. Roberts JR, Lee JJ, Marthers DA. Angiotensin-converting enzyme (ACE)
inhibitor angioedema: the silent epidemic. Am J Cardiol. 1 mars
2012;109(5):774\selectlanguage{english}-5.

14. Weisman DS, Arnouk N, Asghar MB, Qureshi MR, Kumar A, Desale S, et
al. ACE inhibitor angioedema: characterization and treatment versus
non-ACE angioedema in acute hospitalized patients. J Community Hosp
Intern Med Perspect. 2020;10(1):16\selectlanguage{english}-8.

15. Malde B, Regalado J, Greenberger PA. Investigation of angioedema
associated with the use of angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers. Ann Allergy Asthma Immunol Off Publ Am
Coll Allergy Asthma Immunol. janv 2007;98(1):57\selectlanguage{english}-63.

16. Javaud N, Achamlal J, Reuter P-G, Lapostolle F, Lekouara A, Youssef
M, et al. Angioedema Related to Angiotensin-Converting Enzyme
Inhibitors: Attack Severity, Treatment, and Hospital Admission in a
Prospective Multicenter Study. Medicine (Baltimore). nov
2015;94(45):e1939.

17. Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J,
et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme
Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract.
oct 2017;5(5):1402-1409.e3.

18. Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, et
al. Effect of bradykinin receptor antagonism on ACE inhibitor-associated
angioedema. J Allergy Clin Immunol. juill 2017;140(1):242-248.e2.

19. Bas M, Greve J, Stelter K, Bier H, Stark T, Hoffmann TK, et al.
Therapeutic efficacy of icatibant in angioedema induced by
angiotensin-converting enzyme inhibitors: a case series. Ann Emerg Med.
sept 2010;56(3):278\selectlanguage{english}-82.

20. Ba\selectlanguage{polish}ş \selectlanguage{english}M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, et al. A
randomized trial of icatibant in ACE-inhibitor-induced angioedema. N
Engl J Med. 29 janv 2015;372(5):418-25.

21. Bova M, Guilarte M, Sala-Cunill A, Borrelli P, Rizzelli GML,
Zanichelli A. Treatment of ACEI-related angioedema with icatibant: a
case series. Intern Emerg Med. avr 2015;10(3):345-50.

22. Grant NN, Deeb ZE, Chia SH. Clinical experience with
angiotensin-converting enzyme inhibitor--induced angioedema. Otolaryngol
Neck Surg. 1 d\selectlanguage{ngerman}éc 2007;137(6):931\selectlanguage{english}-5.

23. Chiu A, Newkirk K, Davidson B, Burningham A, Krowiak E, Deeb Z.
Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema: A
Multicenter Review and an Algorithm for Airway Management. Ann Otol
Rhinol Laryngol. 1 oct 2001;110:834\selectlanguage{english}-40.

24. Thomsen SF. Epidemiology and natural history of atopic diseases. Eur
Clin Respir J. 2015;2.

25. Maurer M, Magerl M. Differences and Similarities in the Mechanisms
and Clinical Expression of Bradykinin-Mediated vs. Mast Cell--Mediated
Angioedema. Clin Rev Allergy Immunol {[}Internet{]}. 3 fevr 2021 {[}cite
15 fevr 2021{]}; Disponible sur:
https://doi.org/10.1007/s12016-021-08841-w

\textbf{FIGURE 1}

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/727550/articles/709296-initial-characteristics-and-follow-up-of-patients-with-a-confirmed-diagnosis-of-angiotensin-converting-enzyme-inhibitors-induced-angioedema}

\textbf{Figure 1 title: Flow chart of study}

\textbf{Figure 1 legend:} AE: angioedema; ACEi: angiotensin-converting
enzyme inhibitor; C1-INH: C1-inhibitor.

\emph{}

\textbf{TABLE 1}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \textbf{N} & \textbf{Value}\tabularnewline
\midrule
\endhead
\textbf{Male}, n (\%) & 30 & 19 (63\%)\tabularnewline
\textbf{Age at baseline visit} (years old), median (IQR) & 30 & 64
(17)\tabularnewline
\textbf{Duration of follow-up} (months), median (IQR) & 30 & 21
(37)\tabularnewline
Past medical history & &\tabularnewline
\textbf{Personal history of allergy or atopic conditions}, n (\%) & 30 &
6 (20\%)\tabularnewline
- Urticaria, n (\%) & & 0 (0\%)\tabularnewline
- Atopic dermatitis, n (\%) & & 1 (3\%)\tabularnewline
- Asthma, n (\%) & & 2 (7\%)\tabularnewline
- EENT atopy, n (\%) & & 1 (3\%)\tabularnewline
- Food allergy, n (\%) & & 2 (7\%)\tabularnewline
- Drug allergy, n (\%) & & 0 (0\%)\tabularnewline
\textbf{Personal history of autoimmune diseases}, n (\%) & 30 & 0
(0\%)\tabularnewline
\textbf{Familial history of AE}, n (\%) & 30 & 4 (13\%)\tabularnewline
\textbf{Familial history of allergy or atopic conditions}, n (\%) & 30 &
5 (17\%)\tabularnewline
- Urticaria, n (\%) & & 0 (0\%)\tabularnewline
- Atopic dermatitis, n (\%) & & 0 (0\%)\tabularnewline
- Asthma, n (\%) & & 3 (10\%)\tabularnewline
- EENT atopy, n (\%) & & 2 (7\%)\tabularnewline
- Food allergy, n (\%) & & 0 (0\%)\tabularnewline
- Drug allergy, n (\%) & & 0 (0\%)\tabularnewline
Incriminated treatment & &\tabularnewline
\textbf{Therapeutic class(es)} & 30 &\tabularnewline
- ACEi alone, n (\%) & & 25 (83\%)\tabularnewline
- ACEi + ARBs, n (\%) & & 1 (3\%)\tabularnewline
- ACEi + DPP-4i, n (\%) & & 4 (13\%)\tabularnewline
\textbf{Duration of exposure} (total in case of multiple exposures)
(months), median (IQR) & 26 & 23 (103)\tabularnewline
Characteristics of AE attack - onset & &\tabularnewline
\textbf{Number of attacks}, median (IQR) & 29 & 2 (2)\tabularnewline
\textbf{Time span between first and last attacks} (or first attack and
consultation) (months), median (IQR) & 30 & 2 (20)\tabularnewline
\textbf{Time of day of attack onset} & 24 &\tabularnewline
- Attacks preferentially occur in the evening or at night (or are
noticed when waking up), n (\%) & & 6 (25\%)\tabularnewline
- Attacks preferentially occur in the morning or the afternoon, n (\%) &
& 8 (33\%)\tabularnewline
- No preferential time of day identified, n (\%) & & 10
(42\%)\tabularnewline
\textbf{Presence of prodromes}, n (\%) & 29 & 1 (3\%)\tabularnewline
\textbf{Triggering factor}, n (\%) & 30 & 3 (10\%)\tabularnewline
Characteristics of AE attack - plateau & &\tabularnewline
\textbf{Affected sites} & 30 &\tabularnewline
- Lips, n (\%) & & 15 (50\%)\tabularnewline
- Tongue, n (\%) & & 14 (47\%)\tabularnewline
- Uvula, n (\%) & & 3 (10\%)\tabularnewline
- Oral cavity (excluding lips, tongue and uvula), n (\%) & & 7
(23\%)\tabularnewline
- Throat (pharynx, larynx), n (\%) & & 9 (30\%)\tabularnewline
- Face (excluding lips), n (\%) & & 3 (10\%)\tabularnewline
- Digestive tract, n (\%) & & 0 (0\%)\tabularnewline
- Genitalia, n (\%) & & 0 (0\%)\tabularnewline
- Upper limbs, n (\%) & & 0 (0\%)\tabularnewline
- Lower limbs, n (\%) & & 0 (0\%)\tabularnewline
\textbf{Cutaneous symptoms}, n (\%) & 30 & 1 (3\%)\tabularnewline
- Urticaria, n (\%) & & 0 (0\%)\tabularnewline
- Pruritus, n (\%) & & 1 (3\%)\tabularnewline
\textbf{ENT symptoms}, n (\%) & 30 & 10 (33\%)\tabularnewline
- Dyspnea, n (\%) & & 4 (13\%)\tabularnewline
- Dysphonia, n (\%) & & 7 (23\%)\tabularnewline
- Dysphagia, n (\%) & & 5 (17\%)\tabularnewline
\textbf{Digestive symptoms}, n (\%) & 30 & 0 (0\%)\tabularnewline
Characteristics of AE attack - resolution & &\tabularnewline
\textbf{Occurrence of attacks resolving without treatment}, n (\%) & 30
& 9 (30\%)\tabularnewline
Occurrence of attacks resolving \textless{}24h without treatment, n (\%)
& 30 & 8 (27\%)\tabularnewline
Duration of attacks without treatment (hours), median (IQR) & 9 & 24
(42)\tabularnewline
\textbf{Treatments of attacks} & &\tabularnewline
Antihistamines, n (\%) & 30 & 19 (63\%)\tabularnewline
- effective treatment, n (\%) & 19 & 1 (5\%)\tabularnewline
Corticosteroids, n (\%) & 30 & 18 (60\%)\tabularnewline
- effective treatment, n (\%) & 18 & 1 (6\%)\tabularnewline
Adrenalin, n (\%) & 30 & 3 (10\%)\tabularnewline
- effective treatment, n (\%) & 3 & 0 (0\%)\tabularnewline
Tranexamic acid, n (\%) & 30 & 10 (30\%)\tabularnewline
- effective treatment, n (\%) & 10 & 7 (70\%)\tabularnewline
Bradykinin B2-receptor antagonist (icatibant), n (\%) & 30 & 19
(63\%)\tabularnewline
- effective treatment, n (\%) & 19 & 15 (79\%)\tabularnewline
Human or recombinant C1-INH concentrate, n (\%) & 30 & 4
(13\%)\tabularnewline
- effective treatment, n (\%) & 4 & 3 (75\%)\tabularnewline
Upper airway control procedures, n (\%) & 30 & 0 (0\%)\tabularnewline
Biological characteristics & &\tabularnewline
Low CH50 levels, n (\%) & 30 & 0 (0\%)\tabularnewline
Low C4 levels, n (\%) & 30 & 0 (0\%)\tabularnewline
Low C1-INH levels, n (\%) & 30 & 0 (0\%)\tabularnewline
Low C1-INH activity, n (\%) & 30 & 0 (0\%)\tabularnewline
High IgE levels, n (\%) & 8 & 4 (50\%)\tabularnewline
High tryptase levels, n (\%) & 13 & 1 (7\%)\tabularnewline
Hyper-eosinophilia, n (\%) & 27 & 2 (7\%)\tabularnewline
Abnormal TSH, n (\%) & 20 & 0 (0\%)\tabularnewline
Positive anti-thyroperoxydase and/or anti-thyroglobulin antibodies, n
(\%) & 15 & 0 (0\%)\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1 title:} Characteristics of the probable ACEi-AE group

\textbf{Table 1 legend:} ACEi: angiotensin-converting enzyme inhibitors;
AE: angioedema; ARBs: angiotensin-receptor blockers; C1-INH:
C1-inhibitor; C4: complement fraction 4; CH50: total hemolytic
complement; DPP-4i: dipeptidyl peptidase-4 inhibitors; EENT: eyes, ears,
nose and throat; IgE: immunoglobulin E; NSAIDs: non-steroidal
anti-inflammatory drugs; TPO: anti-thyroperoxydase
antibodies\textbf{;}TSH: thyroid-stimulating hormone.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllllllllllll@{}}
\toprule
& \textbf{Present work} & \textbf{Weisman, 2020} & \textbf{Pfaue, 2019}
& \textbf{Sinert, 2017} & \textbf{Sinert, 2017} & \textbf{Straka, 2016}
& \textbf{Straka, 2016} & \textbf{Javaud, 2015} & \textbf{Bova, 2015} &
\textbf{Bas, 2015} & \textbf{Bas, 2015} & \textbf{Roberts, 2012} &
\textbf{Sanchez Borges, 2010} & \textbf{Bas, 2010} & \textbf{Bas, 2010}
& \textbf{Banerji, 2008} & \textbf{Grant, 2007} & \textbf{Malde, 2007} &
\textbf{Bas, 2005} & \textbf{Circadi, 2004} & \textbf{Chiu, 2001} &
\textbf{Agostoni, 1999}\tabularnewline
\midrule
\endhead
\textbf{Sample size} & 30 & 297 & 84 & 60 (placebo) & 61 (icatibant) &
18 (placebo) & 12 (icatibant) & 62 & 13 & 14 (placebo group) & 13
(icatibant group) & 91 & 9 & 47 (historical cohort) & 8 (icatibant) &
220 & 228 & 64 & 25 & 64 & 74 & 39\tabularnewline
\textbf{Study design} & retrospective & retrospective & retrospective &
prospective & prospective & prospective & prospective & prospective &
retrospective & prospective & prospective & retrospective &
retrospective & retrospective & retrospective & retrospective &
retrospective & retrospective & retrospective & retrospective &
retrospective & retrospective\tabularnewline
& case control & case control & descriptive & randomized controlled
trial (icatibant vs placebo in ACEi-AE) & randomized controlled trial
(icatibant vs placebo in ACEi-AE) & randomized controlled trial
(icatibant vs placebo in ACEi-AE) & randomized controlled trial
(icatibant vs placebo in ACEi-AE) & observational & case control &
randomized controlled trial (icatibant vs placebo in ACEi-AE) &
randomized controlled trial (icatibant vs placebo in ACEi-AE) &
descriptive & descriptive & case control & case control & descriptive &
descriptive & descriptive & case control & descriptive & case control &
case control\tabularnewline
& monocenter & multicenter & monocenter & multicenter & multicenter &
multicenter & multicenter & multicenter & monocenter & multicenter &
multicenter & multicenter & monocenter & monocenter & monocenter &
multicenter & monocenter & monocenter & monocenter & monocenter &
multicenter & monocenter\tabularnewline
\textbf{Study period} & 6 years & 4 years & 6 years & 2 years & 2 years
& 8 years & 8 years & 2,5 years & not mentioned & 18 months & 18 months
& 1 year & 5 years & 7 years & not mentioned & 2 years & 4,5 years &
13,5 years & 16 years & 10,5 years & 7 years & 6,5 years\tabularnewline
& 2014-2019 & 2013-2017 & 2010-2016 & 2013-2015 & 2013-2015 & 2007-2015
& 2007-2015 & 2012-2014 & & 2010-2011 & 2010-2011 & 2010-2011 &
2005-2009 & & & 2003-2005 & 1999-2004 & 1991-2004 & 1997-2003 &
1993-2002 & 1993-1999 & 1992-1998\tabularnewline
\textbf{ACEi-AE definition} & no urticaria no C1-INH deficiency no
attacks before introduction no recurrence after discontinuation & not
mentioned & no urticaria or pruritus no evidence of allergy no family
history of AE & no other cause of AE (hereditary, acquired, allergic) no
family history of AE no attacks before ACEi introduction no urticaria
inefficacy of standard therapy & no other cause of AE (hereditary,
acquired, allergic) no family history of AE no attacks before ACEi
introduction no urticaria inefficacy of standard therapy & no urticaria
or pruritus no attacks before ACEi introduction & no urticaria or
pruritus no attacks before ACEi introduction & no other cause according
to AE expert (no rash, no family history of AE, no C1-INH deficiency,
inefficacy of standard therapy) & no other cause (food allergy, insect
bite, drugs, infectious disease, C1-INH deficiency, inefficacy of
standard therapy) & based on expert opinion (exclusion of patients with
urticaria or with attacks before ACEi introduction) & based on expert
opinion (exclusion of patients with urticaria or with attacks before
ACEi introduction) & not mentioned & not mentioned & no other cause
(C1-INH deficiency, allergy, urticaria) no recurrence after
discontinuation & no other cause (C1-INH deficiency, allergy, urticaria)
no recurrence after discontinuation & based on investigators' opinion &
ICD-10 code of AE exclusion of AE from ''unrelated causes'' & based on
drug adverse reaction database & not mentioned (exclusion of allergic
reactions) & no other cause according to AE expert (no personal or
family history of allergy, no other causative agent, no C1-INH
deficiency) \emph{16\% had attacks before ACEi introduction and 13\%
after ACEi discontinuation} & diagnosis code of AE no other likely cause
(traumat, food allergy, medications) & based on expert
opinion\tabularnewline
\textbf{Inclusion criteria} & ACEi-AE referred to AE consult & ACEI-AE
admitted to ED & first attack of RAA-AE referred to ORL departement &
ACEI-AE admitted to ED & ACEI-AE admitted to ED & ACEI-AE admitted to ED
& ACEI-AE admitted to ED & ACEI-AE admitted to ED & ACEi-AE admitted to
ED and treated with icatibant & ACEI-AE admitted to ED & ACEI-AE
admitted to ED & ACEI-AE admitted to ED & ACEi-AE referred to allergy
department & ACEI-AE admitted to ED & ACEI-AE admitted to ED & ACEI-AE
admitted to ED & ACEI-AE admitted to ED & RAA-AE according to drug
adverse reaction database & ACEI-AE admitted to ED & ACEi-AE referred to
AE clinic & ACEI-AE admitted to ED & ACEi-AE referred to AE
clinic\tabularnewline
Patient characteristics & \emph{} & \emph{} & \emph{} & \emph{} &
\emph{} & \emph{} & \emph{} & \emph{} & \emph{} & \emph{} & \emph{} &
\emph{} & \emph{} & \emph{} & \emph{} & \emph{} & \emph{} & \emph{} &
\emph{} & \emph{} & \emph{} & \emph{}\tabularnewline
\textbf{Male} & 63\% & 43\% & 52\% & 42\% & 56\% & 33\% & 42\% & 56\% &
77\% & 57\% & 69\% & 45\% & 78\% & & 63\% & 38\% & 35\%\% & 40\% & 32\%
& 56\% & 26\% & 54\%\tabularnewline
\textbf{Age at baseline visit} & median 64 yo (IQR 17) & mean 62,8 yo
(SD 13,2) & median 71 yo (range 43-94) & mean 61.8 yo (SD 13.4) & mean
60.9 yo (SD 12.1) & mean 60.7 yo (SD 10.8) & mean 56.3 yo (SD 13.4) &
median 63 yo (IQR 54-74) & median 74 yo (IQR 52-86) & mean 69.4 yo (SD
16.6) & mean 62.4 yo (SD 9.7) & median 56 yo (range 26-93) & mean 63,4
yo (range 51-77) & mean 62 yo (SD 11) & range 61-91 yo & mean 60 yo (SD
14) & mean 61.6 yo (range 22-101) & median 59 yo (range 32-92) & mean
69,3 yo (SD 2,3) & median 63 yo (range 46-84) & & median 61 yo (range
40-82)\tabularnewline
\textbf{Follow-up} & median 21 mo (IQR 37) & none & none & 3 day after
discharge & 3 day after discharge & mean 4.36 (SD 2.19) y & mean 4.36
(SD 2.19) y & median 18 yo (IQR 11-30) & 1 visit (exact delay not
mentioned) & 1 visit 14d after discharge & 1 visit 14d after discharge &
none & none & mean 4.3 y & 3 to 6 months & none & & yes (exact duration
not mentioned) & yes (exact duration not mentioned) & median 11 mo
(range 1-80) & none & yes (minimum 6 mo)\tabularnewline
\textbf{Personal history of allergy or atopic conditions} & 20\% & & & &
& seasonal allergy 44\% & seasonal allergy 50\% & & & & & & & & &
asthma, 11\%; food allergy, 6\%; allergic rhinitis, 4\%; atopic
dermatitis, 1\% & & drug allergy 14\% & & & & 0\%\tabularnewline
ACEi exposure & & & & & & & & & & & & & & & & & & & & & &\tabularnewline
\textbf{Therapeutic class(es)} & & & & & & & & & & & & & & & & & & & & &
&\tabularnewline
- ACEi alone & 83\% & 96\% & 80\% & & & 95\% & 100\% & 95\% & 92\% & & &
& & & & & & & & 100\% & &\tabularnewline
- ACEi + ARBs & 3\% & 4\% & 5\% & & & 0\% & 0\% & 0\% & 0\% & & & & & &
& & & & & & &\tabularnewline
- ACEi + DPP-4i & 13\% & & 2\% & & & 5\% & 0\% & 5\% & 8\% & & & & & & &
& & & & & &\tabularnewline
\textbf{Duration of exposure} & median 23 mo (IQR 103) & & 59\% exposed
for \textgreater{} 12 mo & 25\% started within 90d of the attack & 27\%
started within 90d of the attack & mean 63 mo (SD 64) & mean 26 mo (SD
28) & median 12 mo (IQR 1-49) & median 48 mo (range 7-240) & & & & range
30min-2y & mean 37 mo (SD 25) & range 12-132 mo & mean 6 mo (range
1--18) & median 3 mo (range 0-120) & mean 1.8 y (range 1d-10y) & mean
35.8 mo (SD 5.3) & median 12 mo (range 0-156) & & median 6 mo (range
1d-8y)\tabularnewline
Characteristics of AE attack - onset & & & & & & & & & & & & & & & & & &
& & & &\tabularnewline
\textbf{Previous attacks} & median 2 (IQR 2) & 8\% & & 0\% & 7\% & 0\% &
17\% & 34\% (median 3 (IQR 1-3)) & 77\% (range 1-6) & 36\% & 38\% & & &
& & none for most patients & & 8\% (1 or 2) & 0\% & some patients &
&\tabularnewline
\textbf{Preferential attack onsent in evenings and night} & 25\% & &
60\% outside regular working hours & & & & & & & & & & & & & & & & & &
&\tabularnewline
Characteristics of AE attack - plateau & & & & & & & & & & & & & & & & &
& & & & &\tabularnewline
\textbf{Affected sites} & & & & & & & & & & & & & & & & & & & & &
&\tabularnewline
- Lips & 50\% & & & & & 67\% & 83\% & 50\% & 38\% & 29\% & 23\% & 25\% &
44\% & & & 70\% & 54\% & 32\% & & & &\tabularnewline
- Tongue & 47\% & & & & & 61\% & 45\% & 44\% & 85\% & 71\% & 62\% & 28\%
& 55\% & & 50\% & 52\% & anterior 40\%; base 11\% & 20\% & & 39\% & &
46\%\tabularnewline
- Uvula & 10\% & & 5\% & & & & & 5\% & 8\% & & & & & & & & & & & &
&\tabularnewline
- Oral cavity (excluding lips, tongue and uvula) & 23\% & & 75\% & & &
eyelids 17\% & eyelids 25\% & 42\% & 8\% & 64\% & 46\% & 22\% & & & & &
13\% & 13\% & & & &\tabularnewline
- Throat (pharynx, larynx) & 30\% & & 40\% & & & & & 24\% & 54\% &
pharynx 36\%; larynx 50\% & pharynx 31\%; larynx 46\% & & 22\% & & 50\%
& 59\% & pharynx 9\%; larynx 4\% & & & & & 13\%\tabularnewline
- Face (excluding lips) & 10\% & & 27\% & & & 50\% & 58\% & 22\% & 23\%
& cheeks 14\%; face 21\% & cheeks 23\%; face 23\% & & 22\% & & & cheeks
20\%; eyes 10\% & & 19\% & & 86\% & & 85\%\tabularnewline
\textbf{Urticaria} & 0\% & 4\% & & & & 5\% & & & & & & & & & & & & 3\% &
& & &\tabularnewline
\textbf{Dyspnea and/or dyspnhonia} & 33\% & & & & & & & & & & & 4\% & &
& & dyspnea 89\%; dysphonia 29\% & & & & dyspnea 9\% & &
54\%\tabularnewline
Characteristics of AE attack - resolution & & & & & & & & & & & & & & &
& & & & & & &\tabularnewline
\textbf{Duration of attacks without treatment} & median 24 (IQR 42) hr &
& & onset of attack to study drug : median 7.9 (IQR 5.5-9.7) hr study
drug to onset of symptom relief: median 1.6 (IQR 0.5-3.9) hr study drug
to discharge criteria: median 4.0 (IQR 1.0-6.0) hr & onset of attack to
study drug : median 7.8 (IQR 5.6-9.4) hr study drug to onset of symptom
relief: median 2.0 (IQR 0.6-3.1) hr study drug to discharge criteria:
median 4.0 (IQR 2.0-6.0) hr & & & & onset of attack-onset of relief:
median 11 (IQR 7-40) hr onset of attack-complete resolution: median 54
(IQR 33-63) hr & onset of attack-onset of relief: median 7.9 (95\%CI
1.2-11.8) hr onset of attack-complete resolution: median 27.1 (IQR
20.3-48.0) hr & onset of attack-onset of relief: median 2.0 (95\%CI
2.0-6.3) hr onset of attack-complete resolution: median 8.0 (IQR
3.0-16.0) hr & & & onset of attack-complete resolution: mean 33 (SD
19.4) hr & onset of attack-complete resolution: mean 4,4 (SD 0.8) hr & &
& & & & 39\% improved in \textless{}4h from admission & median 12 hr
(range 2-146) (treatment not mentioned)\tabularnewline
\textbf{Treatments of attacks} & & & & & & & & & & & & & & & & & & & & &
&\tabularnewline
Antihistamines & 60\% & 93\% & 85\% & 88\% & 85\% & 89\% & 92\% & 70\% &
77\% & 100\% & 0\% & & 100\% & 100\% & & 73\% & 89\% & 98\% & 100\% ? &
& &\tabularnewline
Corticosteroids & 60\% & 96\% & 85\% & 85\% & 80\% & 89\% & 92\% & 56\%
& 100\% & 100\% & 0\% & & 100\% & 100\% & & 75\% & 89\% & 98\% & 100\% ?
& & &\tabularnewline
Adrenalin & 10\% & 21\% & 85\% & 18\% & 26\% & 17\% & 0\% & 8\% & 54\% &
& & & & & & 10\% & & 14\% & 100\% ? & & &\tabularnewline
Tranexamic acid & 30\% & & & & & & & & & & & & & & & & & & & &
&\tabularnewline
Icatibant & 63\% & & 13\% & & & & & 66\% & 100\% & 21\% (rescue therapy)
& 100\% & & & 0\% & 100\% & & & & & & &\tabularnewline
C1-INH concentrate & 13\% & & & & & 0\% & 100\% & 27\% & & & & & & & & &
& & & & &\tabularnewline
Upper airway control procedures & 0\% & 26\% & 11\% & 0\% & 2\% & 6\% &
17\% & 2\% & 0\% & 7\% & 0\% & 4\% & 11\% & 10\% & 0\% & 7\% & 10\% &
3\% & 4\% & 2\% & 15\% & 3\%\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2 title:} Review of the available literature regarding the
characteristics of ACEi-AE patients

\textbf{Table 2 legend:}

ACEi: angiotensin-converting enzyme inhibitors; AE: angioedema; ARBs:
angiotensin-receptor blockers; C1-INH: C1-inhibitor; d: day; DPP-4i:
dipeptidyl peptidase-4 inhibitors; ED: emergency department\textbf{;}hr:
hours; min: minutes; mo: months; IQR: interquartile range; y: years; yo:
years old\textbf{;} ORL: oto-rhino-laryngology\textbf{;} RAA:
renin-angiotensin-aldosterone\textbf{;} SD: standard deviation.

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