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\begin{document}

\title{Angioedema severity and impacts on quality of life: chronic
histaminergic angioedema versus chronic spontaneous urticaria}



\author[1]{Marina Sabate-Bresco}%
\author[1]{Nuria Rodríguez-Garijo}%
\author[2]{JULIÁN AZOFRA}%
\author[3]{María L. Baeza}%
\author[2]{Carmen Diaz Donado}%
\author[4]{Pere Gaig}%
\author[3]{Mar Guilarte}%
\author[4]{Valeria Herrera-Lasso }%
\author[3]{Moises Labrador-Horrillo}%
\author[3]{Anna Sala-Cunill}%
\author[5]{Beatriz Veleiro}%
\author[1]{Pilar Gil}%
\author[1]{Marta Ferrer}%
\affil[1]{Clinica Universidad de Navarra}%
\affil[2]{Hospital Universitario Central de Asturias}%
\affil[3]{Instituto de Salud Carlos III}%
\affil[4]{Hospital Universitari de Tarragona Joan XXIII}%
\affil[5]{Complexo Hospitalario Universitario A Coruna}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Chronic histaminergic angioedema (CHA) is defined
as recurrent episodes of isolated angioedema (without hives) of unknown
cause that respond to the same treatment as chronic spontaneous
urticaria (CSU). Quality of life (QoL) studies have not been performed
for CHA, except those carried out in the context of CSU associated with
angioedema attacks (CSU-AE). Moreover, biomarkers for monitoring disease
activity in CHA have not been identified. We aim to describe the burden
of CHA and impact on patient QoL, compare the findings to those in
CSU-AE patients, and investigate biomarker associations with disease
severity and QoL parameters. \textbf{Methods:} We performed a
prospective multicenter study that included 68 patients with CHA and 63
patients with CSU-AE. Demographic and clinical variables were collected.
Validated patient-reported questionnaires were employed to analyze the
quality of life and disease activity. Blood and serological parameters,
including blood cell count, C-reactive protein, D-dimer and total IgE,
were also analyzed. \textbf{Results:} Angioedema disease activity was
significantly higher in CSU-AE patients (median AAS7, IQR: 1,
{[}0--1{]}) than CHA patients (0, {[}0--1{]}; p= 0.022). A considerable
impact on QoL was found in both groups, although significantly worse
values were found for CSU-AE (median AEQoL, IQR: 37, {[}10--65{]};
p=0.005). CHA patients were older than CSU-AE patients, and female
predominance was not observed. \textbf{Conclusions:} Angioedema severity
and QoL impacts are significantly worse in CSU than in chronic
histaminergic angioedema. Angioedema should be included in severity
urticaria scores (UAS) as well as in specific quality of life urticaria
scales.%
\end{abstract}%



\sloppy


\textbf{Article type:} Original article

\textbf{Angioedema severity and impacts on quality of life: chronic
histaminergic angioedema versus chronic spontaneous urticaria}

\textbf{Short title:} Quality of life and severity related to angioedema

Nuria Rodr\selectlanguage{ngerman}íguez-Garijo, MD\textsuperscript{1}, Marina Sabaté-Brescó,
PhD\textsuperscript{2,3,4}, Julián Azofra, MD, PhD\textsuperscript{5},
Maria Luisa Baeza, MD, PhD\textsuperscript{6}, Carmen Diaz Donado, MD,
PhD\textsuperscript{5}, Pere Gaig, MD\textsuperscript{7}, Mar Guilarte,
MD, PhD\textsuperscript{4,8}, Valeria Herrera-Lasso,
MD\textsuperscript{7}, Moisés Labrador-Horrillo, MD,
PhD\textsuperscript{4,8}, Anna Sala-Cunill, MD,
PhD\textsuperscript{4,8}, Beatriz Veleiro MD, PhD\textsuperscript{9},
Maria Pilar Gil, MD, PhD\textsuperscript{1}, Marta Ferrer, MD,
PhD\textsuperscript{2,3,4}

\textsuperscript{1}Department of Dermatology, Clinica Universidad de
Navarra, Pamplona, Spain

\textsuperscript{2}Department of Allergy and Clinical Immunology,
Clinica Universidad de Navarra, Pamplona, Spain

\textsuperscript{3}Instituto de Investigación Sanitaria de Navarra
(IdiSNA), Pamplona, Spain

\textsuperscript{4}RETIC de Asma, Reacciones Adversas y Alérgicas
(ARADYAL), Spain

\textsuperscript{5}Allergy Section, Hospital Universitario Central de
Asturias, Oviedo, Spain

\textsuperscript{6}Allergy Service, Hospital General Universitario
Gregorio Marañón, Madrid, Spain; Biomedical, Research Network on Rare
Diseases (CIBERER)-U761, Madrid, Spain. Gregorio Marañón Health Research
Institute, Madrid, Spain

\textsuperscript{7}Allergy Section, Hospital Universitari Joan XXIII de
Tarragona; Institut d'Investigació Sanitària Pere Virgili, Universitat
Rovira i Virgili, Tarragona, Spain

\textsuperscript{8}Allergy Section, Internal Medicine Department,
Hospital Universitari Vall d'Hebron, Barcelona, Spain

\textsuperscript{9}Complexo Hospitalario Universitario de A Coruña, A
Coruña, Spain

\textbf{Corresponding author}

Marta Ferrer Puga, mferrerp@unav.es

Telephone: +34 948 25 54 00

Clínica Universidad de Navarra

Av. Pio XII, 36

31008 Pamplona (SP)

\textbf{Acknowledgments}

This work was supported by grants \#PI16/01304 and \#PI20/01536 from the
Instituto de Salud Carlos III (ISCIII) and the Thematic Networks for
Co-operative Research Centres: ARADyAL network (RD16/0006/0031) from
ISCIII, co-founded by Fondo Europeo de Desarrollo Regional (FEDER).

\textbf{Conflict of interest statement}

The authors have no conflicts of interest to disclose.

\textbf{Manuscript word count:} 2704 words

\textbf{Abstract word count:} 249

\textbf{References:} 35

\textbf{Figures:} 2

\textbf{Tables:} 2



\textbf{Abstract}

\textbf{Background:} Chronic histaminergic angioedema (CHA) is defined
as recurrent episodes of isolated angioedema (without hives) of unknown
cause that respond to the same treatment as chronic spontaneous
urticaria (CSU). Quality of life (QoL) studies have not been performed
for CHA, except those carried out in the context of CSU associated with
angioedema attacks (CSU-AE). Moreover, biomarkers for monitoring disease
activity in CHA have not been identified. We aim to describe the burden
of CHA and impact on patient QoL, compare the findings to those in
CSU-AE patients, and investigate biomarker associations with disease
severity and QoL parameters.

\textbf{Methods:} We performed a prospective multicenter study that
included 68 patients with CHA and 63 patients with CSU-AE. Demographic
and clinical variables were collected. Validated patient-reported
questionnaires were employed to analyze the quality of life and disease
activity. Blood and serological parameters, including blood cell count,
C-reactive protein, D-dimer and total IgE, were also analyzed.

\textbf{Results:} Angioedema disease activity was significantly higher
in CSU-AE patients (median AAS7, IQR: 1, {[}0--1{]}) than CHA patients
(0, {[}0--1{]}; p= 0.022). A considerable impact on QoL was found in
both groups, although significantly worse values were found for CSU-AE
(median AEQoL, IQR: 37, {[}10--65{]}; p=0.005). CHA patients were older
than CSU-AE patients, and female predominance was not observed.

\textbf{Conclusions:} Angioedema severity and QoL impacts are
significantly worse in CSU than in chronic histaminergic angioedema.
Angioedema should be included in severity urticaria scores (UAS) as well
as in specific quality of life urticaria scales.

\textbf{Keywords:} Angioedema, Chronic Histaminergic Angioedema, Chronic
Spontaneous Urticaria, Disease activity, Quality of Life



\textbf{Introduction}

Angioedema (AE) is defined as localized and self-limited swelling of the
deep dermis and subcutaneous or submucosal tissues due to a rapid-onset
increase in vascular permeability, causing local plasma extravasation
secondary to the release of vasoactive mediators.\textsuperscript{1,2}

According to the indicated vasoactive mediator, AE can be classified
into two types: histamine-mediated AE (induced by mast cell activation
and basophil degranulation) and bradykinin-mediated AE (due to excessive
bradykinin), as observed in hereditary angioedema, acquired angioedema
with C1 inhibitor deficiency (related to lymphoproliferative and
autoimmune diseases) and angioedema related to angiotensin-converting
enzyme (ACE) inhibitors.\textsuperscript{3,4}

Histamine-mediated AE is the most frequent form of
angioedema,\textsuperscript{2} and it is classified as chronic
histaminergic acquired angioedema (CHA) when allergies or other causes
have been excluded and positive treatment responses to antihistamines,
corticosteroids, adrenaline, or omalizumab\textsuperscript{5} have been
reported. Histamine-mediated AE can occur isolated as CHA or associated
with wheals in chronic spontaneous urticaria (CSU). Classically, CSU is
characterized by the presence of recurrent episodes of wheals (hives)
with or without angioedema for at least 6
weeks.\textsuperscript{6}Approximately 33--67\% of all patients with CSU
present with wheals and angioedema.\textsuperscript{7} For this reason
and because CHA responds to urticaria treatments, CHA is typically
considered a subtype of CSU without wheals. However, a recent
study\textsuperscript{8} found several features that differentiate CHA
from CSU, suggesting that CHA should be considered a separate entity.

Angioedema can be disfiguring, limit daily activities and have a
significant impact on quality of life.\textsuperscript{9,10} AE impacts
on quality of life (QoL) have been largely explored in
bradykinin-related AE\textsuperscript{11,12}; however, specific QoL
studies for CHA have not been performed, except for those carried out in
the context of CSU associated with angioedema
attacks.\textsuperscript{13}

We previously reported differences in cellular activation and
autoimmunity parameters between CHA and CSU\textsuperscript{8} in the
same cohort of patients. The aim of this study was to describe the
burden of the disease and the impact on QoL in patients with CHA and
compare the disease severity and quality of life of angioedema in
patients suffering from chronic urticaria (CSU-AE).

Finally, due to a growing interest in identifying biomarkers to monitor
disease activity and response to treatment, we selected several
previously reported potential biomarkers for CSU
activity\textsuperscript{14-16} and assessed them in our study
population as well as their relationship with disease activity and
quality of life.

\textbf{Materials and methods}

Patients and clinical data

We performed a prospective study comparing 68 patients with CHA and 63
patients with CSU-AE who were recruited in 6 hospitals across Spain. All
patients were older than 18 and provided signed informed consent to
participate in the study. Ethical approval was obtained in each of the
collaborating centers, and the study followed Good Clinical Practice
guidelines and the Helsinki Declaration.

The inclusion criterion to fulfill the diagnosis of CHA was the presence
of recurrent AE that responds to treatment with antihistamines,
corticosteroids, adrenaline or omalizumab. The exclusion criteria were
the presence of bradykinergic AEs, ACE inhibitor intake,
delayed-pressure AEs, vibratory AEs or edema induced by nonsteroidal
anti-inflammatory drugs (NSAIDs). All patients had normal C1INH, C1q, C3
and C4 protein levels and normal C1INH activity.

We collected demographic features, and the patients were requested to
complete validated patient-reported questionnaires. Disease activity was
determined by the following questionnaires: Angioedema Activity Score
for 7 consecutive days (AAS7) in both CHA and CSU-AE patients and
Urticaria Activity Score over 7 Days (UAS7) in CSU-AE patients. The AAS7
score was categorized into four score levels: no episodes (0), low
(1--6), moderate (7--18) and high (19--105).\textsuperscript{17} UAS7
was also divided into four score bands: no episodes (0), low (1--6),
moderate (7--27) and high (28--42).\textsuperscript{18} The impact on
quality of life was measured by the Angioedema Quality of Life (AE-QoL)
in CHA and CSU-AE patients and by the Chronic Urticaria Quality of Life
(CU-Q\textsubscript{2}oL) questionnaires in CSU-AE patients.

In addition, we collected blood and serologic parameters in the clinical
laboratories of each center: total serum IgE, blood cell counts, D-dimer
and C-reactive protein (CRP).

Statistical analysis

Statistical analyses were performed using Stata (version 12.0;
StataCorp, United States). Graphics were generated with GraphPad Prism 8
(GraphPad Software, United States). Qualitative variables are reported
as the total number and percentage and were compared using chi-squared
tests. Quantitative variables are reported as the mean with standard
deviation or median with range and were compared using Student's t-test
with Welch's correction (normally distributed) or the Mann--Whitney U
test and Kruskal--Wallis test (nonnormally distributed). Spearman's
correlation coefficient (r) is reported for correlations. To test for
normality distribution, we applied the D'Agostino-Pearson test. Values
were considered significant at p\textless{}0.05.

\textbf{Results}

A total of 131 patients were registered: 68 patients with CHA and 63
patients with CSU-AE. The characteristics of the patients are summarized
in Table 1.

Demographic characteristics

As observed in Table 1 and as previously reported for this
cohort,\textsuperscript{8} significantly different gender and age
distributions were observed between the two groups. The male/female
ratio in CHA was 0.78, whereas that in CSU was 0.36. The proportion of
women was significantly higher in CSU. The mean age was significantly
higher in CHA.

Angioedema episodes and treatment

When patients were asked about the duration of angioedema episodes, the
most common answers were 2--3 days in CHA (22.1\%) and 24--48 hours in
CSU-AE (27\%). Although no significant differences were detected, we
observed a trend for a longer duration of angioedema episodes in CHA. No
significant differences in the number of angioedema episodes within the
previous 12 months were found.

Overall, 69.12\% of CHA patients and 82.54\% of CSU-AE patients were
taking medication to prevent those episodes. The number of patients who
followed treatment with H1-antihistamines was significantly higher in
CSU-AE (79.37\%) than in CHA (52.94\%, p=0.001). Additionally, updosing
was more necessary in patients with CSU-AE (36.51\%, p=0.015), and the
number of patients who received fourfold the licensed dose was also
higher in this group (9.52\%, p=0.041). No significant differences in
the other treatments (corticosteroid, omalizumab or others) were
observed. However, the number of different concomitant treatments
administered to the patients was significantly higher in CSU-AE.

Emergency department visits

The majority of patients needed at least one emergency department (ED)
visit after their diagnosis, with 60.3\% in CHA and 71.4\% in CSU-AE. We
did not find differences in the overall number of ED visits since the
diagnosis. However, significant differences in the number of ED visits
within the previous year were found, with a median of one visit in CHA
patients and two visits in CSU-AE patients (p= 0.040).

Angioedema activity score

The details of the AAS7 questionnaire are shown in Table 2. We found
significant differences in angioedema severity between the CHA and
CSU-AE patients. The AAS7 score was significantly higher in CSU-AE
(median, IQR: 1, {[}0--1{]}) than in CHA (median, IQR: 0, {[}0--1{]}, p=
0.022).

In CHA, 58.1\% of patients reported no AE episodes within the previous 7
days, 32.3\% had low scores, 9.7\% had moderate scores, and no patients
had high scores. In CSU-AE, 42.3\% of patients had no AE episodes in the
past 7 days, 38.5\% reported low scores, 11.5\% had moderate scores and
7.7\% had high scores. Only the CSU-AE patients had severe angioedema
episodes in the AAS7 questionnaire (severe AAS7 range: 19--105) (p=
0.041).

Correlation with the Urticaria Activity Score

The median UAS7 score in CSU-AE was 3.75 (IQR: 0--17). Regarding the
relation between AAS7 and UAS7 in the CSU-AE group, we found a
significant association (p\textless{}0.001) with a strong positive
correlation (Spearman's rho= 0.7206).

Quality of life

We found significant differences between the two groups regarding
quality of life (Table 2). When comparing the AE-QoL questionnaire,
quality of life was significantly lower in CSU-AE (median, IQR: 37
{[}10--65{]}) than in CHA (18 (4--40), p=0.005). Across all dimensions,
the AEQoL scores were significantly higher (worse QoL) in CSU-AE. In
both groups, the most affected dimension was fear/shame (38 {[}0--58{]}
in CHA vs. 50 {[}21--79{]} in CSU-AE, p=0.031), followed by fatigue/mood
(15 {[}0--40{]} in CHA vs. 35 (0--65) in CSU-AE, p=0.012), functioning
(0 {[}0--19{]} in CHA vs. 25 (0--56) in CSU-AE, p\textless{} 0.001) and
nutrition (0 {[}0--13{]} in CHA vs. 25 (0--50) in CSU-AE, p=0.007).

Across most dimensions, the mean AEQoL scores were generally higher
among patients reporting a higher disease severity AAS7 score (Figure 1A
and B). This finding is reflected in a moderate positive correlation
between AAS7 and AE-QoL (Spearman's rho= 0.3892, p\textless{}0.001)

For CSU-AE, the median score of the CU-Q\textsubscript{2}oL
questionnaire in CSU-AE patients was 49 (IQR: 27--66). We found a very
strong positive correlation between AE-QoL and CU-Q\textsubscript{2}oL
(Spearman's rho= 0.8809, p\textless{}0.001) and a moderate positive
correlation between UAS7 and CU-Q\textsubscript{2}oL (Spearman's rho=
0.5455, p=0.002).

Biomarkers

We assessed several biomarkers that have been proposed to be associated
with CSU severity, such as CRP, D-dimer, basophil and eosinophil counts
and total IgE. In CSU-AE patients, we observed a significant inverse
correlation between UAS7 and eosinophil count (Spearman's rho= -0.3086,
p=0.0392), while the other 4 parameters did not reach statistical
significance, although a trend was observed for some of them (Figure
2A). For CSU-AE, no significant correlation was observed between AAS7
and any biomarker (Figure 2B), while in CHA, AAS7 showed a significant
inverse correlation with D-dimer (Spearman's rho= -0.3007, p=0.0243),
with no correlations observed with the rest of the biomarkers studied
(Figure 2C).

We also assessed the QoL score correlations with the selected
biomarkers. For CU-Q\textsubscript{2}oL, moderately significant
correlations were obtained for D-dimer (Spearman's rho= 0.4479,
p=0.0005) and eosinophil counts (Spearman's rho= -0.3780, p=0.0034). In
the case of CSU-AE, AE-QoL significantly correlated with the same
biomarkers as CU-Q2oL, namely, D-dimer (Spearman's rho= 0.4636,
p=0.0003) and eosinophil counts (Spearman's rho= -0.2867, p=0.0243). In
CHA, AE-QoL did not present any significant correlations.

\textbf{Discussion}

Although considerable attention has been focused on hereditary
angioedema because of its severity, little attention has been dedicated
to mast cell-mediated angioedema. In the present work, we sought to
depict the direct impact of angioedema in CSU and in CHA (isolated
angioedema), by comparing the same angioedema severity and quality of
life scales.

CSU has a significant impact on quality of life, and although itch is
responsible for much of this effect, angioedema is also a key factor. In
CSU, angioedema has been found to be associated with higher severity,
longer duration and less response to therapeutic options. However,
angioedema is underdiagnosed,\textsuperscript{19} and it is not included
among the most widely used severity scores, namely, UAS and UAS7, which
only includes the number of hives and itch severity\textsuperscript{20};
moreover, angioedema is frequently overlooked as an outcome in clinical
trials, which mostly focus on the main variable,
itch.\textsuperscript{21,22} Some studies have shown the influence of
angioedema in CSU and compared CSU patients with and without angioedema
attacks.\textsuperscript{19,23-29} However, the results are somewhat
controversial, with certain studies indicating a lack of differences in
disease activity\textsuperscript{29} and other studies describing a
greater severity in CSU with angioedema.\textsuperscript{27} However,
the disease severity and impacts on the quality of life of patients with
CHA alone have not been clarified.

Our study compared CSU-AE and CHA for the first time and found
differences in AAS values, suggesting a higher severity of CSU-AE. This
finding appeared to be related to the fact that there were more CSU-AE
patients in the severe level of the AAS7 questionnaire. Similar results
were reported by Sussman et al.,\textsuperscript{19} who found that more
patients with CSU-AE had severe disease activity, as measured by the
UAS, than those with CSU without angioedema attacks. However, one
limitation of the results is the difficulty of differentiating hives,
itch and angioedema when evaluating quality of life.

We indeed found that angioedema in the context of CSU is more severe and
has a greater need for medication and emergency visits than angioedema
with CHA; however, whether these differences are biased by the presence
of hives and itch could not be determined. We also show that the AAS7
tool has a very good correlation with CSU severity; therefore, it might
be useful to design a new urticaria activity score that incorporates AAS
items. In that sense, the Urticaria Control Test (UCT) is more
comprehensive because it includes swelling in the main control question:
``How much have you suffered from the physical symptoms of urticaria
(itch, hives (welts) and/or swelling) in the last four weeks?'' However,
UCT is not a severity score system.

A possible explanation for the differences is that angioedema present in
CSU is produced when skin inflammation is more profound, thus
paralleling a more severe disease. In contrast, CHA is a different and
less severe entity that presents milder angioedema episodes.

We also confirm in this paper that both angioedema and urticaria quality
of life scores correlate very well with disease severity. These
questionnaires also help patients feel understood. With the available
technology, better patient care will be achieved by sending these
questionnaires prior to the clinical visit. In terms of the severity
score, it might be very useful to incorporate the angioedema quality of
life questionnaire into the CSU questionnaire.

Our observations also revealed the considerable impact on quality of
life in CHA and CSU-AE patients. We observed marked emotional stress in
both groups, and the most affected dimension in CSU-AE and in CHA was
fear/shame followed by fatigue/mood. Furthermore, in both groups,
patients with a higher frequency of attacks generally showed worse
quality of life in the total AE-QoL score and its different dimensions.

Last, in recent years, many biomarkers for monitoring CSU have been
described, most of which are related to disease activity, such as CRP,
D-dimer, basophil and eosinophil counts or total
IgE.\textsuperscript{16} Several publications have reported that
increased levels of CRP,\textsuperscript{30}
D-dimer\textsuperscript{31}and total IgE\textsuperscript{32} and
decreased basophil counts\textsuperscript{33} and
eosinopenia\textsuperscript{34} correlate with UAS7. In our study, we
observed a significant inverse correlation between UAS7 and eosinophil
count. Recently, similar results have been reported by Kolkhir et
al.\textsuperscript{34} who found that eosinopenia in patients with CSU
was associated with high disease activity and poor treatment response. A
significant correlation was not observed among the rest of the
biomarkers and UAS7, although a trend was shown, suggesting that
significant results might have been obtained with a larger cohort, where
more patients with high severity could be followed. Again, we did not
find eosinopenia in the CHA group, thus indicating a different
mechanism.

To date, biomarkers associated with histamine-mediated AE have not been
identified. The presence of angioedema in CSU (compared to CSU without
angioedema) has not been shown to be associated with altered levels of
anti-Fc\selectlanguage{english}eRI, anti-IgE, substance P, B cell activation factor and
tryptase,\textsuperscript{15} which is consistent with them being two
presentations of the same entity. However, CHA does seem to present
differences in sex distribution and autoimmunity\textsuperscript{8} or
the presence of basopenia\textsuperscript{8} or eosinopenia. It is very
interesting that in this study, D-dimer was inversely correlated with
CHA disease activity but not observed for CSU-AE patients.

We also assessed the QoL questionnaire correlations with biomarkers as
an additional outcome related to disease severity. Patients with high
severity scores in UAS7 have also been reported to have a poorer quality
of life.\textsuperscript{35} For CSU-AE, both QoL questionnaires
depicted significant moderate correlations with D-dimer and eosinophil
counts, with no correlation observed for CHA based on the AE-QoL. While
not all previously published biomarkers could be confirmed in our
cohort, severity and quality of life questionnaires in CSU-AE presented
more correlations with some of the biomarkers compared to CHA.

In conclusion, in both isolated chronic angioedema and angioedema
associated with hives in chronic spontaneous urticaria, mast
cell-mediated angioedema has a significant impact on quality of life,
which correlates with the disease severity, emergency department visits
and rescue medication use. The quality of life and frequency of
angioedema are greater in chronic spontaneous urticaria than in isolated
chronic histaminergic angioedema.

Differences between CSU-AE and CHA indicate that they are different
entities or at least differing phenotypes. We favor the former view.
Nevertheless, angioedema deserves a better representation in chronic
urticaria severity scores and quality of life questionnaires. It would
be useful for experts designing such tools to highlight angioedema when
it is associated with CSU so that questionnaires for angioedema alone
can be employed for angioedema without urticaria.

\textbf{Data availability statement}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{Contributors}

JA, MLB, CDC, PG, MG, VHL, MLH, ASC, BV and MFP equally contributed to
study design. JA, MLB, CDC, PG, MG, VHL, MLH, ASC, BV and MFP
contributed to participant recruitment for clinical performance
assessment, and NRG, MSB, MPG and MFP performed the technical analysis.
NRG and MSB organized data collection, analysis, and figure preparation.
NRG, MSB, JA, MLB, CDC, PG, MG, VHL, MLH, ASC, BV, MPG and MFP
contributed to the literature search and writing of the original draft
of the manuscript or its critical revision.

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\textbf{Tables}

\textbf{Table 1.} Demographic, episode, treatment and emergency features
of the patients.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{CHA (n=68)} & \textbf{CSU-AE (n=63)} &
\textbf{p-value}\tabularnewline
\midrule
\endhead
Gender, male {[}n (\%){]} & 30 (44.1\%) & 17 (27.0\%) &
\textbf{0.047}\tabularnewline
Male/female ratio & 0.78 & 0.36 &\tabularnewline
Age, years {[}mean (range){]} & 53.1 (20--85) & 47.4 (20--76) &
\textbf{0.035}\tabularnewline
AE episode, duration {[}n (\%){]} & & & 0.181\tabularnewline
1--3 hours & 2 (2.9\%) & 3 (4.8\%) &\tabularnewline
3--6 hours & 9 (13.2\%) & 6 (9.5\%) &\tabularnewline
6--12 hours & 14 (20.6\%) & 15 (23.8\%) &\tabularnewline
12--24 hours & 9 (13.2\%) & 13 (20.6\%) &\tabularnewline
24--28 hours & 12 (17.7\%) & 17 (27.0\%) &\tabularnewline
2--3 days & 15 (22.1\%) & 8 (12.7\%) &\tabularnewline
3--6 days & 7 (10.3\%) & 1 (1.6\%) &\tabularnewline
AE episodes past 12 months {[}median (iqr){]} & 6 (3--14) & 4.5 (2--12)
& 0.390\tabularnewline
Treatment {[}n (\%){]} & 47 (69.12\%) & 52 (82.54\%) &
0.096\tabularnewline
H1-antihistamine {[}n (\%){]} & 36 (52.94\%) & 50 (79.37\%) &
\textbf{0.001}\tabularnewline
single dose {[}n (\%){]} & 24 (35.29\%) & 27 (42.86\%) &
0.375\tabularnewline
updose {[}n (\%){]} & 12 (17.65\%) & 23 (36.51\%) &
\textbf{0.015}\tabularnewline
double dose {[}n (\%){]} & 10 (14.71\%) & 13 (20.63\%) &
0.373\tabularnewline
triple dose {[}n (\%){]} & 1 (1.47\%) & 4 (6.35\%) &
0.145\tabularnewline
quadruple dose {[}n (\%){]} & 1 (1.47\%) & 6 (9.52\%) &
\textbf{0.041}\tabularnewline
Corticosteroid {[}n (\%){]} & 9 (13.24\%) & 13 (20.63\%) &
0.694\tabularnewline
Omalizumab {[}n (\%){]} & 3 (4.41\%) & 0 & 0.086\tabularnewline
Others {[}n (\%){]} & 4 (5.88\%) & 9 (14.29\%) & 0.285\tabularnewline
Number of treatments {[}median (iqr){]} & 1 (1--1) & 1 (1--2) &
\textbf{0.040}\tabularnewline
Patient visits to an emergency department since diagnosis {[}n (\%){]} &
41 (60.3\%) & 45 (71.4\%) & 0.180\tabularnewline
Number of visits to an emergency department {[}n
(\%){]}\textsuperscript{+} & & & 0.333\tabularnewline
0 visits & 0 & 2 (4.2\%) &\tabularnewline
1 visits & 9 (22.5\%) & 7 (14.6\%) &\tabularnewline
2 visits & 10 (25\%) & 7 (14.6\%) &\tabularnewline
3 visits & 2 (5\%) & 7 (14.6\%) &\tabularnewline
4 visits & 7 (17.5\%) & 5 (10.4\%) &\tabularnewline
5 visits & 4 (10\%) & 6 (12.5\%) &\tabularnewline
\textgreater{}5 visits & 8 (20\%) & 14 (29.2\%) &\tabularnewline
Number of visits to an emergency department past 12 months {[}median
(iqr){]} & 1 (0--2) & 2 (1--4) & \textbf{0.015}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{+}Results from 43 patients were not obtained (28 in the
IH-AAE group and 15 in the CSU-AE group).

Statistically significant differences are highlighted in bold.

\textbf{Table 2.} Disease activity and quality of life of the patients.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{CHA (n=68)} & \textbf{CSU-AE (n=63)} & \textbf{p
value}\tabularnewline
\midrule
\endhead
AAS7 {[}median (iqr){]} & 0 (0--1) & 1 (0--1) &
\textbf{0.022}\tabularnewline
AAS7 levels {[}n (\%){]}\textsuperscript{+} & & & 0.089\tabularnewline
No & 36 (58.1\%) & 22 (42.3\%) & 0.094\tabularnewline
Low & 20 (32.3\%) & 20 (38.5\%) & 0.489\tabularnewline
Moderate & 6 (9.7\%) & 6 (11.5\%) & 0.747\tabularnewline
High & 0 & 4 (7.7\%) & \textbf{0.041}\tabularnewline
AE-QoL {[}median (iqr){]}\textsuperscript{++} & 18 (4--40) & 37 (10--65)
& \textbf{0,005}\tabularnewline
Functioning & 0 (0--19) & 25 (0--56) & \textbf{\textless{}
0.001}\tabularnewline
Fatigue/Mood & 15 (0--40) & 35 (0--65) & \textbf{0.012}\tabularnewline
Fear/Shame & 38 (0--58) & 50 (21--79) & \textbf{0.031}\tabularnewline
Nutrition & 0 (0--13) & 25 (0--50) & \textbf{0.007}\tabularnewline
UAS7 {[}median (iqr){]} & & 3.75 (0--17) &\tabularnewline
UAS 7 levels {[}n (\%){]} \selectlanguage{ngerman}\textsuperscript{§} & & &\tabularnewline
No & & 15 (33.3\%) &\tabularnewline
Low & & 14 (31.1\%) &\tabularnewline
Moderate & & 13 (28.9\%) &\tabularnewline
High & & 3 (6.7\%) &\tabularnewline
CU-QO2 L {[}median (iqr){]} & & 49 (27--66) &\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{+}Results from 17 patients were not obtained (6 in the
CHA group and 11 in the CSU-AE group).

\textsuperscript{++}Results from 5 patients were not obtained (1 in the
IH-AEE group and 4 in the CSU-AE group).

\selectlanguage{ngerman}\textsuperscript{§}Results from 18 patients were not obtained.

AAS7 level was categorized as follows: no episodes (0), low (1--6),
moderate (7--18), high (19--105).

UAS7 levels were categorized as follows: no episodes (0), low (1--6),
moderate (7--27), high (28--42).

Statistically significant differences are highlighted in bold.



\textbf{Figure legends}

\textbf{Figure 1.} Angioedema Quality of Life questionnaire by the
severity of the attacks on the Angioedema Activity Score. A) Total
AE-QoL score in CHA and CSU-AE grouped according to the AAS7 score
levels as follows: no episodes (AAS7:0), low (1--6), moderate (7--18)
and high (19--105). B) AE-QoL score of the different dimensions in CHA
and CSU-AE with patients grouped according to the AAS7 score levels.

\textbf{Figure 2.} Levels of the different biomarkers (PCR, D-dimer,
basophil counts, eosinophil counts, and total IgE) in patients
categorized according to UAS7 in CSU-AE (A) and AAS7 in CSU-AE (B) and
CHA (C). Individual data are presented, with values shown as the mean
and SD.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1-AEQoL-new2/Figure1-AEQoL-new2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2-biomarkers-new2/Figure2-biomarkers-new2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

