\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Chronic Urticaria in Children -- New Insights from a Large Cohort}



\author[1]{idit Lachover Roth}%
\author[2]{Ahmad Rabie}%
\author[1]{Anat Cohen - Engler}%
\author[1]{Yossi Rosman}%
\author[1]{Keren Meir-Shafrir}%
\author[1]{Ronit Confino-Cohen}%
\affil[1]{Meir Medical Center}%
\affil[2]{Tel Aviv University Sackler Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Chronic spontaneous urticaria is well-described in adults,
but less so in children. The aim of this study is to describe the
demographics, clinical characteristics, comorbidities, and outcomes of
children with chronic, spontaneous urticaria. Methods: This
retrospective study followed children up to 18 years-old, diagnosed with
chronic spontaneous urticaria, between the years 2002-2018 and treated
in a tertiary referral allergy and clinical immunology center. Data
including demographics, clinical characteristics, comorbidities,
treatments and outcomes was extracted from electronic medical records.
Results: Records of 380 children coded to have chronic urticaria were
reviewed, of which 250 (65.8\%) fulfilled the diagnostic criteria for
chronic spontaneous urticaria. There were 136 females (54.4\%). Mean age
at diagnosis was 11.4 years, 122 (48\%) were adolescents. The average
duration of chronic spontaneous urticaria was 12.25\selectlanguage{ngerman}±15.2 months. The
urticaria in 208 children )83.2\%) resolved within 24 months.
Eighty-seven patients (34.8\%) had at least one atopic disease. Atopic
comorbidities included atopic dermatitis in 17.2\%, allergic rhinitis in
16\%, asthma in 13.2\% and food allergy in 3.2\%. Eighteen patients
(7.2\%) had a concomitant autoimmune disease. Nine (3.6\%) had thyroid
disease. Conclusions and clinical relevance: Chronic spontaneous
urticaria in children is a self-limited disease with favorable
prognosis. Atopic diseases are more prevalent in children with chronic
spontaneous urticaria than in the general pediatric population;
increasing the possibility of a special subgroup of TH2-related chronic
urticaria in children.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Key Message:}

The literature regarding the characteristics and underlining mechanisms
of chronic spontaneous urticaria in children is limited.

This retrospective cohort study included 250 children with chronic
spontaneous urticaria. Chronic spontaneous urticaria in children is a
self-limited disease. Urticaria lasted up to 2 years in most of the
children. One third had at least one atopic disease. Atopic dermatitis
and allergic rhinitis were the most prevalent, and significantly more
common than in the general pediatric population.

\textbf{Introduction}

Urticaria is a common phenomenon that affects 15-25\% of the population
at least once in a lifetime. While most episodes are
acute\textsuperscript{1,2}, a minority are prolonged, hence termed
chronic urticaria (CU). CU is defined as recurrent urticarial lesions,
appearing most of the days of the week, for at least 6
weeks.\textsuperscript{2-4}The prevalence of CU in adults is estimated
to be 1.8\%, affecting women more than men and with up to 50\% remission
rate within one to three years.\textsuperscript{5} In adults, autoimmune
or auto-allergy mechanisms are suggested as possible etiologies for CU.
In most patients, no underline cause is found or can be proven, and the
urticaria is termed chronic spontaneous urticaria
(CSU).\textsuperscript{6}

The literature regarding the characteristics and underlining mechanisms
of CSU in children is limited.\textsuperscript{2,5,7-14} It is estimated
that its prevalence in children is 0.1-0.3\%\textsuperscript{15-18} with
an equal distribution between genders, except among
adolescents.\textsuperscript{5,13} However, a recent review demonstrated
1.1--1.5\% prevalence of CU in children.\textsuperscript{19} The
remission rate of CSU in children after one year is reported to be low
(16.5\% - 37\%).\textsuperscript{2,5,18}

A few small studies demonstrated an association between pediatric CSU
and atopic diseases, including asthma, allergic rhinitis (AR), atopic
dermatitis (AD) and food allergy.\textsuperscript{5,8-10} An overall,
coexisting prevalence of 30\% to 50\% has been
described.\textsuperscript{5,10,13} Chansakulporn et al. followed a
small group of 92 patients and reported that one-third of the children
with CU had atopic diseases, with an unusually high prevalence of food
allergy (15.2\%).\textsuperscript{5} Netchiporouk et al. reported that
28\% of 139 children with CSU had atopy, but they did not distinguish
between the different types of atopic diseases and age
groups.\textsuperscript{9} In addition to atopic diseases, autoimmune
diseases, including thyroid diseases, celiac and systemic lupus
erythematosus (SLE) were also found to be associated with CU in
children.\textsuperscript{20,21,22}

The aim of the current study was to describe the demographics, clinical
characteristics, comorbidities, and outcomes of a large pediatric cohort
with CSU.

\textbf{Materials and Methods}

This retrospective study included children up to age 18 years, with the
diagnosis of CSU, treated at the Allergy Unit of Meir Medical Center,
Israel, 2002--2018. CSU was defined in accordance with Sahiner et
al.\textsuperscript{2-4} Briefly, urticarial lesions appearing most days
for at least 6 weeks, with or without accompanying angioedema.

Data for the entire cohort were retrieved from Clalit Health Services
electronic record system. All medical records were reviewed by a
specialist in allergy and clinical immunology from the date of CSU
diagnosis to December 2018.

Data collected included: (a) Demographic parameters, (b) CSU duration,
treatment, and relapses, (c) Laboratory tests, (d) Co-morbidities
including asthma, allergic rhinitis, food allergy, atopic dermatitis,
autoimmune thyroid diseases, celiac, SLE, diabetes mellitus, juvenile
rheumatoid arthritis, inflammatory bowel disease, irritable bowel
syndrome (IBS) and psychiatric disorders and (e) Chronic medications for
other comorbidities.

Treatment modalities with antihistamines were defined as: Regular doses
of antihistamines included 5 mg desloratadine daily or according to
weight, 10 mg/day loratadine or according to weight, or 180 mg
fexofenadine. High-dose antihistamines included up to 20 mg daily
desloratadine or comparable dose of other antihistamine drugs.

Relapse was defined as a second episode of CSU with a gap of at least 6
months, without urticaria and without treatment for urticaria.

To analyze potential various age-related differences, patients were
grouped according to age at CSU diagnosis: 0-3, 4-8, 9-12, and 13-18
years.

As CSU can be confused with AD, we analyzed the results with and without
the patients diagnosed with both CSU and AD. Only data with significant
differences are presented.

The study was approval by the Ethics Committee of Meir Medical Center.

\emph{\textbf{Statistical analyses}}

Data are presented as numbers and percentage for nominal parameters and
as mean and standard deviation for continuous variables. Two groups were
compared using Student's t test for continuous variables and Chi-square
or Fisher's Exact test for categorical variables, each when appropriate.
Comparison with data from the literature was compared with Z scores. All
tests of hypotheses were considered significant when two-sided
probability values were P\textless{}0.05. All statistical analyses were
performed using IBM, SPSS-25, Armonk, NY, USA.

\textbf{Results}

Patient demographics

During 2002-2018, 380 children with a diagnosis of CSU recorded in their
medical records were evaluated. After reviewing the medical files, 250
patients (65.8\%) had CSU according to the defined criteria and were
included in the study. The remaining 130 were excluded either because
they did not fulfill the criteria for CSU (113 children) or due to lack
of follow-up data (17 children). Of the 250 patients included, 136 were
females (54.4\%). The mean age at diagnosis was 11.4 \selectlanguage{ngerman}± 5.1 years, median
12 years (range 0.9-18.0). Among the study group, 122 (48\%) were
adolescents (13-18 years old). There was no significant difference in
the prevalence of CSU by sex; except for the adolescents, where females
comprised 60\% of the group (p=0.07) (Table 1).

Duration of CSU

The average duration of CSU was 12.3±15.2 months, median 6 months (range
1.5 -- 84 months). A total of 135 patients (54\%) had CSU for 12--24
months and overall, the urticaria resolved within 24 months in 208
patients (83.2\%). Concomitant angioedema was present in 30\% (n=75). No
significant differences were found when comparing the duration of
disease or the presence of angioedema between the various age groups or
sexes (Table 1).

Relapse of CSU

The average follow-up time was 8.1 years (range 0.3-15.1). During this
period, 24 patients (9.6\%) had a relapse of CSU. Most (17 patients,
70.8\%) were adolescents (p\textless{} 0.05, RR= 2.55). No relapses were
documented in the youngest age group (0-3 years) (Table 1).

\textbf{Comorbidities}

A total of 87 patients (34.8\%) had at least one atopic disease (Figure
1A): in 64.4\% (56/87) the diagnosis of atopic disease was established
before or concurrently with CSU. The atopic comorbidities found in the
study cohort were: AD (n=43, 17.2\%), AR (n=40, 16.1\%), asthma (n=33,
13.3\%) and food allergy (n=8, 3.2\%). Thirty patients (12\%) had more
than one atopic co-morbidity. After excluding the patients diagnosed
with AD, the prevalence of atopic comorbidities did not differ
significantly: AR (n=27, 13\% vs. 16.1\% in the total cohort, p=0.36),
asthma (n=21, 10.1\% vs. 13.3\% in the total cohort, p=0.3) and food
allergy (n=7, 3.4\% vs. 3.2\% in the total cohort, p=0.9). Consequently,
the rest of the analyses are presented for the entire group.

No correlation was found between the prevalence of AR, AD, asthma, or
food allergy and the duration of CSU. Furthermore, there was no
difference in the probability of relapse and the presence of atopic
disease as a co-morbidity (9.8\% vs. 9.2\%, p=0.87).

The prevalence of the different atopic diseases in CSU patients and the
general pediatric population in Israel and in the world was compared
(Figure 1B): The prevalence of AD in two age groups (4-8 years and 13-18
years) of the study population was significantly different compared to
the general population in Israel\textsuperscript{7,23,24} and in the
world\textsuperscript{25} (p\textless{}0.01). Differences in the
prevalence of allergic rhinitis were statistically significant only in
adolescents when compared to the general population of adolescents in
Israel\textsuperscript{7,23,26} and in the
world\textsuperscript{27}(p\textless{}0.01). The differences in the
prevalence of food allergy between participants in the current study and
the general world population\textsuperscript{28,29} were statistically
significant in children age 4-8 years (p\textless{}0.05) but did not
reach significance when compared to adolescents in the current study and
adolescents in Israel\textsuperscript{7,30} (p=0.83). Differences in the
prevalence of asthma between the current study and the general
population in Israel\textsuperscript{7,24,26} and in the world
\textsuperscript{31}did not reach significance in any age group
(p=0.46--0.99).

Overall, 18 patients (7.2\%) had a concomitant autoimmune disease
compared to 1.9\% in the general adolescent population in Israel
(p\textless{}0.01). Nine (3.6\%) were diagnosed with thyroid disease, 7
with hypothyroidism and 2 with hyperthyroidism. Psoriasis was found in 6
patients (2.4\%), type I diabetes mellitus in 2 patients (0.8\%) and 1
patient was diagnosed with juvenile rheumatoid arthritis (0.4\%). Celiac
disease, irritable bowel disease and SLE were not diagnosed in our
cohort. IBS was diagnosed in 5 patients (2\%).

Seven patients (2.8\%) had psychiatric disorders, including depression,
anxiety, bipolar disorder, and schizophrenia. All were diagnosed after
the first CSU episode.

Treatment of CSU

Treatment protocols were available for 213 patients (85.2\%) (Table 2).
Monotherapy was given to 161 (64.4\%) and 52 (20.8\%) received a
combination of at least two medications. Of the 161 treated with
monotherapy, 153 (95\%) received antihistamine in the regular
recommended dose and 7 (4.35\%) received high dose antihistamines. One
patient was treated with corticosteroids only. Of the 52 children
treated with combination therapies, 32 (61.5\%) received a regular dose
of antihistamine and oral corticosteroids. Six patients needed a
combination of three medications, 1 (16.66\%) was treated with a
combination that included omalizumab. Details regarding the treatment
regimens are listed in Table 2.

Relapses were treated with regular dose antihistamines in 41.6\%.
However, relapsing patients used high dose antihistamine, or combination
therapy more often (8.3\% and 29.1\%, respectively vs. 2.8\% and 20.8\%
for the first episode, p=NS). Three of six patients who were treated
with a combination of three medications in the first episode, suffered
from relapse during the following years; significantly more than those
treated with monotherapy or a combination of two medications (50\% vs.
10.14\%, p\textless{} 0.01, RR = 4.93).

\emph{Medications used for co-morbidities}

Thirty-six patients (14.4\%) used methylphenidate (or other comparable
drugs) as a chronic medication for attention deficit disorder with or
without hyperactivity. Although not statistical significantly, the
percentage of patients who used methylphenidate increased parallel to
the duration of CSU (11\% of patients with CSU \textless{}12 months,
15.6\% of patients with CSU for 12-24 months and 20\% of patients with
CSU \textgreater{} 24 months).

Laboratory tests

Complete blood count was available for 202 patients (80.8\%) at the
initial diagnosis of CSU. Eosinophilia (defined as eosinophil count
\textgreater{} 500 cells/\selectlanguage{greek}µ\selectlanguage{english}L) was found in 29 patients (14.4\%, range
500-1800 cells/\selectlanguage{greek}µ\selectlanguage{english}L) and was more common in children \textless{} 13 years
(27.6\% vs. 6.2\% p\textless{} 0.01). Eosinophilia did not correlate
with CSU duration or the presence of atopic diseases.

Total IgE was available for 60 patients (24\%). High total IgE (defined
as IgE \textgreater{} 100 IU), was found in 32 (53.3\%). No correlation
was found between high total IgE and atopic diseases or duration of
urticaria.

C-reactive protein was measured in 109 patients at CSU presentation and
was within the normal range in all cases. Antinuclear antibody was
measured in 51 patients and found abnormal in 6 (11.8\%). Of them, in
the following years, one patient was diagnosed with hyperthyroidism, 1
with hypothyroidism and IBS, and 1 with Alport's syndrome.

\textbf{Discussion}

Chronic urticaria is a common medical condition, well-described in the
adult population. Data regarding CSU in children is scarce. In the
current report, we aimed to better characterize this disorder in a large
cohort of children with a long follow-up period. We found that pediatric
CSU is frequently accompanied by atopic diseases and has a favorable
outcome.

The study cohort had an encouraging clinical course. CSU was not
accompanied by angioedema in most children and there was a good clinical
response to regular doses of antihistamines, without need for additional
medications. In most cases, hives persisted for no longer than two years
and relapses were rare. These findings are supported by previous smaller
series that found CSU in children is a disease with good
prognosis.\textsuperscript{2,9,13} In accordance with the favorable
outcome, laboratory tests in our cohort were within the normal range.
Probably, indicating that routine laboratory tests in children with CSU
are not essential. This notion is supported by Grattan et al. who left
the decision to perform laboratory tests in cases of CSU to the
discretion of the treating physician.\textsuperscript{4}

Traditionally, CSU is considered a disease of unknown etiology.
Nonetheless, in some patients, an underlining autoimmune mechanism may
be present. This concept is supported by the fact that, in adults,
autoimmune diseases, mostly affecting the thyroid gland, frequently
accompany CSU.\textsuperscript{6} Moreover, a canonic work by Hide et
al. \textsuperscript{32} reported autoantibodies against IgE and its
receptor, as a potential trigger for the disease. These findings
established the notion that CSU is a TH1 derived phenomenon. Atopy,
including AD, AR, food allergy and asthma are considered TH2-related
diseases. In the current study, one-third of the children with CSU had
at least one atopic disease. AD and AR were significantly more prevalent
in children with CSU, as compared to the general pediatric population in
Israel and in the world. Food allergy was significantly more prevalent
in children ages 4 to 12 years, with CSU, as compared to the general
pediatric population. An exception is the difference in the prevalence
of asthma; although higher in children with CSU than in the general
pediatric population, it did not reach significance.

It can be speculated that the high prevalence of atopic comorbidities
can be attributed, in part, to confusion between CSU and AD. When
patients with AD were excluded from the analysis, the prevalence of
other atopic diseases and the significant differences between patients
with CSU and the general pediatric population remained similar.

High levels of IgE were found in more than half of the results. This
finding did not overlap with the patients with clinical atopy. This
laboratory abnormality might provide additional support to the underling
atopic background accompanying these children.

The co-existence of atopic diseases had no effect on the likelihood of
relapsing or on the duration of CSU. These findings are in concordance
with other studies that showed a similar prevalence of atopic diseases
in smaller cohorts of pediatric patients with
CSU.\textsuperscript{5,8,9} Recently, one large cohort, that included
Israeli adolescents, showed a robust link between CSU and atopic
diseases.\textsuperscript{7} These publications all support the
assumption that there is a subgroup of CSU patients with TH2-driven
disease.

This study is subject to the limitations inherent to any retrospective
work; some of the data were incomplete. As the follow-up period was very
long, changes in the treatment modalities for CSU were inevitable.
Treatment with anti-IgE was approved for children with CSU older than 12
years of age, only at the end of the follow-up period. As such, its
effect on childhood CSU was not evaluated in this study.

In conclusion, CSU in children is mostly a mild disease. It does not
tend to relapse and can be managed with antihistamines alone. Atopy was
found to be prevalent in children with CSU. However, these atopic
diseases did not influence the duration or severity of the disease.
Whether CSU in children should be part of the spectrum of atopic
diseases requires further investigation in larger, prospective studies.

\textbf{References}

1. Kanwar AJ, Greaves MW. Approach to the patient with chronic
urticaria. \emph{Hosp Pract (1995).} 1996;31(3):175-179,183-174,187-179.

2. Sahiner UM, Civelek E, Tuncer A, et al. Chronic urticaria: etiology
and natural course in children. \emph{Int Arch Allergy
Immunol.}2011;156(2):224-230.

3. Zuberbier T, Bindslev-Jensen C, Canonica W, et al. EAACI/GA2LEN/EDF
guideline: management of urticaria. \emph{Allergy.} 2006;61(3):321-331.

4. Grattan CE, Humphreys F, British Association of Dermatologists
Therapy G, Audit S. Guidelines for evaluation and management of
urticaria in adults and children. \emph{Br J
Dermatol.}2007;157(6):1116-1123.

5. Chansakulporn S, Pongpreuksa S, Sangacharoenkit P, et al. The natural
history of chronic urticaria in childhood: a prospective study. \emph{J
Am Acad Dermatol.} 2014;71(4):663-668.

6. Kaplan AP. What the first 10,000 patients with chronic urticaria have
taught me: a personal journey. \emph{J Allergy Clin
Immunol.}2009;123(3):713-717.

7. Rosman Y, Hershko AY, Meir-Shafrir K, et al. Characterization of
chronic urticaria and associated conditions in a large population of
adolescents. \emph{J Am Acad Dermatol.} 2019;81(1):129-135.

8. Goldstein S, Gabriel S, Kianifard F, Ortiz B, Skoner DP. Clinical
features of adolescents with chronic idiopathic or spontaneous
urticaria: Review of omalizumab clinical trials. \emph{Ann Allergy
Asthma Immunol.} 2017;118(4):500-504.

9. Netchiporouk E, Sasseville D, Moreau L, Habel Y, Rahme E, Ben-Shoshan
M. Evaluating Comorbidities, Natural History, and Predictors of Early
Resolution in a Cohort of Children With Chronic Urticaria. \emph{JAMA
Dermatol.} 2017;153(12):1236-1242.

10. Lee XH, Ong LX, Cheong JY, et al. A stepwise approach in the
management of chronic spontaneous urticaria in children. \emph{Asia Pac
Allergy.} 2016;6(1):16-28.

11. Eser I, Yologlu N, Baydemir C, Aydogan M. The predictive factors for
remission of chronic spontaneous urticaria in childhood: Outcome from a
prospective study. \emph{Allergol Immunopathol
(Madr).}2016;44(6):537-541.

12. Kilic G, Guler N, Suleyman A, Tamay Z. Chronic urticaria and
autoimmunity in children. \emph{Pediatr Allergy
Immunol.}2010;21(5):837-842.

13. Jirapongsananuruk O, Pongpreuksa S, Sangacharoenkit P, Visitsunthorn
N, Vichyanond P. Identification of the etiologies of chronic urticaria
in children: a prospective study of 94 patients. \emph{Pediatr Allergy
Immunol.} 2010;21(3):508-514.

14. Ozyilmaz-Bozat G, Sahiner UM, Buyuktiryaki B, Uysal-Soyer O, Sekerel
BE. Children with chronic spontaneous urticaria: Recurrence after
remission and its predictors. \emph{J Allergy Clin Immunol
Pract.}2020;8(2):796-798 e791.

15. Greenberger PA. Chronic urticaria: new management
options.\emph{World Allergy Organ J.} 2014;7(1):31.

16. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features
and natural history of physical urticaria in children. \emph{Pediatr
Allergy Immunol.} 2008;19(4):363-366.

17. Caffarelli C, Cuomo B, Cardinale F, et al. Aetiological factors
associated with chronic urticaria in children: a systematic
review.\emph{Acta Derm Venereol.} 2013;93(3):268-272.

18. Harris A, Twarog FJ, Geha RS. Chronic urticaria in childhood:
natural course and etiology. \emph{Ann Allergy.} 1983;51(2 Pt
1):161-165.

19. Saini S, Shams M, Bernstein JA, Maurer M. Urticaria and Angioedema
Across the Ages. \emph{J Allergy Clin Immunol
Pract.}2020;8(6):1866-1874.

20. Levy Y, Segal N, Weintrob N, Danon YL. Chronic urticaria:
association with thyroid autoimmunity. \emph{Arch Dis
Child.}2003;88(6):517-519.

21. Ferriani MP, Silva MF, Pereira RM, et al. Chronic Spontaneous
Urticaria: A Survey of 852 Cases of Childhood-Onset Systemic Lupus
Erythematosus. \emph{Int Arch Allergy Immunol.} 2015;167(3):186-192.

22. Caminiti L, Passalacqua G, Magazzu G, et al. Chronic urticaria and
associated coeliac disease in children: a case-control
study.\emph{Pediatr Allergy Immunol.} 2005;16(5):428-432.

23. Romano-Zelekha O, Graif Y, Garty BZ, Livne I, Green MS, Shohat T.
Trends in the prevalence of asthma symptoms and allergic diseases in
Israeli adolescents: results from a national survey 2003 and comparison
with 1997. \emph{J Asthma.} 2007;44(5):365-369.

24. Graif Y, Garty BZ, Livne I, Green MS, Shohat T. Prevalence and risk
factors for allergic rhinitis and atopic eczema among schoolchildren in
Israel: results from a national study. \emph{Ann Allergy Asthma
Immunol.} 2004;92(2):245-249.

25. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI, Group
IPTS. Global variations in prevalence of eczema symptoms in children
from ISAAC Phase Three. \emph{J Allergy Clin
Immunol.}2009;124(6):1251-1258 e1223.

26. Kivity S, Sade K, Abu-Arisha F, Lerman Y, Kivity S. Epidemiology of
bronchial asthma and chronic rhinitis in schoolchildren of different
ethnic origins from two neighboring towns in Israel. \emph{Pediatr
Pulmonol.} 2001;32(3):217-221.

27. Ait-Khaled N, Pearce N, Anderson HR, et al. Global map of the
prevalence of symptoms of rhinoconjunctivitis in children: The
International Study of Asthma and Allergies in Childhood (ISAAC) Phase
Three. \emph{Allergy.} 2009;64(1):123-148.

28. Nwaru BI, Hickstein L, Panesar SS, et al. The epidemiology of food
allergy in Europe: a systematic review and meta-analysis.\emph{Allergy.}
2014;69(1):62-75.

29. Grabenhenrich L, Trendelenburg V, Bellach J, et al. Frequency of
food allergy in school-aged children in eight European countries - the
EuroPrevall-iFAAM birth cohort. \emph{Allergy.} 2020.

30. Nachshon L, Schwartz N, Elizur A, et al. The Prevalence of Food
Allergy in Young Israeli Adults. \emph{J Allergy Clin Immunol
Pract.}2019;7(8):2782-2789 e2784.

31. Akinbami LJ, Simon AE, Rossen LM. Changing Trends in Asthma
Prevalence Among Children. \emph{Pediatrics.} 2016;137(1).

32. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW.
Autoantibodies against the high-affinity IgE receptor as a cause of
histamine release in chronic urticaria. \emph{N Engl J
Med.}1993;328(22):1599-1604.

\textbf{Figures and tables}

Table 1. Characterization of chronic urticaria in various age groups\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{0-3 years}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{4-8 years}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{9-12 years}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{13-18 years}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Total}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Total (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Total (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
19\textsuperscript{+} (7.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
71 (28.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
38 (15.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
122\textsuperscript{+} (48.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
250 (100\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Sex (\% of age group)\textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9 (47.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
38 (53.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
18 (47.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
49 (40.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
114 (45.6\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
10 (52.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
33 (46.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
20 (52.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
73 (59.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
136 (54.4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Duration of urticaria (\% of age group)\textsuperscript{*,++}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}6 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
8 (11.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1 (3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11 (9.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
20 (8.4\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6-12 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3 (15.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12 (17.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11 (33.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
27 (23.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
53 (22.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12-24 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13 (68.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
44 (63.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17 (51.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
61 (52.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
135 (56.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textgreater{}24 months\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3 (15.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5 (7.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4 (12.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
18 (15.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
30 (12.6\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Relapse of urticaria (\% of age group)\textsuperscript{**}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Relapse of urticaria (\% of age group)\textsuperscript{**}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 (5.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 (5.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7 (5.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
17 (13.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24 (9.6\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{+}In the youngest age group (0-3 years) there were more
patients with atopic dermatitis, while in the oldest age group (13-18
years) fewer patients had concomitant atopic dermatitis
(p\textless{}0.05).

* p=Not significant for all comparisons

** p\textless{} 0.05

\textsuperscript{++} In 12 patients (4.8\%), data regarding the duration
of urticaria were missing and they were excluded from this sub-analysis.

Table 2. Type of medication and number of drugs among 274 pediatric
patients with chronic spontaneous urticaria (CSU)\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{No. of medications}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Type of medications}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{First CSU episode}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Relapse of CSU}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
No. of Patients (\% of total cohort)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
No. of Patients (\% of total cohort)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{1}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine regular dose\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
153 (61.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (41.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (2.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (8.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Steroids course\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Montelukast only\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (4.2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Total}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{161} \textbf{(64.4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{13} \textbf{(54.2\%)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{2}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine regular dose + Steroids\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
32 (12.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (8.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose + Steroids\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (3.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine regular dose + Montelukast\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (0.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose + Montelukast\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (1.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (8.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Montelukast + Omalizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (4.2\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Total}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{46} \textbf{(18.4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{5} \textbf{(20.8\%)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{3}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose + Steroids + Montelukast\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose + steroids + Omalizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Total}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{6} \textbf{(2.4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{4}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Antihistamine high dose + Steroids + Montelukast + Omalizumab\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (8.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
No record of medications\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
No record of medications\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
37 (14.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (16.7\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Total of patients}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Total of patients}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{250}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{24}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

CSU - Chronic spontaneous urticaria

Figure 1. Prevalence of atopic diseases in children with CSU compared to
the general population. A. Prevalence of atopic diseases in CSU
patients, by age groups. B. Atopic diseases in current study and the
general pediatric population in Israel and in the world
(\textsuperscript{*}p\textless{}0.05). Prevalence data in Israel and the
world are incomplete due to lack of epidemiological studies.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/CU-figures/CU-figures}

\end{center}
\end{figure}

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

