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\begin{document}

\title{Tree nut and peanut allergy in a Portuguese pediatric cohort -- clinical
characterization and anaphylaxis predictors}



\author[1]{Rita Brás}%
\author[1]{Leonor Esteves Caldeira}%
\author[1]{Cláudia Varandas}%
\author[1]{Fátima Cabral Duarte}%
\author[1]{Célia Costa}%
\affil[1]{Centro Hospitalar Universitario Lisboa Norte EPE}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Tree nuts and peanuts (TN/P) are frequent causes of
anaphylaxis in children. Aim: to characterize a Portuguese pediatric
cohort with TN/P allergy and to assess skin tests (ST), specific IgE
(sIgE) and molecular components (mcIgE), as well as sIgE/total IgE
ratio's utility in anaphylaxis prediction. \textbf{Methods:}
Retrospective study (2017-2021) of pediatric patients with TN/P allergy,
grouped according to reaction severity (anaphylaxis--G1 \emph{vs} milder
reaction--G2). ST mean papule diameter (MPD), sIgE (ImmunoCAP\selectlanguage{ngerman}®), mcIgE
(ISAC®) and sIgE/total IgE ratio were compared (SPSS®, p\textless{}0.05:
statistically significant). \textbf{Results:} 98 patients, 64\% male,
88\% concomitant allergic disorder, 40\% allergy family history. Major
culprit nuts: peanut (63\%), hazelnut (59\%) and walnut (53\%). Index
reaction manifestations were mostly cutaneous (46\%), followed by
anaphylaxis (36\%). Chestnut and cashew sensitizations were
significantly associated with anaphylaxis (OR=5.023, p=0.002; OR=2.901,
p=0.018). MPD was higher in G1 for almond, cashew and pistachio
(p\textless{}0.05). sIgE was not a good severity predictor for any TN/P,
however, a significantly higher value of sIgE/total IgE ratio was found
in G1 for walnut (p=0.023). mcIgE was obtained in 49\%: peanut Ara h2
and Ara h6 were more represented in G1 (2.8 vs 0 ISU-E, p=0.042; 1.3 vs
0 ISU-E, p=0.020). \textbf{Conclusion:} Peanut, hazelnut and walnut were
the most frequent nuts. Anaphylaxis was the first manifestation in 36\%,
significantly higher in chestnut and cashew allergic children. MPD
should be valued not only for diagnosis, but also for anaphylaxis risk
prediction in almond, cashew and pistachio allergic patients. sIgE/total
IgE ratio seems to be useful in anaphylaxis prediction.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Tree nut and peanut allergy in a Portuguese pediatric cohort --
clinical characterization and anaphylaxis predictors}\selectlanguage{english}
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Leonor Esteves Caldeira\textsuperscript{1,\#}, Rita
Br\selectlanguage{ngerman}ás\textsuperscript{1,\#}, Cláudia Varandas\textsuperscript{1}, Fátima
Cabral Duarte\textsuperscript{1}, Célia Costa\textsuperscript{1,2}

\textsuperscript{1}Immunoallergology Department, Hospital de Santa
Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisbon,
Portugal

\textsuperscript{2}Clínica Universitária de Imunoalergologia, Faculdade
de Medicina, Universidade de Lisboa, Lisbon, Portugal

\# These authors have contributed equally and are designated to have
co-first authorship.

\textbf{Corresponding Author:}

Rita Brás

Immunoallergology Department, Hospital de Santa Maria -- Centro
Hospitalar Universitário Lisboa Norte

Avenida Prof. Egas Moniz s/n, 1649-035 Lisboa, Portugal

Tel: +351 21 780 5000

E-mail: ritasabras@gmail.com

\textbf{Text word count:} 2478 words

\textbf{Number of tables and figures:} 2+2\selectlanguage{english}
\begin{figure}[H]
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\textbf{ORCID identification:}

Leonor Esteves Caldeira\emph{https://orcid.org/0000-0003-2347-4658}

Rita Br\selectlanguage{ngerman}ás\emph{https://orcid.org/0000-0002-3059-786X}

Cláudia Varandas \emph{https://orcid.org/0000-0002-8785-4097}

Fátima Cabral Duarte \emph{https://orcid.org/0000-0002-0323-9936}

Célia Costa\emph{https://orcid.org/0000-0001-8313-1505}

\textbf{CONFLICT OF INTERESTS}

The authors declare that they have no conflict of interests.

\textbf{FUNDING}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{ABSTRACT}

\textbf{Background:} Tree nuts and peanuts (TN/P) are frequent causes of
anaphylaxis in children. Aim: to characterize a Portuguese pediatric
cohort with TN/P allergy and to assess skin tests (ST), specific IgE
(sIgE) and molecular components (mcIgE), as well as sIgE/total IgE
ratio's utility in anaphylaxis prediction.

\textbf{Methods:} Retrospective study (2017-2021) of pediatric patients
with TN/P allergy, grouped according to reaction severity
(anaphylaxis--G1 \emph{vs} milder reaction--G2). ST mean papule diameter
(MPD), sIgE (ImmunoCAP®), mcIgE (ISAC®) and sIgE/total IgE ratio were
compared (SPSS®, p\textless{}0.05: statistically significant).

\textbf{Results:} 98 patients, 64\% male, 88\% concomitant allergic
disorder, 40\% allergy family history. Major culprit nuts: peanut
(63\%), hazelnut (59\%) and walnut (53\%). Index reaction manifestations
were mostly cutaneous (46\%), followed by anaphylaxis (36\%). Chestnut
and cashew sensitizations were significantly associated with anaphylaxis
(OR=5.023, p=0.002; OR=2.901, p=0.018). MPD was higher in G1 for almond,
cashew and pistachio (p\textless{}0.05). sIgE was not a good severity
predictor for any TN/P, however, a significantly higher value of
sIgE/total IgE ratio was found in G1 for walnut (p=0.023). mcIgE was
obtained in 49\%: peanut Ara h2 and Ara h6 were more represented in G1
(2.8 vs 0 ISU-E, p=0.042; 1.3 vs 0 ISU-E, p=0.020).

\textbf{Conclusion:} Peanut, hazelnut and walnut were the most frequent
nuts. Anaphylaxis was the first manifestation in 36\%, significantly
higher in chestnut and cashew allergic children. MPD should be valued
not only for diagnosis, but also for anaphylaxis risk prediction in
almond, cashew and pistachio allergic patients. sIgE/total IgE ratio
seems to be useful in anaphylaxis prediction.

\textbf{KEYWORDS:}

Anaphylaxis; Component-resolved diagnosis; Food allergy; Peanut allergy;
Sensitization profile; Tree nut allergy.

\textbf{INTRODUCTION}

Tree nut (TN) and peanut allergy prevalence has been increasing over the
last 20 years, particularly in pediatric age, as a presumable result of
changes in recent eating habits.\textsuperscript{1-3}

Allergy prevalence for each TN appears to vary in different parts of the
world. A current systematic worldwide review of studies estimated the
global prevalence of probable TN allergy to range from 0.05\% to 4.9\%,
and peanut allergy between 0.5\% and 2.5\%.\textsuperscript{1,4,5}

These food allergies can be potentially life-threatening, accounting for
a high number of fatal food-induced anaphylaxis, even when ingested in
very small quantities or inadvertently, as occult
allergens.\textsuperscript{1-3} Recent studies reported TN and peanut
allergies as the responsible for 70--90\% of deaths from food-induced
anaphylaxis, with TN alone accounting for 18--40\%.\textsuperscript{6}

TN and peanut allergies usually develop early in life and tend to
persist into adulthood. According to previous published data,
acquisition of natural tolerance to TN and peanut occurs in only
9\%--20\% of allergic patients.\textsuperscript{7-9}

The constant need for caution when choosing food and the potential risk
of anaphylaxis, frequently leading to diet and social activities
restrictions, significantly affects both patient and family's quality of
life. Presently, and regardless of years of research, the management
cornerstone of these patients remains strict avoidance of the
incriminated nut, in addition to patient and family's education on
prompt recognition of anaphylaxis and immediate use of
adrenaline.\textsuperscript{10,11} Other treatment possibilities have
been largely explored, namely oral immunotherapy, for peanut and TN
allergic patients, but their use is still limited.\textsuperscript{12}

Homology amongst nut proteins and cross-reactivity between their main
allergens (namely 2S albumins, 7S and 11S globulins, lipid transport
proteins {[}LTPs{]}, and PR-10) leads to frequent co-sensitization in
nut allergic patients, which does not always mean a true concurrent
allergy to different nuts.\textsuperscript{13} As a result, it can be
challenging to manage these patients and a distinction between
cross-sensitization and clinically relevant cross-reactivity between
different TN and peanut is critical, although it frequently requires
multiple oral food challenges (OFC) with the associated risk of a
possible anaphylaxis. For this fact, dietary restriction of all TN and
peanut is a common practice. Deeper knowledge of sensitization patterns
and investigation of possible anaphylaxis predictors would be of great
value to establish a more precise diagnostic approach and individual
dietary guidance for patients allergic to these
foods.\textsuperscript{1-5}

In non-English-speaking countries, like Portugal, data on sensitization
patterns and anaphylaxis predictors is sparse. We aimed to characterize
a pediatric cohort with TN and peanut allergy followed in an
Immunoallergology department of a Portuguese tertiary hospital, and to
assess the utility of skin tests (ST), specific IgE (sIgE) and molecular
components (mcIgE), as well as ratio sIgE/total IgE in predicting the
anaphylaxis risk.

\textbf{METHODS}

\textbf{Study design and population}

A five-year single-center, observational, retrospective study was
conducted, including Portuguese children (0-18 years-old) referred to
Food Allergy consultation for TN and/or peanut IgE-mediated allergy
suspicion between January 2017 and December 2021. The study was approved
by the hospital's ethics committee and all patients' parents/guardians
gave an informed consent.

\textbf{Data collection and Interventions}

Patients' charts were reviewed for demographic, clinical and analytical
data collection. Detailed information for the characterization of the
index reaction (first nut reaction which motivated referral to Food
Allergy Consultation) was obtained. Post-index nut reactions or nut
allergies diagnosed during patients' allergological investigation were
also assessed. Patients were considered allergic to a specific nut if
they had a suggestive clinical history and at least one positive test of
the following: (1) skin prick/prick-prick tests (SPT/SPPT); (2) sIgE;
(3) OFC. In the absence of previous contact or in cases of previous
ingestion without reaction, and evidence of sensitization to a specific
nut (positive SPT/SPPT and/or sIgE), only those with a positive OFC were
considered allergic. Previous personal and family history of atopy was
also recorded.

Allergological investigation included ST, serum analysis of total IgE,
sIgE for TN and peanut and mcIgE, and OFC. For ST, mean papule diameter
(MPD) \selectlanguage{english}[?]3mm above the negative control was considered a positive result.
When SPT was negative or commercial extract was unavailable, SPPT was
carried out. Regarding serum analysis, cut-off value for positive result
for total IgE and sIgE (ImmunoCAP(r), Thermo Fisher Scientific) was
\textgreater{}0.35 kU/L, while for mcIgE (ImmunoCAP(r) ISAC-112, Thermo
Fisher Scientific) was \selectlanguage{english}[?]0.1 ISU-E. OFC was performed only in selected
cases, as it is the gold standard for allergy confirmation or exclusion.

\textbf{Anaphylaxis predictors assessment}

Children were grouped according to reaction severity for anaphylaxis
risk assessment. Patients with a reaction compatible with anaphylaxis
(definition based on Muraro et al. criteria\textsuperscript{12,14}) were
included in group 1 (G1), while those with a milder reaction (oral
allergy syndrome or systemic reaction without severity to fulfil
anaphylaxis criteria) were included in group 2 (G2). The following
variables were compared between groups: MPD of ST (for methodologic
uniformization only SPPT were considered in this analysis), sIgE and
mcIgE values, as well as ratio sIgE/total IgE.

\textbf{Statistical analysis}

Continuous variables were presented as means and standard deviations, or
medians and interquartile ranges for variables with skewed
distributions, and categorical variables as frequencies and percentages.
Normal distribution was confirmed using Shapiro-Wilk test. Categorical
variables were compared using Fisher's exact test or the Chi-square
test, as appropriate, while t-independent test and Mann-Whitney test
were used to compare parametric and non-parametric independent samples,
respectively. \emph{P} -values \textless{}0.05 were considered
statistically significant. Analyses were performed with the use of IBM
SPSS software (version 25.0).



\textbf{RESULTS}

\textbf{Clinical characterization}

A total of 150 clinical records of children with suspected TN and/or
peanut allergy were reviewed, of which 52 were excluded (38 for
exclusion of nut allergy and 14 for incomplete data). As a result, 98
patients were included in this study, of whom 63 were male (64\%).

The majority of patients (n=86, 88\%) had a concomitant allergic
disorder: 76 (78\%) allergic rhinoconjunctivitis, 50 (51\%) asthma, 45
(46\%) another food allergy, including 30 (31\%) with egg allergy, and
43 (44\%) eczema. Thirty-nine (40\%) patients had a family history of
allergy \textbf{(Table 1)} .

Major culprit nuts were peanut (n= 62, 63\%), hazelnut (n=58, 59\%),
walnut (n=52, 53\%), almond (n=37, 38\%) and cashew (n=31, 32\%),
followed by chestnut (n=19, 19\%), pistachio (n=18, 18\%) and pine nut
(n=6, 6\%). Eighty-eight (86\%) patients reported a single-nut reaction,
although only 31 (32\%) were monosensitized after allergological
investigation was carried out (16 to peanut, 7 to walnut, 4 to cashew, 2
to hazelnut and 2 to pine nut). In 96 (98\%), symptoms appeared within
30 minutes after exposure. The index reaction occurred before 2 years in
26\% of patients and in the majority (59\%) before the 5
years.\textbf{(Table 1)} .

\textbf{Index reaction}

Patients' mean age of index reaction was 5.8 years (standard deviation
(SD) 4.6, range 0.2-17), being significantly lower in patients
describing peanut reactions (4.6 years (SD 3.5, range 0.2-17 years),
comparing with patients describing TN reactions (6.7 years, SD 5.8,
range 0.2-17 years) (p=0.02) \textbf{(Table 1)} .

Index reaction manifestations were more frequently cutaneous (n=45,
46\%), with urticaria/angioedema in 38 (84\%) children and eczema
exacerbation in 7 (16\%). Thirty-five (36\%) patients described a
reaction compatible with anaphylaxis. Gastrointestinal symptoms were
reported by 16 (16\%) patients, of whom 9 (56\%) oral allergy syndrome,
5 (31\%) nausea and vomiting and 2 (13\%) abdominal pain. Lastly, 2
(2\%) patients presented shortness of breath \textbf{(Figure 1)} .

\textbf{Skin tests and laboratory parameters}

More than half of the allergic population (n=50, 51\%) had positive SPT
results to various nuts and 38 (39\%) had positive SPPT. MPD of SPT and
SPPT to the respective nuts are represented in \textbf{table 2} , as
well as whole extract sIgE. Mean value of total IgE was 1860 U/mL (SD
1984, range 17-6314 U/mL).

Molecular components were obtained for 48 (49\%) patients. The most
frequent allergens were from LTP family, predominantly Pru p 3, for
which 20 (42\%) patients showed positivity. Subsequently, the most
relevant was Ara h 9 (n=17, 35\%), followed by Jug r 3 (n=16, 33\%), Cor
a 8 (n=12, 25\%) and Tri a 14 (n=4, 8\%). The 2S albumin family was the
second most documented, namely Jug r 1 (n=18, 38\%), Ara h 2 (n=13,
27\%) and Ara h 6 (n=11, 23\%).

\textbf{Oral Food Challenges}

A total of 17 OFCs were performed, of which 15 were conducted to
diagnose secondary nut allergy, with non-culprit nuts, and 2 to clarify
index reactions to a specific nut. Of the first 15 OFCs, 9 were
performed to other nut to which patients were sensitized, but not
exposed to before, all of them with negative or low levels of sIgE
(\textless{}2 kU/L) to the respective nut. In the remaining 6 OFCs,
patients had negative skin tests/sIgE and an OFC was performed to
confirm non-allergy and safety in nut introduction. Six (35\%) OFCs were
positive (4 with non-culprit nuts and 2 with the suspected nut). All
these patients had mild cutaneous reactions (2 pruritus, without
lesions, and 4 urticaria), 4 of them with spontaneous resolution. The
remaining 2 had symptoms resolution after treatment with oral
antihistamines.

\textbf{Anaphylaxis Predictors}

A significant association was found between anaphylaxis and allergy to
chestnut (OR 5.023 {[}IC 95\% 1.691-14.922{]}, p=0.002) and cashew (OR
2.901 {[}IC 95\% 1.184-7.107{]}, p=0.018) (\textbf{Figure 2A} ).
Reaction severity was independent of the number of nut sensitizations
(p=0.655). Considering SPPT, MPD was significantly higher in G1 for
almond (6.5 vs 4mm, p=0.015), cashew (10 vs 5mm, p=0.049) and pistachio
(8 vs 3.75mm, p=0.046) (\textbf{Figure 2B} ). sIgE values were not good
predictors of reaction severity for any nut (\textbf{Figure 2C} ).
However, a significantly higher value of sIgE/total IgE ratio was found
in G1 for walnut (0.0125 vs 0.0005, p=0.023) (\textbf{Figure 2D} ).
There was no significant association between symptoms severity and serum
eosinophils (682.9 vs 596.6/\selectlanguage{greek}µ\selectlanguage{english}L, p=0.261) or total IgE (603.4 vs 1879.6
kUA/L, p=0.068). As for the mcIgE, peanut Ara h2 and Ara h6 were
identified in more patients from G1 \emph{vs} G2, with higher median
mcIgE values (2.8 vs 0 ISU-E, p 0.042; 1.3 vs 0 ISU-E, p=0.020)
(\textbf{Figure 2E} ).

\textbf{DISCUSSION}

In this retrospective Portuguese pediatric study that included 98
patients, the most frequent nuts involved were peanut (63\%), hazelnut
(59\%) and walnut (53\%). Mean age at first reaction was 5.8 years,
being younger in patients with peanut allergy comparing with other nuts
(4.6 years versus 6.7 years, p=0.02). We assume that it is a possible
consequence of a recent rising nuts consumption in pediatric population
in our country, predominantly of peanut. In Spain, Haroun-D\selectlanguage{ngerman}íaz E\emph{et
al} . reported these same three nuts (hazelnut, peanut and walnut) as
the most frequent nuts eliciting allergy.\textsuperscript{15}Allergy
prevalence for each TN seems to vary in different regions of the world:
hazelnut allergy is the most frequent in continental Europe; peanut,
brazil nut, walnut and almond are the most commonly reported in the
United Kingdom, and walnut and cashew allergies in the United States.
These differences are representative of the variations in nuts
consumption in each country, leading to different sensitization
patterns.\textsuperscript{8, 16,17}

Most patients had history of atopy (n=86, 88\%), including 44\% with
eczema and 31\% with egg allergy. Cetinkaya PG \emph{et al.} reported a
higher frequency of these atopic conditions in patients allergic to
nuts, with 72\% having atopic dermatitis and 50\% egg allergy, probably
related to a higher number of involved children.\textsuperscript{18} The
epithelial barrier dysfunction characteristic of atopic dermatitis is a
confirmed risk factor for the development of allergic sensitization,
food allergy and other allergic diseases. Many epidemiological studies,
and recently also studies in animals, demonstrated the connection
between skin and digestive tract. Damaged keratinocytes produce IL-33,
that stimulates group 2 innate lymphoid cells (ILC2) in the small
intestine. These in turn produce IL-4 and IL-13, which leads to the
expansion of activated mast cells, resulting in an increment of
intestinal permeability and consequent transmission of allergens that
can trigger food allergy.\textsuperscript{19,20}

Nut reactions may be severe on the first contact. About one third of our
patients presented with anaphylaxis, and more than half were
polysensitized to several nuts, which in accordance with recent data of
international cohorts.\textsuperscript{1, 18} Avoidance of all nuts has
been the rule for many years in patients allergic to one nut, but the
possible introduction of other nuts has recently been investigated in
several studies.\textsuperscript{21,22} In our study, 9 out of the 15
OFCs performed with non-culprit nuts to which patients were sensitized,
but not exposed to before, were negative, favoring the above-mentioned
idea of avoiding unnecessary nuts restrictions. Additionally, 31 (32\%)
were monosensitized after allergological investigation (16 to peanut, 7
to walnut, 4 to cashew, 2 to hazelnut and 2 to pine nut).

IgE sensitization to pan-allergen LTP were the most prevalent in our
population, differently from a Spanish cohort that found the 2S albumin
family of the seed storage proteins as the most
frequent.\textsuperscript{1} It is, however, in line with recently
published Portuguese data.\textsuperscript{23}

In our pediatric cohort, anaphylaxis was more common in patients with
chestnut and cashew allergies. Severe systemic reactions in patients
sensitized to cashew have been frequently reported in
Europe.\textsuperscript{9,12,14} A Portuguese study on TN anaphylaxis in
preschool age children concluded that cashew was the major culprit,
accounting for 11 of the 25 cases.\textsuperscript{24} Data on chestnut
allergy is sparce, especially considering prevalence and reaction's
severity. Our results could be explained by Portuguese eating habits,
with chestnut being one of the most appreciated nuts, typical of the
colder months.

Allergological investigation proved to be useful in anaphylaxis risk
prediction. MPD should be valued not only for diagnosis but also for
anaphylaxis risk prediction. In our study, MPD was significantly higher
for almond, cashew and pistachio in patients with anaphylaxis to these
TNs. Other authors reported utility of ST in diagnosis prediction (MPD \selectlanguage{english}[?]
8mm), but not in anaphylaxis risk prediction.\textsuperscript{9,12} sIgE
did not differ significantly between groups. However, it should be taken
into account that there was limited availability of whole extract sIgE
for some of the nuts analyzed (namely cashew, pistachio, chestnut and
pine nut) and that not all patients did sIgE measurements. In addition,
as previously postulated,\textsuperscript{25,26} our study highlights
the important adding value that sIgE/total IgE ratio could bring to
clinical practice. For example, sIgE measurement for walnut was not a
good predictor of anaphylaxis but, when integrated in sIgE/total IgE
ratio, it reached statistical significance. Component-resolved diagnosis
was used as a study complement, showing interest in risk stratification,
particularly for peanut, with Ara h 2 and Ara h 6 being significantly
higher in patients with anaphylaxis, which is in line with other
reports.\textsuperscript{26}

The present study has some limitations, such as the small sample of
patients, which limits extrapolation of the results, and its
retrospective design, that could itself weaken our findings. However, it
is the first Portuguese study which extensively characterizes a
pediatric population with TN and peanut allergy, analyzing the clinical
utility of ST, sIgE and mcIgE measurements and, importantly and sparsely
reported, sIgE/total IgE ratio in anaphylaxis prediction, and so the
authors believe that it could add significant value to clinical
practice.

\textbf{Impact Statement:}

The present study characterizes a Portuguese cohort of 98 pediatric
patients with tree nut and peanut allergy, pointing out the clinical
utility of skin tests, specific IgE and molecular components in
anaphylaxis prediction, as well as the interesting adding value of
sIgE/total IgE ratio for nut allergy in clinical practice.

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\textbf{TABLES AND FIGURES}

\textbf{Table 1.} Demographic and clinical characterization of patients
with tree nut and peanut allergy\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Characteristics & Patients (n=98)\tabularnewline
\midrule
\endhead
Gender, n (\%) - Male - Female & 63 (64\%) 35 (36\%)\tabularnewline
Atopic comorbidities, n (\%) - Allergic rhinoconjunctivitis - Asthma -
Another food allergy - Eczema & \textbf{86 (88\%)} 76 (78\%) 50 (51\%)
45 (46\%) 43 (44\%)\tabularnewline
Family history of allergy, n (\%) & \textbf{39 (40\%)}\tabularnewline
Culprit nuts, n (\%) - Peanut - Hazelnut - Walnut - Almond - Cashew -
Chestnut - Pistachio - Pine nut & 62 (63\%) 58 (59\%) 52 (53\%) 37
(38\%) 31 (32\%) 19 (19\%) 18 (18\%) 6 (6\%)\tabularnewline
Single-nut reaction, n (\%) Monosensitized, n (\%) & \textbf{88 (86\%)}
31 (32\%)\tabularnewline
Index reaction - Symptoms [?] 30 minutes after exposure, n (\%) - Mean age
of index reaction, years {[}range{]} & 96 (98\%) 5.8 (SD 4.6)
{[}0.2-17{]}\tabularnewline
Age distribution of index reaction by ranges - 0-2 years - 3-5 years -
6-10 years - 11-18 years & 25 (26\%) 32 (33\%) 24 (24\%) 17
(17\%)\tabularnewline
\bottomrule
\end{longtable}

SD: standard deviation.

\textbf{Figure 1.} Clinical manifestations of the index reaction among
the studied population.

\textbf{Table 2.} Results of mean papule diameter of skin prick (SPT)
and skin prick-prick tests (SPPT) and mean values of serum-specific IgE
levels (sIgE) (ImmunoCAP\selectlanguage{ngerman}®) to the respective nuts.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& SPT (mm) (Mean papule diameter \selectlanguage{ngerman}± SD) & SPPT (mm) (Mean papule diameter
\selectlanguage{ngerman}± SD) & sIgE (kUA/L) (Mean \selectlanguage{ngerman}± SD)\tabularnewline
\midrule
\endhead
Histamine (10 mg/mL) & 5.6 \selectlanguage{ngerman}± 1.6 & - & -\tabularnewline
Peanut & 7.3 \selectlanguage{ngerman}± 3.4 & 9.1 \selectlanguage{ngerman}± 7.8 & 18.8 \selectlanguage{ngerman}± 28.8\tabularnewline
Walnut & 6.4 \selectlanguage{ngerman}± 3.5 & 9.3 \selectlanguage{ngerman}± 4.9 & 13.8 \selectlanguage{ngerman}± 23.7\tabularnewline
Hazelnut & 4.3 \selectlanguage{ngerman}± 1.9 & 9.3 \selectlanguage{ngerman}± 4.2 & 10.8 \selectlanguage{ngerman}± 14.2\tabularnewline
Almond & 5.3 \selectlanguage{ngerman}± 2.4 & 6.9 \selectlanguage{ngerman}± 2.9 & 5.1 \selectlanguage{ngerman}± 9.7\tabularnewline
Cashew & 7.1 \selectlanguage{ngerman}± 3.6 & 11.2 \selectlanguage{ngerman}± 7.3 & 5.8 \selectlanguage{ngerman}± 7.7\tabularnewline
Chestnut & 5 \selectlanguage{ngerman}± 1.5 & 7.0 \selectlanguage{ngerman}± 4.2 & 2.0 \selectlanguage{ngerman}± 2.3\tabularnewline
Pine nut & 8 \selectlanguage{ngerman}± 2.8 & 5.9 \selectlanguage{ngerman}± 3.1 & 0.5 \selectlanguage{ngerman}± 0.04\tabularnewline
Pistachio & 6.3 \selectlanguage{ngerman}± 3.4 & 8.8 \selectlanguage{ngerman}± 7.5 & 7.3 \selectlanguage{ngerman}± 8.3\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

The mean diameter of papules was expressed in millimeters (mm) and those
with a diameter of 3 mm above the negative control were considered
positive. SD - standard deviation.

\textbf{Figure 2.} Differences between anaphylaxis (G1) vs
non-anaphylaxis (G2) groups regarding culprit nuts (A), mean papule
diameter (MPD) of SPPT (B), sIgE (C), sIgE/total IgE ratio (D) and mcIgE
(E). *p \textless{} 0.05\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

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

