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\begin{document}

\title{Infants and toddlers with sensitization to peanut are often
co-sensitized to tree nuts}



\author[1]{Lara Meixner}%
\author[1]{Stephanie Heller}%
\author[1]{Friederike Bluhme}%
\author[1]{Valérie Trendelenburg}%
\author[1]{Kirsten BEYER}%
\author[1]{Birgit Kalb}%
\affil[1]{Humboldt Universitat zu Berlin Institute of Corporate Finance}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background} Due to changes in dietary habits tree nuts (TN) are
consumed in many households and TN allergy appears to be increasing. One
risk factor seems to be allergies to other food such as peanuts. The aim
of our study was to investigate, how often peanut-sensitized infants and
toddlers are co-sensitized to cashew, hazelnut and walnut and to
determine the likelihood of its clinical relevance by their 2S
albumin-specific (s)IgE. \textbf{Methods} Sera of 101 peanut-sensitized
children, 5 to 24 months of age (median 16 months) were analyzed
regarding sIgE to hazelnut, walnut and cashew and to their 2S-albumins
Cor a 14, Jug r 1 and Ana o 3 as well as to Ara h 1 and 2, by using the
NOVEOS \textsuperscript{TM} immunoanalyzer system. \textbf{Results} 96\%
of the peanut-sensitized children were co-sensitized to at least one TN
with 94.1\% to hazelnut, 87.1\% to walnut and 84.2\% to cashew. More
than half (58.4\%) of the children were sensitized to at least one 2S
albumin with similar rates for infants and toddlers, 26.7\% to all
three. Moreover, sensitization rates were similar in peanut allergic and
tolerant children. Estimating the likelihood of clinical relevance,
15.8\% of all peanut-sensitized children had an at least 90\%
probability to be hazelnut and/or cashew allergic. \textbf{Conclusion}
TN sensitization seems to be common among peanut-sensitized infants and
toddlers. Many had a high likelihood to be TN allergic. Therefore, it
should be considered to determine TN-sIgE in peanut-sensitized children
if TN are not consumed so far.%
\end{abstract}%



\sloppy


\textbf{Infants and toddlers with sensitization to peanut are often
co-sensitized to tree nuts}

\textbf{Authors:} Lara Meixner\textsuperscript{1}, Stephanie
Heller\textsuperscript{1}, Friederike Bluhme\textsuperscript{1}, Val\selectlanguage{ngerman}érie

Trendelenburg\textsuperscript{1}, Kirsten Beyer\textsuperscript{1¥}/
Birgit Kalb\textsuperscript{1¥}

\textbf{Affiliations:} 1 Department of Pediatric Respiratory Medicine,
Immunology and Critical

Care Medicine, Charité -- Universitätsmedizin Berlin, corporate member
of

Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany

\textsuperscript{¥}These authors jointly supervised this work.

\textbf{Email:}lara.meixner@charite.de; stephanie.heller@charite.de;
friederike.bluhme@charite.de; valerie.trendelenburg@gmail.com;

birgit.kalb@charite.de; kirsten.beyer@charite.de

\textbf{Corresponding author:} Lara Meixner, lara.meixner@charite.de

Department of Pediatric Respiratory Medicine, Immunology

and Critical Care Medicine, Charité -- Universitätsmedizin

Berlin, corporate member of Freie Universität Berlin and

Humboldt-Universität zu Berlin, Augustenburgplatz 1,

13353 Berlin, Germany

\textbf{Word count:} Abstract 246, Text 2495

\textbf{Number of tables and figures:} 1 table, 3 figures

\textbf{Appendices:} Table S1 as supportive information

\textbf{Conflicts of interests:}

Kirsten Beyer reports advisory board/consulting fees or speakers bureau
from Aimmune Therapeutics, Bencard, Danone/Nutricia, DBV, Hycor,
Infectopharm, Mabylon, Meda Pharma/Mylan, Nestle, Novartis and
ThermoFisher as well as research grants from Aimmune, ALK,
Danone/Nutricia, DBV Technologies, Hipp, Hycor, Infectopharm and
Novartis outside the submitted work. Birgit Kalb reports advisory
board/consulting fees from Viatris. Valérie Trendelenburg received
speaker's fees from Nutricia/Danone. Friederike Bluhme, Stephanie Heller
and Lara Meixner have nothing to disclose.

\textbf{Financial support:} This study was funded in part by the
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) as
part of the clinical research unit (CRU339): Food allergy and tolerance
(FOOD@) -- 409525714.

\textbf{Background}

Due to changes in dietary habits tree nuts (TN) are consumed in many
households and TN allergy appears to be increasing. One risk factor
seems to be allergies to other food such as peanuts. The aim of our
study was to investigate, how often peanut-sensitized infants and
toddlers are co-sensitized to cashew, hazelnut and walnut and to
determine the likelihood of its clinical relevance by their 2S
albumin-specific (s)IgE.

\textbf{Methods}

Sera of 101 peanut-sensitized children, 5 to 24 months of age (median 16
months) were analyzed regarding sIgE to hazelnut, walnut and cashew and
to their 2S-albumins Cor a 14, Jug r 1 and Ana o 3 as well as to Ara h 1
and 2, by using the NOVEOS\textsuperscript{TM} immunoanalyzer system.

\textbf{Results}

96\% of the peanut-sensitized children were co-sensitized to at least
one TN with 94.1\% to hazelnut, 87.1\% to walnut and 84.2\% to cashew.
More than half (58.4\%) of the children were sensitized to at least one
2S albumin with similar rates for infants and toddlers, 26.7\% to all
three. Moreover, sensitization rates were similar in peanut allergic and
tolerant children. Estimating the likelihood of clinical relevance,
15.8\% of all peanut-sensitized children had an at least 90\%
probability to be hazelnut and/or cashew allergic.

\textbf{Conclusion}

TN sensitization seems to be common among peanut-sensitized infants and
toddlers. Many had a high likelihood to be TN allergic. Therefore, it
should be considered to determine TN-sIgE in peanut-sensitized children
if TN are not consumed so far.

\textbf{Keywords} Tree nut sensitization, infants, toddlers, eczema,
peanut sensitization, food allergy

\textbf{Abbreviations}

DBPCFC Double-blind Placebo Controlled Food Challenge

HEAP Randomized placebo-controlled trial of hen's egg consumption for
primary prevention in infants

IgE Immunoglobulin E

OFC Oral Food Challenge

PRACTALL PRACTical issus of ALLergology, Joint United States/European
Union Initiative

\textbf{Background}

IgE-mediated food allergy affects up to 8\% of infants and children in
industrialized countries and often starts early in infancy (1).
Especially infants with eczema are at high risk for developing food
allergies and it is the current understanding that sensitization occurs
via the cutaneous route due to an impaired skin barrier function (2, 3).
Accordingly, a high peanut consumption in the household has been shown
to be a possible risk factor for developing peanut allergy in infancy
(4). Moreover, we demonstrated that food proteins, such as peanut and
hen's egg can be found not only in the eating area, but also in bed dust
and increase with consumption, further supporting the hypothesis of
cutaneous sensitization (5, 6). Therefore, German S3-guidelines on
allergy prevention recommend that peanut allergy should first be ruled
out in infants with moderate to severe atopic dermatitis, before
introducing peanut into the infant´s diet for preventive purposes (7).
What about other food allergens such as tree nuts? It has been shown
that infants with eczema are at risk for multiple food sensitizations
(8). During the last decades, nutrition across Western countries has
changed substantially as for example vegan and plant-based diets have
become a growing trend (9). Tree nuts, such as cashews, hazelnuts and
walnuts are a nutritional mainstay of plant-based diets (10). Moreover,
plant-based alternatives for milk and milk-products often contain tree
nuts and such products are gaining in popularity among consumers (11).
These changes in dietary habits may lead to a wider spread of tree nut
allergens in households, increasing the risk for cutaneous exposure in
infants. Moreover, tree nuts are very potent allergens, as evidenced by
having caused up to 21\% of all fatal anaphylaxis cases among children
between 1992 and 2018 in the United Kingdom (12). Among tree nuts,
hazelnut, cashew and walnut are the most common triggers inducing
anaphylaxis in children in Europe (13). Regarding the clinical
reactivity, sensitization to 2S albumins of peanut and tree nuts have
been shown to be associated with severe allergic reactions (14). Ana o
3, the 2S albumin of cashew, discriminates between allergic and tolerant
children better than cashew-specific IgE and probability curves for Ana
o 3-specific IgE have been calculated, a 95\% probability could be
estimated at 2.0 kU/l (15). Similarly, the 2S albumin of hazelnut, Cor a
14, estimates the probability for a positive clinical reaction, with a
90\% probability for hazelnut allergy at 47.8 kU/l (16). Concerning
walnut, the 2S albumin Jug r 1 has been shown most accurate for
estimating the risk for clinical relevant walnut allergy (17). There are
hints, that individuals with peanut allergy have a higher likelihood of
being allergic to tree nuts compared to the general population (18, 19).
Therefore, the question comes up what to recommend in a peanut-allergic
child: To eat, to screen, or to avoid as it has been recently discussed
in this journal (20)? To date, there are scarce data on the
sensitization patterns to tree nuts in very young infants and children
with peanut sensitization. Therefore, the aim of this study was to
investigate, how often peanut-sensitized infants and toddlers are
sensitized to cashew, hazelnut and walnut and their seed storage
proteins, which might be associated with a high risk for clinical
reactivity. We hope to add some important information to this
discussion.

\textbf{Methods}

\textbf{Study design and population}

The study cohort consists of infants and toddlers who were referred to
our clinic with suspected peanut allergy. Some patients underwent an
oral food challenge (OFC) for routine diagnostics between 2007 and 2020.
Patient history, atopic comorbidities, OFC test results and objective
clinical symptoms were obtained from the ongoing EFA (Eczema and Food
Allergy) registry. Blood was collected from all patients in the frame of
routine diagnostics. Inclusion criteria for the analysis of
co-sensitization was age \selectlanguage{english}[?] 2 years and specific IgE (sIgE) to peanut \selectlanguage{english}[?]
0.1 kU/l. Parents provided written informed consent. The study was
approved by the ethics committee of the Charite Universitatsmedizin,
Berlin.

\textbf{Study procedures: oral food challenges}

OFCs were performed either in an open (6.2\%) or double-blind,
placebo-controlled (93.8\%) manner (DBPCFC) by trained staff following
the PRACTALL criteria (21). Allergens were blinded in a food matrix
(e.g. apple sauce) and fed in seven increasing doses (amounts equal to 3
mg, 10 mg, 30 mg, 100 mg, 300 mg, 1 g and 3 g of peanut protein) over
30-minutes intervals under clinical supervision. A positive challenge
outcome was defined by objective clinical reactions (e.g.
urticaria/angioedema, vomiting, wheezing/stridor,
rhinitis/conjunctivitis and/or a decrease in blood pressure). After
completion of all 7 titration steps without the occurrence of any kind
of objective allergic reaction, patients received a subsequent
cumulative dose of 4.5 g of peanut on the following day, proving
clinical tolerance in case of no objective symptoms.

\textbf{Laboratory investigations}

The detection of sIgE to peanut, hazelnut, walnut and cashew and to
their respective 2S albumins Ara h 2, Cor a 14, Jug r 1, Ana o 3 as well
as to the 7S vicilin-like globulin Ara~h~1, was performed by using the
NOVEOS\textsuperscript{TM} immunoanalyzer (Garden Grove, California,
USA). Sensitization was defined as specific IgE \selectlanguage{english}[?] 0.1 kU/l.

\textbf{Statistical Analysis}

All statistical analyses were performed using R version 4.2.0 (R Core
Team 2022). Categorical data are shown as absolute and relative
frequencies; continuous data are expressed as median and range. To test
if there were significant differences in sensitization patterns between
patients that were allergic or tolerant to peanut, chi-squared tests
were used (key basic assumptions of the test were not fulfilled
regarding sensitization to hazelnut and walnut). Wilcoxon tests were
performed to analyze if there were significant differences in sIgE
levels between peanut-allergic and peanut-tolerant patients. P-Values
were adjusted using the Bonferroni adjustment. A p-value of \textless{}
0.05 was considered to indicate a significant difference. In order to
determine the probability for a positive hazelnut food challenge by Cor
a 14\selectlanguage{english}-sIgE and for a positive cashew food challenge by Ana o 3\selectlanguage{english}-sIgE for
each patient, probability curves by Beyer et al. and Lange et al. were
utilized (15, 16). Since there is no probability curve available for
walnut, the individual risk for a positive OFC with walnut could not be
estimated.

\textbf{Results}

\textbf{Patient characteristics}

In total, sera from 101 peanut-sensitized patients (peanut-sIgE \selectlanguage{english}[?] 0.1
kU/l) were analyzed. The median age of the patients at the time of blood
drawing was 16 months (range: 5-24 months). 26 patients (25.7\%) were \selectlanguage{english}[?]
12 months of age. Nearly all patients (98\%) suffered from eczema. A
high proportion was sensitized to Ara h 1 (83.2\%) and Ara h 2 (70.3\%).
Of 81 (80.2\%) patients undergoing an OFC with peanut, 33 (40.7\%)
showed objective symptoms of an immediate type allergic reaction and
were therefore proven to be allergic. Details on patient characteristics
are provided in table 1.

\textbf{Pattern of sensitization}

Specific IgE \selectlanguage{english}[?] 0.1 kU/l to at least one tree nut was detected in 96.0\%
(n=97) of the peanut-sensitized infants and toddlers. Most children were
sensitized to hazelnut (n=95; 94.1\%; sIgE median 1.21 kU/l; range,
0.11-101 kU/l), followed by walnut (n=88; 87.1\%; sIgE median 0.87 kU/l;
range, 0.10-101 kU/l) and cashew (n=85; 84.2\%; sIgE median 0.97 kU/l;
range, 0.10-101 kU/l) (Figure 1). More than half (59/101; 58.4\%) were
sensitized to at least one 2S albumin with 42 patients (41.6\%) were
sensitized to Cor a 14 (median, 0.39 kU/l; range, 0.10-101 kU/l) and Jug
r 1 (median, 0.41 kU/l; range, 0.10-101 kU/l), while 40 patients
(39.6\%) were sensitized to Ana o 3 (median, 0.46 kU/l; range, 0.10-101
kU/l) (Figure 1). We detected sIgE \selectlanguage{english}[?] 0.1 kU/l to all three tree nuts in
80.2\% (n=81) and to all of the corresponding 2S albumins in 26.7\%
(n=27) of the children. Of the participants aged \selectlanguage{english}[?]12 months 88.5\%
(n=23) were sensitized to at least one tree nut, 46.2\% (n=12) to at
least one 2S albumin and 34.6\% (n=9) to all three 2S albumins (data are
not shown).

\textbf{Sensitization pattern in patients with peanut allergy or
tolerance}

In 81 (80.2\%) of the 101 peanut-sensitized children OFCs have been
performed in order to determine their clinical reactivity. Their
characteristics are shown in Table S1. As expected, peanut-allergic
patients had significantly higher levels of peanut- and Ara h 2-sIgE
(Table S1). We observed no significant difference between
peanut-allergic (n=33) and peanut-tolerant (n=48) children regarding
their sensitization to tree nuts (Figure 2, Table S1).

\textbf{Clinical reactivity to tree nuts according to probability
curves}

Clinical reactivity to hazelnut and cashew was estimated according to
probability curves for Cor a 14- and Ana o 3-sIgE, respectively, as
published in the literature (15, 16). As shown in Figure 3, five of the
101 peanut-sensitized infants and toddlers (5.0\%) would have reacted
with 90\% probability to hazelnut and 14 (13.9\%) to cashew. In total,
15.8\% (n=16) of all peanut-sensitized children had an at least 90\%
predicted probability to be allergic to hazelnut and/or cashew. Of
these, 18.8\% (n=3) were known to be allergic to peanut, 75.0\% (n=12)
were clinical tolerant and for one the clinical relevance was not known
(data not shown). Moreover, 13.9\% (n=14) of the 101 infants and
toddlers would have an \textgreater{} 50\% probability to be hazelnut
and 23.8\% (n=24) to be cashew allergic (Figure 3).

\textbf{Discussion}

We were able to show that peanut-sensitized infants and toddlers are
often co-sensitized to tree nuts and their 2S albumins. Regarding
co-existing tree nut allergy among peanut-allergic children several
observational studies have been conducted. In the population-based
Australian HealthNuts study cohort of 5,276 participants, 27\% (95\% CI:
16.1\%, 39.7\%) of children with peanut allergy at the age of one year
had tree nut allergy at 6 years of age (19). The authors of the
SchoolNuts study, a cohort of 9816 school children aged 10--14 years,
reported that tree nut allergy co-existed in 41.5\% of peanut-allergic
children (18). Moreover, our data indicates that even very young
peanut-sensitized children below 2 years of age may frequently be
sensitized to tree nuts and their seed storage proteins. Calculating the
likelihood of clinical relevance, we could show that many of these
infants and toddlers would present allergic symptoms.

Almost all of the children included in our analysis (98\%) suffered from
eczema, which is known to be a major risk factor for sensitization and
the development of food allergy (3). In the HEAP study, we observed that
65\% of infants with eczema were sensitized to hen's egg at the early
age of 4 to 6 months compared to only 9\% of sensitized infants without
eczema (22). It seems that low-dose concentrations of food allergens in
the environment, for example in house dust, can penetrate a disrupted
skin barrier, ultimately leading to Th2-response and IgE production (2).
In this context, results from the PreventADALL birth cohort showed that
a high transepidermal water loss, a marker for impaired skin barrier
function, is able to predict sensitization at 6 months of age with
61.7\% sensitivity and 78.1\% specificity (8). Moreover, we have
observed that food allergens like peanut and hen's egg proteins can be
detected in house dust and that they even can be found in the infant's
bed after consumption in the eating area (5, 6). These findings reflect
the dual-allergen-hypothesis proposing that an early cutaneous exposure
to allergens in children with eczema occurring before the first oral
intake enhances the risk for sensitization but also allergy to these
foods (2). Thus, Martin et al. demonstrated that infants with eczema had
an 11 times higher risk to develop peanut allergy and were 6 times more
likely to have hen's egg allergy by the age of 12 months compared to
infants without eczema (23). Finally, a recently published meta-analysis
concluded that the overall prevalence of challenge-proven food allergy
among patients with eczema is 40\%, whereby the association between
eczema and food allergy was stronger in children (3). In our study,
peanut-allergic as well as peanut-tolerant patients were at equal risk
to be sensitized to tree nuts and its seed storage proteins,
highlighting that eczema itself is a major risk factor for the
sensitization to food allergens.

Even though the household consumption of tree nuts of the families
taking part in our study is unknown, tree nuts in general are becoming
more present in many households and are highly potent allergens (11,
13). In principal, experts tending to argue against pre-emptive testing
of additional allergens (24). Nevertheless, our analysis has revealed
that peanut-sensitized infants and young children were already
sensitized to the 2S albumins of tree nuts to a high extent. Being
sensitized to 2S albumins is associated with allergic reactions (14).
More than 15\% of our peanut-sensitized infants and toddlers were very
likely to be allergic to hazelnut and/or cashew and 32.7\% had a more
than 50\% probability, according to probability curves outlined in
literature (15, 16). Given these findings, it should be considered to
test peanut-sensitized infants and toddlers also for sensitization to
tree nuts if tree nuts are not already part of their diet. This might
become more relevant if specific recommendations not only for the
prevention of peanut but also tree nut allergy will come into place. So
far it has been shown in the LEAP trial that the early introduction of
peanut significantly reduces the risk for developing peanut allergy
(25). Therefore, international guidelines suggest introducing peanuts
into the infant's diet in an age-appropriate form as part of
complementary feeding in order to prevent peanut allergy in infants and
young children in populations where there is a high prevalence of peanut
allergy. As Germany is not a country with high prevalence of peanut
allergy our S3 guideline states that introduction and regular
consumption of peanuts in an age-appropriate form may be considered in
infants with atopic dermatitis living in families with regular peanut
consumption, however, peanut allergy should first be ruled out,
especially in infants with moderate to severe atopic dermatitis (7) as
it had been performed in the LEAP trial (25). Due to a lack of
interventional trials, so far, no specific recommendations for tree nuts
have been formulated. However, in the HealthNuts study, none of the
children who consumed cashew by the age of 12 months developed cashew
allergy (0\%; 95\% CI, 0\%-2.6\%), compared with 3.6\% (95\% CI,
2.9\%-4.4\%) of those that had not eaten cashew by one year of age (26).
Nevertheless, further randomized-controlled trials are needed to observe
the effectiveness regarding allergy prevention and safety of an early
introduction of tree nuts into the infant's diet.

Limitations of our study have to be mentioned. As this was a
retrospective analysis of stored serum samples, we had no data on the
clinical relevance of the tree nut sensitization. Therefore clinical
reactivity could only be estimated using probability curves published in
literature.

In conclusion our study demonstrates that a very high proportion of
peanut-sensitized infants and toddlers are already co-sensitized to tree
nuts with a high likelihood of clinical relevance in many of them. These
findings should be considered for future strategies in screening,
diagnostics and the prevention of tree nut allergy in children.

\textbf{Acknowledgment}

We thank all the families who participated in the study and our
dieticians Saskia Albroscheit and Susanne Schwarz for their kind and
attentive support during the study. Moreover, we thank Anja Alfandega
for her work in the laboratory and Erin Sprunken for the statistical
consideration.

\textbf{Impact statement}

Sensitization to hazelnut, cashew and walnut seems to be common among
peanut-sensitized infants and toddlers. They also seem to be frequently
sensitized to the corresponding tree nut 2S albumins, what might be
associated with clinical reactivity to these tree nuts. Based on our
findings, it should be considered to test peanut-sensitized infants and
toddlers also for sensitization to tree nuts if these have not been
introduced into the diet so far.

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\textbf{Tables}

TABLE 1: Characteristics of the study population\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{All n=101}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Hazelnut sensitized} \textbf{n=95}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Walnut} \textbf{sensitized} \textbf{n=88}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Cashew} \textbf{sensitized} \textbf{n=85}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{Gender male\textsuperscript{+}} \textbf{(n (\%))}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
68 (71.6)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
67 (72.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
65 (74.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
62 (72.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Age in months, median (range)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (5-24)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (5-24)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (5-24)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
16 (5-24)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Eczema (n (\%))}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
99 (98.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
93 (97.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
86 (97.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
83 (97.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{sIgE to peanut in kU/l, median (range)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.23 (0.10-75.93)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.17 (0.10-75.93)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.08 (0.10-75.93)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.23 (0.10-75.93)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{sIgE to Ara h 1 (n (\%))}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
84 (83.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
81 (85.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
75 (85.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
74 (87.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{sIgE to Ara h 1 in kU/l, median (range)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.38 (0.10-12.64)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.4 (0.10-12.64)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.43 (0.10-12.64)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.40 (0.10-12.64)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{sIgE to Ara h 2 (n (\%))}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
71 (70.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 (70.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (68.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
60 (70.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{sIgE to Ara h 2 in} \textbf{kU/l, median (range)}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.98 (0.10-43.94)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.8 (0.10-43.94)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.69 (0.10-43.94)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.78 (0.10-43.94)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{OFC-challenge proven peanut allergy\textsuperscript{++}}
\textbf{(n (\%))}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (40.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31 (39.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (35.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (38.03)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{kU/l, kilounits/liter; sIgE, specific immunoglobulin E}
\textsuperscript{+}\textbf{data from n=95}
\textsuperscript{++}\textbf{data from n=81}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{kU/l, kilounits/liter; sIgE, specific immunoglobulin E}
\textsuperscript{+}\textbf{data from n=95}
\textsuperscript{++}\textbf{data from n=81}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{kU/l, kilounits/liter; sIgE, specific immunoglobulin E}
\textsuperscript{+}\textbf{data from n=95}
\textsuperscript{++}\textbf{data from n=81}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{kU/l, kilounits/liter; sIgE, specific immunoglobulin E}
\textsuperscript{+}\textbf{data from n=95}
\textsuperscript{++}\textbf{data from n=81}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{kU/l, kilounits/liter; sIgE, specific immunoglobulin E}
\textsuperscript{+}\textbf{data from n=95}
\textsuperscript{++}\textbf{data from n=81}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure Legends}

FIGURE 1: Figure 1 shows the proportion of peanut-sensitized patients
(n=101) being sensitized (specific IgE [?] 0.1 kU/l) to hazelnut, walnut
and cashew and to their corresponding 2S albumins Cor a 14, Ana o 3 and
Jug r 1 as well as median and range of the corresponding specific IgE
levels.

FIGURE 2: Figure 2 shows the proportion of peanut allergic and peanut
tolerant patients being sensitized (specific IgE [?] 0.1 kU/l) to
hazelnut, walnut and cashew and to their corresponding 2S albumins Cor a
14, Ana o 3 and Jug r 1 as well as median and range of the corresponding
specific IgE levels (clinical relevance of peanut sensitization was
known in 81 out of 101 patients).

FIGURE 3: Predicted values for an allergic reaction to hazelnut (A) and
cashew (B) for each patient. Values were estimated according to the
patient\selectlanguage{ngerman}´s individual Cor a 14\selectlanguage{english}-sIgE and Ana o 3\selectlanguage{english}-sIgE values. Those were
compared to a given probability for a positive OFC outcome at a certain
sIgE value outlined in the prediction curves for Cor a 14 by Beyer et
al. (16) and for Ana o 3 by Lange et al (15), respectively.

\textbf{Author Contributions}

Lara Meixner: Investigation (equal); formal analysis (lead); validation
(equal); writing -- original draft (lead); writing -- review and editing
(equal). Stephanie Heller: Investigation (equal); validation (equal);
writing -- review and editing (equal). Friederike Bluhme: Investigation
(equal); writing -- review and editing (equal). Valerie Trendelenburg:
Investigation (equal); writing -- review and editing (equal). Birgit
Kalb: Conceptualization (equal); formal analysis (supporting); writing
-- original draft (supporting); writing -- review and editing (equal);
funding acquisition (equal); supervision (equal). Kirsten Beyer:
Conceptualization (equal); formal analysis (supporting); writing --
review and editing (lead); funding acquisition (equal); supervision
(equal).\selectlanguage{english}
\begin{figure}[H]
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\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}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

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