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\begin{document}

\title{Treatment-required accidental ingestion and risk factors among nursery
children with wheat allergy}



\author[1]{Noriyuki Yanagida}%
\author[1]{Motohiro Ebisawa}%
\author[2]{Toshio Katsunuma}%
\author[3]{Jyoji  Yoshizawa}%
\affil[1]{Sagamihara National Hospital}%
\affil[2]{The Jikei University Daisan Hospital}%
\affil[3]{The Jikei University School of Medicine}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\textbf{Treatment-required accidental ingestion and risk factors among
nursery children with wheat allergy}

\textbf{Conflicts of interest}

M. Ebisawa serves in the clinical medical advisory board of DBV
Technologies. Motohiro Ebisawa have received speaker honoraria from
Mylan EPD. All other authors declare no conflicts of interest.

\textbf{Financial support}

This study was supported by funds from the Ministry of Health, Labour
and Welfare of Japan.

\textbf{To the Editor:}

A nationwide questionnaire-based survey conducted throughout nursery
schools in Japan revealed that 7.6\% children have accidental ingestion
within one year.\textsuperscript{1} Younger age, male sex, and wheat
allergy are risk factors for accidental
ingestion.\textsuperscript{2}However, the frequency of accidental
ingestion of each allergen and risk factors for treatment-required
moderate-to-severe accidental ingestion remain unknown in nursery
schools. This study examined the prevalence of accidental ingestion of
four common allergens and risk factors for treatment-required accidental
ingestion in nursery schools in Japan.\textsuperscript{2}

Data were analyzed using a large dataset from a previous nationwide
questionnaire survey, entitled ``Survey on allergic disease status of
children admitted to nursery schools and allergy measures at nursery
schools.'' Web-based survey forms containing instructions were
dispatched to all childcare facilities in Japan through post (Table
S1),\textsuperscript{1} covering two-thirds of preschool children who
attended nursery schools in Japan (Supplementary Information). The
survey had questions about the presence of accidental ingestion between
April 2015 and February 2016 and details about the accidental ingestion.
We enrolled children with egg, milk, wheat, or peanut allergy (four
common allergens) and excluded children with allergy to multiple foods
or to foods other than egg, milk, wheat, or peanut. We also excluded
patients with missing data.

This study was approved by the ethics committee of Jikei University.
Informed consent from the guardians of the participating children was
not required because no personal data that identified the participants
were obtained. Detailed methods of the survey administered to nursery
schools and the regulations in Japan are listed in Supplementary
Information.

Food allergy was defined as doctor-diagnosed IgE-mediated food
allergy\textsuperscript{3} with written evidence submitted to the
nursery school. If children experienced multiple episodes of allergic
symptoms due to accidental ingestion, the most severe episode was
investigated. Accidental ingestion was defined as unintended accidental
allergen intake leading to allergic symptoms. Treatment-required
accidental ingestion was defined as accidental ingestion that required
treatment at the clinic or hospital.

Data are expressed as n (\%) or arithmetic mean (standard deviations).
Fisher's exact tests, with Bonferroni correction and Mann-Whitney U
tests, were used, and\emph{p} \textless{}0.05 was considered
statistically significant. Logistic regression was used to perform
multivariate analysis. SPSS Statistics for Windows, version 25.0 (IBM
Corp., Armonk, NY, USA), was used for statistical analyses.

In total, 1,390,481 children were enrolled in the survey (Figure S1).
Among 56,121 children with food allergy, 10,315 were excluded owing to
missing data. We further excluded 17,794 children with allergy to
multiple foods and 5,251 children with allergy to foods other than egg,
milk, peanut, or wheat. Finally, 22,761 children with egg, milk, wheat,
or peanut allergy met the inclusion criteria. Mean age of the children
was 2.0 \selectlanguage{ngerman}± 1.5 years (median: 2.0 years) (Table 1). Egg allergy was most
common, followed by allergy to milk, peanuts, and wheat (Table S1).
Overall, 1383 (6.1\%) children experienced accidental ingestion and
presented with symptoms during the last 1 year, 78 (5.6\%) of whom
required treatment at the clinic or hospital and 12 (0.9\%) were
hospitalized. Only 1 child (0.01\%) used an adrenaline auto-injector in
their nursery school. There were no fatal cases requiring treatment in
the intensive care unit or resuscitation. Misdistribution of meals was
the most common reason for accidental ingestion (31.3\%) and eating
other children's meal was the second common reason (11.9\%).

Accidental ingestion correlated with male sex, younger age, and history
of anaphylaxis to causative food (Table 1). The incidence of accidental
ingestion was highest (10.6\%) in wheat allergic children and
significantly higher than that in egg (5.9\%) (\emph{p} =0.001) and
peanut (5.3\%) allergy (\emph{p} =0.011), even after Bonferroni
correction (Figure 1). Significant differences were not seen in milk
(6.8\%) allergy after Bonferroni correction (\emph{p} =0.07). Similarly,
among children with accidental ingestion, the incidence of
treatment-required accidental ingestion was most common in wheat allergy
(31.4\%), followed by peanut (18.8\%) (\emph{p} =0.49), milk (10.7\%)
(\emph{p} =0.019), and egg (8.6\%) (\emph{p} \textless{}0.001) allergy
(Figure 1).

Risk factors for treatment-required accidental ingestion were assessed
among children with accidental ingestion during the last 1 year (Table
2). Multivariate analysis revealed the factors significantly associated
with treatment-required accidental ingestion for adjusted odds ratio
(aOR) adjusted for parameters listed in Table 1. History of anaphylaxis
to causative foods was a significant risk factor in egg (aOR: 3.069),
milk (aOR: 5.325), peanut (aOR: 30.286), and wheat (aOR: 11.721)
allergy. Younger age was a significant risk factor in egg (per one-year
increase; aOR: 0.758) and milk (per one-year increase; aOR: 0.668)
allergy.

Among wheat allergic children with a history of anaphylaxis to wheat (n
= 69), 16 (23.2\%) experienced accidental ingestion (Figure S2). Nine
(36.3\%) of the 16 patients had treatment-required symptoms.

Our study is the first to confirm the potential risk of accidental
ingestion of wheat in the general setting of nursery schools based on a
nationwide survey.

Although our previous results indicated that wheat allergy was a major
risk factor for accidental ingestion among nursery school children in
Japan\textsuperscript{2}, the study design could not clarify the
incidence of accidental ingestion among different food allergens in
participants with multiple food allergy. In this study, we compared the
frequency and severity of symptoms due to accidental ingestion of each
allergen. Wheat allergic children had accidental ingestion more
frequently than children allergic to foods other than wheat. Wheat is
one of the most lethal food allergens in the Japanese population, often
inducing anaphylaxis\textsuperscript{4}. Reactions that require
treatment are more common in oral food challenges (OFCs) to wheat than
in OFCs to other foods.\textsuperscript{5,6}. Our results are similar to
the results of previous studies. The prevalence of wheat allergy differs
between countries,\textsuperscript{7} and wheat allergy is more common
in Asian countries than in European countries and the United
States.\textsuperscript{8,9} Wheat is the third most common allergen and
the primary cause of anaphylaxis in Japan.\textsuperscript{3} Therefore,
we should consider common allergens that cause anaphylaxis in preschool
children according to the country.

A history of anaphylaxis to causative food was a risk factor for
treatment-required accidental ingestion. A history of anaphylaxis is a
risk factor for severe reaction during OFC among school-aged high-risk
patients.\textsuperscript{4} In a study of anaphylaxis recurrence,
one-fifth of children with a history of food anaphylaxis experienced at
least one anaphylaxis recurrence at a mean interval of 12
months.\textsuperscript{10} We confirmed similar results in younger and
generalized populations. Indeed, one-fourth of the children with a
history of anaphylaxis had accidental ingestion within 1 year, and
one-third of them were treated in the hospital or clinic for accidental
ingestion (Figure S2). Therefore, we should consider the causative food
type and a history of anaphylaxis when children enter nursery school to
prevent accidental ingestion.

Our study had several limitations. The study is a questionnaire-based
survey and therefore has the potential for bias. We excluded many
patients with multiple food allergens known as risk factors for
recurrent anaphylaxis,\textsuperscript{10} which may indicate selection
bias. This survey did not consider complications including bronchial
asthma and allergic rhinitis, which may affect the severity of
accidental ingestion.

In conclusion, we should recognize and understand the difference in the
incidence of accidental ingestion induced by each food allergen and risk
factors for treatment-required accidental ingestion, including a history
of anaphylaxis in nursery school children. To generalize these results,
further prospective studies on accidental ingestion in other populations
will be needed.

\textbf{Keywords} : Accidental exposure, Anaphylaxis, Food allergy,
Ingestion, Nursery schools, Pediatric, Risk factors

Noriyuki Yanagida, MD\textsuperscript{a,b}, Motohiro Ebisawa, MD,
PhD\textsuperscript{b}, Toshio Katsunuma, MD, PhD\textsuperscript{c},
Jyoji Yoshizawa, MD, PhD\textsuperscript{d}

\textsuperscript{a}Department of Pediatrics, National Hospital
Organization, Sagamihara National Hospital, Kanagawa, Japan

\textsuperscript{b}Japan Clinical Research Center for Allergy and
Rheumatology, National Hospital Organization, Sagamihara National
Hospital, Kanagawa, Japan

\textsuperscript{c}Department of Pediatrics, The Jikei University Daisan
Hospital, Tokyo, Japan

\textsuperscript{d}Division of Pediatric Surgery, Department of Surgery,
The Jikei University

School of Medicine, Tokyo, Japan

\textbf{Acknowledgements} : We are particularly grateful to the staff
members who participated in the survey and data collection. Assistance
in English language editing was provided by Editage, Cactus
Communications.

\textbf{References}

1. Yanagida N, Ebisawa M, Katsunuma T, Yoshizawa J. Ministry of Health
''2015 Penultimate Year Children and Survey and Research Project
Promoting the Parenting Support'' Actual conditions report on the
results of the investigation on allergy control in day-care centers
admissions children of allergic diseases situation and day-care
centers{]}. Arerugi 2018;67:202-210.

2. Yanagida N, Ebisawa M, Katsunuma T, Yoshizawa J. Accidental ingestion
of food allergens: A nationwide survey of Japanese nursery schools.
Pediatr Allergy Immunol 2019;30:773-776.

3. Ebisawa M, Ito K, Fujisawa T, Committee for Japanese Pediatric
Guideline for Food Allergy TJSoPA, Clinical Immunology TJSoA. Japanese
guidelines for food allergy 2017. Allergol Int 2017;66:248-264.

4. Akiyama H, Imai T, Ebisawa M. Japan food allergen labeling regulation
-- history and evaluation. Adv Food Nutr Res 2011;62:139-171.

5. Yanagida N, Sato S, Asaumi T, Ogura K, Ebisawa M. Risk factors for
severe reactions during double-blind placebo-controlled food challenges.
Int Arch Allergy Immunol 2017;172(3):173-182.

6. Cianferoni A, Khullar K, Saltzman R, et al. Oral food challenge to
wheat: a near-fatal anaphylaxis and review of 93 food challenges in
children. World Allergy Organ J 2013;6(1):14.

7. Siripipattanamongkol N, Vichyanond P, Jirapongsananuruk O, Veskitkul
J, Visitsunthorn N, Pacharn P. Age of resolution from IgE-mediated wheat
allergy. Asian Pac J Allergy Immunol 2017;35(2):113-117.

8. Ricci G, Andreozzi L, Cipriani F, Giannetti A, Gallucci M, Caffarelli
C. Wheat allergy in children: A comprehensive update. Medicina (Kaunas)
2019;55(7):400.

9. Cianferoni A. Wheat allergy: diagnosis and management. J Asthma
Allergy 2016;9:13-25.

10. Pouessel DG. Recurrent food anaphylaxis and risk factors in
children. Pediatr Allergy Immunol 2020. doi: 10.1111/pai.13429. Epub
ahead of print.

\textbf{Table 1.} Characteristics of children with food allergy\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Total (n = 22,761)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Accidental ingestion (n = 1,383)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
No exposure or no symptoms due to accidental ingestion (n =
21,378)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\emph{p}-value\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Sex (male) (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13755 (60.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
877 (63.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12878 (60.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.020\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (years) (mean, SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.0 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1.9 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2.0 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
History of anaphylaxis to causative food (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1701 (7.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
222 (16.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1479 (6.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

SD, standard deviation

Accidental ingestion was defined as unintended accidental exposure to
the allergen leading to allergic symptoms.

At least 83.3\% of the children submitted documents with details about
their food allergies and related instructions, written by their doctors,
to their nursery school.

\textbf{Table 2.} Risk factors for treatment-required accidental
ingestion among children with accidental ingestion during the last 1
year\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted OR* (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted OR* (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted OR* (95\% CI)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adjusted OR* (95\% CI)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Egg (n = 1118)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Milk (n = 198)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Peanut (n = 32)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Wheat (n = 35)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Sex (male)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.764 (0.411--1.420) \emph{p} = 0.394\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.521 (0.189--1.432) \emph{p} = 0.206\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
2.100 (0.114--38.751) \emph{p} = 0.618\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.807 (0.122--5.315) \emph{p} = 0.823\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.758 (0.593--0.968) \emph{p} = 0.027\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.668 (0.450--0.994) \emph{p} = 0.046\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.400 (0.495--3.955) \emph{p} = 0.526\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.784 (0.472--1.301) \emph{p} = 0.346\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
History of anaphylaxis to causative food\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
3.069 (1.579--5.964) \emph{p} = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
5.325 (1.936--14.641) \emph{p} = 0.001\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30.286 (1.982--462.843) \emph{p} = 0.014\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
11.721 (1.847--74.394) \emph{p} = 0.009\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

OR, odds ratio; CI, confidence interval.

*OR was adjusted using the significant variables shown in Table 1: sex,
age, and history of anaphylaxis to causative foods.

Odds ratio of ``Age'' per one-year increase

Risk factors for treatment-required accidental ingestion were examined
among children with accidental ingestion between April 2015 and February
2016. All children with treatment-required accidental ingestion received
treatment at a clinic or hospital.

\textbf{Figure legend}

\textbf{Figure 1:} Proportion of children who developed symptoms of food
allergy in their nursery school during the last 1 year.

This figure shows the proportion of children who developed symptoms of
food allergies in their nursery school between April 2015 and February
2016.

Among children with accidental ingestion, the incidence of accidental
ingestion is most common in children with allergy to wheat (31.4\%),
followed by children with allergy to peanut (18.8\%) (p=0.49), allergy
to milk (10.7\%) (p=0.019), and allergy to egg (8.6\%)
(p\textless{}0.001).

All children with treatment-required accidental ingestion received
treatment at a clinic or hospital.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
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