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\begin{document}

\title{Clinical cross-reactivity to quail's egg in patients with hen's egg
allergy}



\author[1]{Masatoshi Mitomori}%
\author[1]{Noriyuki Yanagida}%
\author[1]{Mari Takei}%
\author[1]{Kinji Tada}%
\author[1]{Makoto Nishino}%
\author[1]{Sakura Sato}%
\author[1]{Motohiro Ebisawa}%
\affil[1]{National Hospital Organization, Sagamihara National Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Clinical cross-reactivity to quail's egg in patients with hen's
egg allergy}

Masatoshi Mitomori\textsuperscript{a}, Noriyuki
Yanagida\textsuperscript{a}, Mari Takei\textsuperscript{b}, Kinji
Tada\textsuperscript{b}, Makoto Nishino\textsuperscript{a, c}, Sakura
Sato\textsuperscript{b}, Motohiro Ebisawa\textsuperscript{b}

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

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

\textsuperscript{c}Course of Allergy and Clinical Immunology, Juntendo
University Graduate School of Medicine, Tokyo, Japan

\textbf{Running title:} Clinical cross-reactivity of HE \& QE

\textbf{Corresponding author:}

Noriyuki Yanagida

18-1, Sakuradai, Minamiku, Sagamihara, Kanagawa 252-0392, Japan

Tel.: +81 042 742 8311 Fax: +81 042 742 5314

E-mail: yana@foodallergy.jp

\textbf{Word count:1153}

\textbf{No. of Tables:} 1

\textbf{No. of Figures:} 2

\textbf{Material in electronic repository:} 1 table and 1 figure

\textbf{i. A statement with potential conflict of interests related to
the manuscript content:}

Motohiro Ebisawa received lecture fees from DBV Technologies and Mylan
EPD. Sato Sakura received lecture fees from Mylan EPD. The other authors
declare that they have no conflicts of interest.

\textbf{ii. Financial support:} None.

\textbf{iii. Keywords}

hen's egg, quail's egg, food allergy, cross-reactivity, oral food
challenge, child, pediatric

\textbf{iv. Main text:}

To the Editor,

Hen's egg (HE) is consumed worldwide and is one of the most frequent
causes of food allergy.\textsuperscript{1,2} In Japan, HE is consumed
most frequently among avian eggs, followed by quail's egg (QE). Quails
(\emph{Coturnix japonica} ) belong to the same \emph{Galliformes
Phasianidae} family as chicken (\emph{Gallus gallus domesticus} );
therefore, cross-reactivity may occur between HE and QE. Consequently,
HE allergic patients are generally advised to avoid QE consumption.
However, there has been only one report on the serological
cross-reactivity of HE and QE\textsuperscript{3} and one case report on
clinical cross-reactivity.\textsuperscript{4} Moreover, whether all HE
allergic patients need to avoid QE consumption remains unclear. This
study, therefore, aimed to evaluate the clinical cross-reactivity
between HE and QE by performing oral food challenge (OFC) tests.

We conducted a prospective study to determine whether HE allergic
patients show cross-reactivity to QE. We performed QE-OFC in patients
with HE allergy between January 2018 and October 2019. HE allergy was
diagnosed through OFCs, which were performed stepwise, starting from a
low-dose HE-OFC (containing 1/25 of a heated HE). Patients with negative
results proceeded to a medium-dose HE-OFC (containing 1/8 of a heated
HE). Patients with positive low-dose or medium-dose HE-OFC were included
in this study. Patients with missing clinical data were excluded. QE-OFC
was performed using one heated QE. All OFCs were performed in a
single-dose or two-dose administration. In the two-dose OFCs, the
challenged food was distributed at 60-min intervals. Symptom severity
during OFCs was assessed according to the Japanese guidelines for food
allergy.\textsuperscript{2} Serum levels of total immunoglobulin E (IgE)
and specific IgE to HE white (HEw-sIgE), HE ovomucoid (OVM-sIgE), and QE
white (QEw-sIgE) (ImmunoCAP\textsuperscript{TM}; Thermo Fisher
Scientific/Phadia, Uppsala, Sweden) were measured within four months of
conducting QE-OFC, and skin prick test (SPT) was performed during
QE-OFC. The SPT procedure is described in Supplemental Methods. This
study was approved by the ethics committee of Sagamihara National
Hospital (approval number: 2017-021), and was registered at the
University Hospital Medical Information Network Clinical Trials Registry
(no: UMIN000034820). The written informed consent was obtained from the
guardians of all patients.

Among 870 patients who underwent HE-OFC, 183 failed in the low-dose or
medium-dose HE-OFC, 22 of whom underwent a QE-OFC. Two patients were
excluded because of missing clinical data, and the remaining 20 were
enrolled (Figure 1). Median patient age was 2.9 (range, 1.0--16.4)
years, and nine (45\%) patients had a history of anaphylaxis to HE. The
median HEw-sIgE, OVM-sIgE, and QEw-sIgE levels were 9.95 (2.67--365),
8.66 (\textless{}0.10--191), and 4.15 (0.73--\textgreater{}100)
kU\textsubscript{A}/L, respectively (Table 1). There was a correlation
between HEw-sIgE and QEw-sIgE levels (Supplemental Figure 1). SPT was
performed in 13 patients, and 12 (92\%) were found to be sensitized to
QE. The median SPT wheal diameters for HEw and QEw were 15 (3--32) and
12 (0--25) mm, respectively.

Among the 20 patients, four reacted to the low-dose HE-OFC (threshold
dose, 1/25 of a heated HE or lower), and 16 passed the low-dose HE-OFC
but reacted to the medium-dose HE-OFC (threshold dose,
\textgreater{}1/25--1/8 of a heated HE). Of the 20 patients, 9 (45\%)
failed in the QE-OFC. The median interval between QE-OFC and HE-OFC was
2.8 months. The rate of positive QE-OFC results was significantly higher
in patients with a threshold dose of [?]1/25 of a heated HE than in those
with a threshold dose of \textgreater{}1/25--1/8 of a heated HE (100\%
{[}4/4{]} vs. 31\% {[}5/16{]}, \emph{p} = 0.026; Figure 2). Patients'
symptoms, severity, and treatment during the QE-OFC are described in
Supplemental Table 1. Three patients presented with symptoms in multiple
organs; however, their symptoms improved after treatment with
antihistamine and steroid or inhalation of \selectlanguage{greek}\emph{β}
\selectlanguage{english}\textsubscript{2}stimulants. The HEw-sIgE, OVM-sIgE, and QEw-sIgE levels
were significantly higher in patients with a positive QE-OFC result than
in those with a negative QE-OFC result. There was no significant
difference in the SPT wheal diameter to HEw and QEw between patients who
reacted to QE-OFC and those who did not (Table 1).

To our knowledge, this is the first prospective study to evaluate the
clinical cross-reactivity between HE and QE through OFC tests. In this
study, clinical cross-reactivity to QE was observed in almost half of
the patients who were allergic to HE.

In a previous case report, a patient with HE allergy showed
cross-reactivity to QE.\textsuperscript{4} Furthermore, approximately
70\% of HE allergic children had a positive SPT result to
QEw\textsuperscript{5}; however, whether they showed clinical
cross-reactivity to QE was not confirmed. In our study, 92\% of the HE
allergic patients had a positive SPT result to QEw, and 45\% reacted to
one QE.

The mean weight of HE and QE is 58g and 11.3g,
respectively.\textsuperscript{6} Because the ratio of egg white and egg
yolk mass in HE is almost equivalent to that of
QE\textsuperscript{6,7}and the percentage of protein in HEw is also
equivalent to that of QEw,\textsuperscript{6} the amount of protein in
the egg white of one QE would be equivalent to approximately 1/5 of that
in one HE. Since the main antigen of immediate-type egg allergy is egg
white, if the antigenicity of HEw and QEw is deemed to be identical, all
HE allergic patients with a threshold dose of [?]1/8 of a heated HE would
be expected to fail a QE-OFC. However, in this study, while all the
patients with a threshold dose of [?]1/25 of a heated HE failed the
QE-OFC, only 31\% patients with a threshold dose of
\textgreater{}1/25--1/8 of a heated HE failed. Therefore, QEw
antigenicity seemed to be lower than that of HEw when comparing in terms
of the same amount of protein, and whether HE allergic patients reacted
to one QE appeared to depend on their threshold of HE.

This study has some limitations. First, OFCs were not double-blind and
placebo-controlled. However, as most patients exhibited objective
symptoms during OFCs, the number of false-positive OFC results would be
low. Second, some patients may have achieved tolerance during the
interval between the OFCs. However, the interval between QE-OFC and
HE-OFC was relatively short, with a median of 2.8 months. Moreover, the
median age of the subjects in this study was 2.9 years, and since it has
been reported that only 30\% of Japanese HE allergic patients achieve
tolerance between 3 and 6 years old,\textsuperscript{8} the influence of
the interval between the OFCs is considered minimal. Third, we did not
evaluate whether patients with negative QE-OFC results were reactive to
amounts larger than one QE. Therefore, our study may have underestimated
the rate of patients who had true clinical cross-reactivity to QE.
Further studies with a larger number of patients, including those with a
higher HE threshold, are necessary.

In conclusion, this study showed that some HE allergic patients are
clinically cross-reactive to QE. Furthermore, patients with a lower
threshold of HE were more likely to react to QE. Therefore, HE allergic
patients, especially those with a low threshold, should consider
avoiding QE consumption.

Masatoshi Mitomori, MD\textsuperscript{a}, Noriyuki Yanagida,
MD\textsuperscript{a}, Mari Takei, MD\textsuperscript{b}, Kinji Tada,
MD\textsuperscript{b}, Makoto Nishino, MD\textsuperscript{a, c}, Sakura
Sato, MD\textsuperscript{b}, Motohiro Ebisawa, MD,
PhD\textsuperscript{b}

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

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

\textsuperscript{c}Course of Allergy and Clinical Immunology, Juntendo
University Graduate School of Medicine, Tokyo, Japan.

\textbf{v. Acknowledgments}

We thank Editage (www.editage.jp) for their assistance with the English
language editing.

\textbf{vi. Impact statement}

Some patients with allergy to hen's egg are also clinically reactive to
quail's egg. Therefore, such patients, especially those with a low
threshold dose, should consider avoiding the consumption of quail's egg.

\textbf{vii. References}

\begin{enumerate}
\tightlist
\item
  Sicherer SH, Sampson HA. Food allergy: A review and update on
  epidemiology, pathogenesis, diagnosis, prevention, and management. J
  Allergy Clin Immunol 2018;141:41-58.
\item
  Ebisawa M, Ito K, Fujisawa T. Committee for Japanese Pediatric
  Guideline for Food Allergy, The Japanese Society of Pediatric Allergy
  and Clinical Immunology, Japanese Society of Allergology, Japanese
  Guidelines for Food Allergy 2020. Allergol Int 2020;69;370-386.
\item
  Takahashi K, Horiguchi M, Bando N, Tsuji H, Ogawa T, Asao T.
  Immunochemical characterization of ovomucoid from Japanese quail egg
  white using monoclonal antibodies. J Nutr Sci Vitaminol (Tokyo)
  1999;45:491-500.
\item
  Alessandri C, Calvani M Jr, Rosengart L, Madella C. Anaphylaxis to
  quail egg. Allergy 2005;60:128-129.
\item
  Moghtaderi M, Nabavizadeh SH, Hosseini Teshnizi S. The frequency of
  cross-reactivity with various avian eggs among children with hen's egg
  allergy using skin prick test results: fewer sensitizations with
  pigeon and goose egg. Allergol Immunopathol (Madr) 2020;48:265-269.
\item
  Tolik D, Po\selectlanguage{polish}ł\selectlanguage{english}awska E, Charuta A, Nowaczewski S, Cooper R.
  Characteristics of egg parts, chemical composition and nutritive value
  of Japanese quail eggs--a review. Folia Biol (Krakow) 2014;62:287-292.
\item
  Standard Tables of Food Composition in Japan 2020 (Eighth Revised
  Edition)
\item
  Ohtani K, Sato S, Syukuya A, et al. Natural history of immediate-type
  hen's egg allergy in Japanese children. Allergol Int 2016;65:153-157.
\end{enumerate}

\textbf{viii. Tables}

Table 1. Characteristics of the study patients and comparison of
patients with QE-OFC positive and negative results\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Characteristics & \textbf{All patients} & \textbf{QE-OFC positive} &
\textbf{QE-OFC negative} & \emph{p}\textbf{~value*}\tabularnewline
& \textbf{n~=~20} & \textbf{n~=~9} & \textbf{n~=~11} &\tabularnewline
Age (years) & 2.9 (1.0--16.4) & 2.6 (1.0--11.1) & 3.2 (1.0--16.4) &
0.656\tabularnewline
Sex (male) & 14 (70) & 7 (78) & 7 (64) & 0.642\tabularnewline
History of anaphylaxis to HE & 9 (45) & 5 (56) & 4 (36) &
0.653\tabularnewline
Food allergy other than HE, current & 9 (45) & 3 (33) & 6 (55) &
0.406\tabularnewline
Atopic dermatitis, current & 16 (80) & 8 (89) & 8 (73) &
0.591\tabularnewline
Bronchial asthma, current & 3 (15) & 1 (11) & 2 (18) & \textgreater{}
0.999\tabularnewline
Allergic rhino-conjunctivitis, current & 3 (15) & 0 (0) & 3 (27) &
0.218\tabularnewline
Total IgE (kIU/L) & 322 (31.1--4040) & 526 (58.4--1170) & 280
(31.1--4040) & \textgreater{} 0.999\tabularnewline
HEw-sIgE (kU\textsubscript{A}/L) & 9.95 (2.67--365) & 62.3 (5.43--365) &
8.22 (2.67--33.5) & 0.025\tabularnewline
OVM-sIgE (kU\textsubscript{A}/L) & 8.66 (\textless{} 0.10--191) & 53.2
(3.22--191) & 4.57 (\textless{} 0.10--18.7) & 0.004\tabularnewline
QEw-sIgE (kU\textsubscript{A}/L) & 4.15 (0.73--\textgreater{}
100)\selectlanguage{ngerman}\textsuperscript{¶} & 36.8 (2.75--\textgreater{}
100)\selectlanguage{ngerman}\textsuperscript{¶} & 3.28 (0.73--14.2)\textsuperscript{+} &
0.019\tabularnewline
SPT wheal diameter to HEw (mm) & 15 (3--32) & 23
(11--32)\textsuperscript{++} & 14 (3--22)\selectlanguage{ngerman}\textsuperscript{§} &
0.101\tabularnewline
SPT wheal diameter to QEw (mm) & 12 (0--25) & 13
(10--25)\textsuperscript{++} & 11 (0--24)\selectlanguage{ngerman}\textsuperscript{§} &
0.295\tabularnewline
\bottomrule
\end{longtable}

Values are reported as median (range) or number (\%).

* Comparisons between subjects with QE-OFC positive and negative results
were conducted using~Mann-Whitney \emph{U} test for continuous variables
or using chi-square or Fisher's exact test for categorical variables.

\textsuperscript{+}In 2 patients, QEw sIgE data were missing

\textsuperscript{++}In 3 patients, SPT data were missing.

\selectlanguage{ngerman}\textsuperscript{§}In 4 patients, SPT data were missing.

\textsuperscript{¶}QEw-sIgE concentrations exceeding 100
kU\textsubscript{A}/L were not evaluated by dilution.

\textbf{Abbreviations:} QE-OFC, quail's egg oral food challenge; HE,
hen's egg; HEw, hen's egg white; OVM, hen's egg ovomucoid; QEw, quail's
egg white; IgE, immunoglobulin E; sIgE, specific IgE; SPT, skin prick
test

\textbf{ix. Figure legends}

Figure 1. Flowchart of the study participation selection process

\textbf{Abbreviations:} HE, hen's egg; QE, quail's egg; OFC, oral food
challenge

Figure 2. Positive rates in quail's egg oral food challenge.

\textbf{Abbreviations:} HE, hen's egg; QE, quail's egg; OFC, oral food
challenge

\textbf{Author Contributions}

Masatoshi Mitomori: Conceptualization (equal); data curation (lead);
formal analysis (lead); investigation (lead); methodology (lead);
project administration (lead); resources (lead); software (equal);
supervision (equal); validation (supporting); visualization
(supporting); writing-original draft (lead); writing-review and editing
(equal). Noriyuki Yanagida: Conceptualization (lead); data curation
(supporting); formal analysis (supporting); investigation (equal);
methodology (equal); project administration (equal); resources (equal);
software (equal); supervision (lead); validation (lead); visualization
(lead); writing-original draft (equal); writing -review and editing
(lead). Mari Takei; Conceptualization (supporting); data curation
(supporting); formal analysis (supporting); investigation (equal);
methodology (supporting); project administration (supporting); resources
(supporting); software (supporting); supervision (supporting);
validation (supporting); visualization (supporting); writing-original
draft (supporting); writing-review and editing (supporting). Kinji Tada:
Conceptualization (supporting); data curation (supporting); formal
analysis (supporting); investigation (equal); methodology (supporting);
project administration (supporting); resources (supporting); software
(supporting); supervision (supporting); validation (supporting);
visualization (supporting); writing-original draft (supporting);
writing-review and editing (supporting). Makoto Nishino:
Conceptualization (supporting); data curation (supporting); formal
analysis (supporting); investigation (equal); methodology (supporting);
project administration (supporting); resources (supporting); software
(supporting); supervision (supporting); validation (supporting);
visualization (supporting); writing-original draft (lead);
writing-review and editing (equal). Sakura Sato: Conceptualization
(lead); data curation (supporting); formal analysis (supporting);
investigation (equal); methodology (equal); project administration
(equal); resources (equal); software (equal); supervision (lead);
validation (lead); visualization (lead); writing-original draft (equal);
writing-review and editing (lead). Motohiro Ebisawa: Conceptualization
(lead); data curation (supporting); formal analysis (supporting);
investigation (equal); methodology (equal); project administration
(equal); resources (equal); software (equal); supervision (lead);
validation (lead); visualization (equal); writing-original draft
(equal); writing-review and editing (lead).

\textbf{Key Message}

This study showed that some hen's egg allergic patients are also
clinically reactive to quail's egg. Therefore, such patients, especially
those with a low threshold dose, should consider avoiding the
consumption of quail's egg.\selectlanguage{english}
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