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\begin{document}

\title{Previous history of immediate reactions changes predictive accuracy for
pediatric peanut allergy}



\author[1]{Naoko Fusayasu}%
\author[1]{Tomoyuki Asaumi}%
\author[1]{Kyohei Takahashi}%
\author[2]{Ken-ich  Nagakura}%
\author[1]{Makoto Nishino}%
\author[1]{Sakura Sato}%
\author[1]{Noriyuki Yanagida}%
\author[1]{Motohiro Ebisawa}%
\affil[1]{National Hospital Organization, Sagamihara National Hospital}%
\affil[2]{National Hospital Organization Sagamihara National Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\textbf{Previous history of immediate reactions changes predictive
accuracy for pediatric peanut allergy}

Naoko Fusayasu\textsuperscript{a}, MD, Tomoyuki
Asaumi\textsuperscript{a}, MD, Kyohei Takahashi\textsuperscript{a,b},
MD, Ken-ichi Nagakura\textsuperscript{a,c} , MD, PhD, Makoto
Nishino\textsuperscript{a,b}, MD, Sakura Sato\textsuperscript{b,d}, MD,
Noriyuki Yanagida\textsuperscript{a,d}, MD, Motohiro
Ebisawa\textsuperscript{d}, MD, PhD,

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

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

\textsuperscript{c}Department of Pediatrics, Jikei University School of
Medicine, Tokyo, Japan

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

\textbf{Running title}

Previous history of immediate reaction and peanut allergy

Corresponding author:

Noriyuki Yanagida, MD

Department of Pediatrics, National Hospital Organization Sagamihara
National Hospital, Kanagawa, Japan

Tel: +81-42-742-8311, Fax: +81-42-742-5314,

E-mail:\emph{sagami@foodallergy.jp}

Word count (excluding abstract, figure legend, and reference): 1199

Number of tables: 1 + 5 Supplementary Tables

Number of figures: 1 + 3 Supplementary Figures

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

M. Ebisawa received lecture fee from DBV Technologies Scientific. S.
Sato received lecture fee from Mylan EPD G.K.. The rest of the authors
declare that they have no relevant conflicts of interest.

\textbf{Financial Support:}

This study was partially supported by the Japan Agency for Medical
Research and Development (AMED; Grant no. 15ek0410019h0101).

\textbf{Keywords:}

Peanut allergy, Ara h 2, IgE, Oral food challenge

\textbf{Main text:}

\emph{To the Editor}

Peanuts are one of the most common food allergens.\textsuperscript{1} In
Japan, 5.1\% of all food allergy cases are peanut
allergies.\textsuperscript{2} Although oral food challenge (OFC) is the
gold standard to diagnose peanut allergy, severe reactions sometimes
occur.\textsuperscript{3}

Recently, specific immunoglobulin E (sIgE) to peanut allergen components
can be measured. \emph{Arachis Hypogaea} (Ara h) 2 is one of the peanut
allergen components, and sIgE levels to Ara h 2 could be a predictive
marker in diagnosing a peanut allergy.\textsuperscript{4} However,
predictive values were different between studies, because these values
depend on disease prevalence as well as patient
age.\textsuperscript{5}We have reported that a previous history of
immediate reactions may change the predictive decision point (PPV) of
positive buckwheat OFC.\textsuperscript{6} Similarly, one Australian
study of 1-year-old infants showed that a previous history of peanut
reactions altered the 95\% PPV of peanut sIgE for peanut allergy;
however, no study has evaluated the influence of the presence of a
previous history of immediate reactions on PPV of Ara h 2 sIgE and 5\%
PPV of peanut sIgE.\textsuperscript{7} Here, we evaluated it in
children.

This study retrospectively analyzed data from subjects aged
\textless{}18 years who underwent a 3 g peanut (containing 750 mg peanut
protein) OFC on admission between March 2010 and March 2016 at
Sagamihara National Hospital.

Overall, 128 patients, with a median age of 6.7 years, were assessed
(See Supplementary Figure S1, Patient Enrollment and Background
Characteristics and Supplementary Table S1). The median levels of peanut
sIgE and Ara h 2 sIgE were 9.7 kU\textsubscript{A}/L and 1.1
kU\textsubscript{A}/L, respectively. Of 128 patients, 49 patients (38\%)
had a history of immediate reactions to peanuts, and 16 (12\%) had a
history of anaphylaxis due to peanuts.

Among 128 patients, 50 patients (39 \%) reacted and 18 patients (36\%)
presented with an anaphylactic reaction during OFC. Statistically
significant differences were observed between patients with positive and
negative OFC results depending on whether they had a previous history of
immediate reactions to peanuts, a previous history of anaphylactic
reactions to peanuts, atopic dermatitis and total IgE level. Patients
with positive results had significantly higher levels of peanut sIgE
(11.4 vs 7.3 kU\textsubscript{A}/L, \emph{p} = 0.038) and Ara h 2 sIgE
(9.84 vs 0.19 kU\textsubscript{A}/L, \emph{p} \textless{} 0.001)
(Supplementary Table S2).

Multivariate analyses were performed with adjusting by three
statistically significant predictors for positive OFC results: age, a
previous history of immediate reactions to peanuts, and atopic
dermatitis (Supplementary Table S3). Peanut sIgE level (adjusted odds
ratio: 4.5, 95\% confidence interval {[}CI{]}: 1.7--12.1, \emph{p} =
0.002) and Ara h 2 sIgE level (adjusted odds ratio: 8.3, 95\% CI:
3.7--18.3, \emph{p} \textless{} 0.001) were significant risk factors for
positive OFC results. The areas under the peanut sIgE and Ara h 2 sIgE
receiver operating characteristic curves (AUC) were also calculated
(Supplementary Table S4). The AUC of peanut and Ara h 2 sIgE were 0.735
and 0.829 in patients with a previous history of immediate reactions and
0.673 and 0.899 in patients without a history, respectively.

We also developed fitted probability curves for patients with and
without a previous history of immediate reactions (Figure 1). The 95\%
PPV for peanut and Ara h 2 sIgE levels were 96.3 and 38.4
kU\textsubscript{A}/L in patients with a previous history of immediate
reactions, whereas those in patients without a history could not be
obtained. However, the 5\% PPV for peanut and Ara h 2 sIgE levels were
0.70 and 0.23 kU\textsubscript{A}/L in patients without a previous
history of immediate reactions, respectively, whereas those in patients
with a history could not be obtained (Table 1).

In this study, we found that the presence of a previous history of
immediate reactions changed PPV for a peanut allergy.

In patients with a previous history of immediate reactions, peanut and
Ara h 2 sIgE levels higher than 96.3 kU\textsubscript{A}/L and 38.4
kU\textsubscript{A}/L, respectively, were correlated to a high
likelihood of positive OFC results. These patients may not need OFC to
be diagnosed with peanut allergy. On the other hand, we could not
calculate the 5\% PPV, therefore patients with a previous history of
immediate reactions should undergo an OFC even if their specific IgE
levels are low. Especially we should mind that approximately 20\% of
patients with a negative Ara h 2 sIgE developed symptoms in OFC in our
fitted probability curve.

In patients without a previous history of immediate reactions, we could
not calculate the 95\% PPV. Peanut sIgE and Ara h 2 sIgE levels lower
than 0.70 kU\textsubscript{A}/L and 0.23 kU\textsubscript{A}/L,
respectively, are correlated to a high chance of ingesting peanuts
without experiencing symptoms. These patients may not need an OFC and
they may try consuming peanuts in their diets. In our fitted probability
curve, more than half of patients without a previous history of
immediate reactions to peanuts had negative OFC even if they had 100
kU\textsubscript{A}/L of peanut sIgE. Therefore, in patients without a
previous history of immediate reactions to peanuts, high levels of
peanut sIgE alone should not lead to avoiding peanuts and testing for
Ara h 2 sIgE levels is useful in determining whether to undergo peanut
OFC. Using the above information, we can assess a patient suspected of
peanut allergy with a flowchart (Supplementary Figure S2).

Peters \emph{et al.} have reported the probability for a positive peanut
food challenge, by peanut sIgE and Ara h 2 sIgE.\textsuperscript{8} In
the study, although OFCs were performed with 6 g of peanuts and the
ratio of patients with a history of immediate reactions to peanuts was
not described, the 95\% PPV of peanut and Ara h 2 sIgE was 87.9
kU\textsubscript{A}/L and 42.2 kU\textsubscript{A}/L, respectively.
These values were similar to the results of our study. One Australian
study found that 95\% PPV of peanut sIgE to peanut allergy was 1.0
kU\textsubscript{A}/L and 39 kU\textsubscript{A}/L with and without a
previous history of immediate reactions,
respectively.\textsuperscript{7} These PPVs were lower than those in our
study. The reasons for this difference were considered as follows.
First, 9 g of peanut was used for the OFC. Second, all participants were
1 year old while in our study the ages ranged from 1 to 17 years. It has
been reported that infants are more likely to have lower 95\% PPVs than
children aged 2 or older.\textsuperscript{5} Considering that age may
influence PPVs, we developed fitted probability curves for patients
\textless{}6 years and those 6 years or older. There was no obvious
difference between these groups (Supplementary Figure S3).

This study has some limitations. First, although older children were
included, OFCs were open-challenge tests and not double-blind
placebo-controlled food challenge tests. Second, analysis of the skin
prick test could not be performed because only a small number of
participants underwent this test. Third, this study presented fitted
predictive probability curves for the positive outcome of a 3 g peanut
OFC. These probability curves should not be used for predicting results
of OFC using \textgreater{}3 g of peanuts. Finally, potential risks of
bias and limitations related to the retrospective study design cannot be
ruled out.

In conclusion, a previous history of immediate reactions changes the
predictive accuracy for peanut allergy in children. The presence of a
previous history of immediate reactions should be considered when
performing OFC.

\textbf{ACKNOWLEDGEMENTS}

We would like to thank Editage (\emph{www.editage.com}) for assistance
in English language editing.

\textbf{IMPACT STATEMENT:}

Our study is the first to show that a previous history of peanut
reactions altered the predictive decision point of Ara h 2 and peanut
specific IgE for positive peanut oral food challenge in children. Having
a previous history of immediate reactions should be considered when we
performing OFC.

\textbf{References:}

Bock SA, Mu\selectlanguage{ngerman}ñoz-Furlong A, Sampson HA. Fatalities due to anaphylactic
reactions to foods. J Allergy Clin Immunol 2001;107:191-193.

2. Imai T, Sugizaki C, Ebisawa M. {[}A report on a 2011 nationwide
survey of immediate type food allergies in Japan (Supported by a grant
from ``Consumer Affairs Agency, Government of Japan''){]}. Arerugi
2016;65:942--946 (in Japanese).

3. Simons FER, Ardusso RF, Dimov V et al. World Allergy Organization
Anaphylaxis Guidelines: 2013 Update of the Evidence Base. Int Arch
Allergy Immunol 2013;9:193-204.

4. Klemans RJB, van Os-Medendorp H, Blankestijn M, Bruijnzeel-Koomen C,
Knol E, Knulst A. Diagnostic accuracy of specific IgE to components in
diagnosing peanut allergy: a systematic review. Clin Exp Allergy
2014;45:720-730.

5. Komata T, Söderström L, Borres MP, Tachimoto H, Ebisawa M. The
predictive relationship of food-specific serum IgE concentrations to
challenge outcomes for egg and milk varies by patient age. J Allergy
Clin Immunol 2007;119:1272-1274.

6. Yanagida N, Sato S, Takahashi K, Nagakura K, Ogura K, Asaumi T,
Ebisawa M. Reaction of Buckwheat-hypersensitive patients during oral
food challenge are rare, but often anaphylactic. Int Arch Allergy
Immunol 2017;172:116-122.

7. Peters RL, Allen KJ, Dharmage SC et al. Skin prick test responses and
allergen-specific IgE levels as predictors of peanut, egg, and sesame
allergy in infants. J Allergy Clin Immunol 2013;132:874-880.

8. K. Beyer, L. Grabenhenrich, Predictive values of component-specific
IgE for the outcome of peanut and hazelnut food challenges in children.
Allergy 2015;70:90-98.

9. Ebisawa M, Ito K, Fujisawa T, Committee for Pediatric Guideline for
Food Allergy, The Japanese Society of Pediatric Allergy and Clinical
Immunology, The Japanese Society of Allergology. International Japanese
guidelines for food allergy 2017. Allergol Int 2017;66:1-17.

10. Muraro A, Werfel T, Hoffmann-Sommergruber K et al. EAACI Food
Allergy and Anaphylaxis Guidelines: diagnosis and management of food
allergy. Allergy 2014;69:1008-1025.

\textbf{Tables:}

\textbf{Table 1:} Predictive decision points for positive peanut food
challenge results by peanut specific IgE and Ara h 2specific IgE\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Predictive decision point (PPV) & With a previous history of immediate
reactions to peanuts & With a previous history of immediate reactions to
peanuts & Without a previous history of immediate reactions to peanuts &
Without a previous history of immediate reactions to
peanuts\tabularnewline
\midrule
\endhead
& Peanut specific IgE (kU\textsubscript{A}/L) & Ara h 2 specific IgE
(kU\textsubscript{A}/L) & Peanut specific IgE (kU\textsubscript{A}/L) &
Ara h 2 specific IgE (kU\textsubscript{A}/L)\tabularnewline
5\% PPV & NA & NA & 0.70 & 0.23\tabularnewline
10\% PPV & NA & NA & 2.77 & 0.52\tabularnewline
90\% PPV & 36.9 & 13.7 & NA & 65.3\tabularnewline
95\% PPV & 96.3 & 38.4 & NA & NA\tabularnewline
\bottomrule
\end{longtable}

PPV, predictive decision point; NA, not applicable

\textbf{Figure Legends:}

\textbf{Figure 1:} Probability of positive peanut oral food challenge by
peanut specific IgE (A) and Ara h 2 specific IgE (B) for patients with
and without a previous history of immediate reactions

The solid lines indicate the range of probability calculated by specific
IgE levels of our subject, the dashed lines indicate the range of
probability calculated by extrapolation. The surrounded grayed area
indicates 95\% CI.\selectlanguage{english}
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