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\begin{document}

\title{Allergy tests for the diagnosis of culprit allergens in eosinophilic
esophagitis: A systematic review.}



\author[1]{Constantinos Pitsios}%
\author[2]{Emilia Vassilopoulou}%
\author[1]{Katerina Pantavou}%
\author[3]{Terreehorst Ingrid}%
\author[4]{Anna Nowak-Wegrzyn}%
\author[5]{Antonella Cianferoni}%
\author[1]{Georgios Panagiotis Tsigkrelis}%
\author[1]{Maria Papachristodoulou}%
\author[6]{Stefanos Bonovas}%
\author[1]{Georgios K. Nikolopoulos}%
\affil[1]{Panepistemio Kyprou}%
\affil[2]{Diethnes Panepistemio tes Ellados}%
\affil[3]{Amsterdam Universitair Medische Centra}%
\affil[4]{New York University Department of Pediatrics}%
\affil[5]{Hospital of the University of Pennsylvania}%
\affil[6]{Humanitas University}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\textbf{Allergy tests for the diagnosis of culprit allergens in
eosinophilic esophagitis: A systematic review.}

To the Editor,

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease with
esophageal dysfunction and marked eosinophil-predominant infiltration of
the esophagus and a clinicopathologic diagnosis (1,2). Dietary
interventions have confirmed the etiological role of food allergens and
their combination with topical glucocorticoids is the standard treatment
of EoE (1). Three different dietary approaches are usually practiced; an
elemental formula diet, ``empiric'' food eliminations diets (e.g. the
6-FED) and diets based on multimodality allergy testing(1). Skin prick
tests (SPT), serum specific (s)IgE, atopy patch tests (APT), but also
serum specific (s)IgG4 have been used as allergy diagnostic tools for
such diets(1).

Elimination diets can serve as the first step to identify the culprit
antigens in EoE; after symptoms' remission foods can be sequentially
reintroduced and food triggers can be defined clinicopathologically
(1,2). In the present systematic review, the outcomes of a
food-reintroduction diagnostic approach served as comparator to the
results of allergy tests serving as diagnostic tools of the EoE food
triggers. Our aim was to review the literature on the diagnostic value
of allergy tests used in everyday practice.

The detailed methods of the present systematic review are reported in
the published protocol (3). The evidence search and selection process
are presented in Figure 1. Fourteen studies fulfilling the quality
assessment criteria were included in the review; their characteristics
are summarized in Table 1 (references in the supplement). The
Risk-of-Bias ratings are shown in Table S1. The studies were assessing
complete data of 453 EoE patients. Biopsies were used for re-evaluation
in all studies, and as the main criterion of EoE remission in most of
the studies.

The positive predictive value (PPV) of allergy tests is reported in
Table S2. It is deduced by the percentage of allergy tests that have
correctly predicted the culprit allergen out of the total number of
allergy tests resulting positive. The percentage of patients who
responded to treatment was calculated by dividing the number of patients
who presented EoE remission after food elimination diets based on
positive allergy tests, out of the total number of patients following
such diets. Reviewed studies have offered either, or both, of these
data.

Studies have followed a protocol with a single allergy test, or with the
combination of two (SPT+sIgE, SPT+APT), or three. Most
single-allergy-test studies have reported PPVs lower than 50\%. PPV was
better for combined tests; PPV of SPT+APT combination was 67.1\%, with
65-88.3\% of patients presenting symptom amelioration after following a
relevant elimination diet. A study combining SPT+APT+sIgE reported
symptoms' improvement in 67\% of the patients.

The effectiveness of amino-acid-based elemental diet is approximately
90\%, while 6-FED shows a 72.1\% effectiveness (4) . The empiric
elimination of cow's milk or dairies is a slightly less-effective
strategy. According to our review's outcomes, allergy-test-driven
elimination diets have a maximum efficacy of 66-88.3\%, so following
them is not superior to empirical diets. The decision to follow any of
these options, or alternatively a 4-FED or 2-FED, is individualized
according to what best fits to patient's lifestyle.

Esophageal prick testing (EPT) performed with food extracts directly on
the esophageal lining is a new diagnostic method offering the advantage
to examine the local esophageal response to dietary triggers, that might
be completely different to IgE-detection with the usual allergy tests
(5). Ex vivo food antigen stimulation method, using stimulation of
esophageal biopsies with food extracts is another promising alternative
(6).

Concluding, although the use of food specific IgE-detection and the
performance of APT do not seem useful for selecting which food should be
eliminated, it is a fact that personalized elimination of different
foods in each patient is highly advised.

\textbf{Conflict of interest}

No author has any conflict of interest to declare.

\textbf{Authorship Contributors}

CP, IT and AC were involved in the conception of the study. Methodology
was set by KP, SB and GN. Investigation was performed by KP, who curated
the data. Literature citations were imported to Rayyan web application
and abstracts were independently checked by CP and EV. ANW was involved
a referee. Data were abstracted into a customized data sheet by GPT and
MP. Outcomes were validated by KP, SB and GN. CP and EV were involved in
original manuscript writing that was reviewed and edited by ANW, IT, AC,
SB, CP and GN. All authors approved the final version of the manuscript.



\textbf{References}

1. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA et
al. Eosinophilic esophagitis: Updated consensus recommendations for
children and adults. \emph{J Allergy Clin Immunol} 2011;128:3-20.e6.

2. Cianferoni A, Spergel J. Eosinophilic esophagitis: A comprehensive
review. \emph{Clin Rev Allergy Immunol} 2016; 50(2):159-74

3. Pitsios C, Pantavou K, Terreehorst I, Cianferoni A, Nowak-Wegzryn A,
Vidal C et al. Use of allergy tests to identify dietary and
environmental triggers of eosinophilic esophagitis: protocol for
a~systematic review. \emph{Allergo J Int} 2020;29:280--283.

4. Arias \selectlanguage{ngerman}Á, González-Cervera J, Tenias JM, Lucendo AJ. Efficacy of
dietary interventions for inducing histologic remission in patients with
eosinophilic esophagitis: A systematic review and
meta-analysis.\emph{Gastroenterology} 2014;146(7):1639-48

5. Warners MJ, Terreehorst I, van den Wijngaard RM, Akkerdaas J, van
Esch BCAM, van Ree R et al. Abnormal Responses to Local Esophageal Food
Allergen Injections in Adult Patients With Eosinophilic
Esophagitis.\emph{Gastroenterology} 2018;154:57-60.e2.

6. Kleuskens MT, Haasnoot ML, Diks MA, Akkerdaas JH, van Ree R, Van
Ampting MT et al. Ex vivo food antigen stimulation of esophageal
biopsies from adults with eosinophilic esophagitis: A potential guide
for elimination diets? \emph{Allergy} 2021;76:S534.

Constantinos Pitsios\textsuperscript{1}, Emilia
Vassilopoulou\textsuperscript{2}, Katerina Pantavou\textsuperscript{1},
Ingrid Terreehorst\textsuperscript{3}, Anna
Nowak-Wegzryn\textsuperscript{4}, Antonella
Cianferoni\textsuperscript{5}, Georgios Panagiotis
Tsigkrelis\textsuperscript{1}, Maria
Papachristodoulou\textsuperscript{1}, Stefanos
Bonovas\textsuperscript{6,7}, Georgios K.
Nikolopoulos\textsuperscript{1}

\begin{enumerate}
\tightlist
\item
  Medical School, University of Cyprus, Nicosia, Cyprus
\item
  Department of Nutritional Sciences and Dietetics, International
  Hellenic University, Thessaloniki, Greece
\item
  ENT Department, Amsterdam University Medical Centre, Amsterdam, The
  Netherlands
\item
  Allergy and Immunology, Department of Pediatrics, Hassenfeld
  Children's Hospital, New York University School of Medicine, New York,
  New York, USA
\item
  Children's Hospital of Philadelphia, University of Pennsylvania
  Medical School, Philadelphia, Pennsylvania, USA
\item
  Department of Biomedical Sciences, Humanitas University, Pieve
  Emanuele, Milan, Italy
\item
  IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
\end{enumerate}

\textbf{Correspondence}

Constantinos Pitsios

Email; pitsios.constantinos@ucy.ac.cy

Telephone; +30 6974348638

\textbf{Hosted file}

\verb`Figure 1.docx`  available at \url{https://authorea.com/users/321920/articles/560426-allergy-tests-for-the-diagnosis-of-culprit-allergens-in-eosinophilic-esophagitis-a-systematic-review}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/321920/articles/560426-allergy-tests-for-the-diagnosis-of-culprit-allergens-in-eosinophilic-esophagitis-a-systematic-review}

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