Gastroscopic Esophageal Prick Test in adult Eosinophilic Esophagitis Patients: a pilot study

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the
esophagus, that leads to progressive narrowing of the lumen. Histologically
there is a prominent eosinophilic infiltration and inflammation of the
esophagus, which can cause transient narrowing of the lumen by edema, and
progressive fixed narrowing by remodeling and fibrosis. EoE presents in adults
as dysphagia and food impaction. EoE is diagnosed based on symptoms of
esophageal dysfunction and the presence of more than 15 eosinophils per
high-power field (eos/hpf) in esophageal biopsies, which persists after the
exclusion of other causes of esophageal eosinophilia.
Since EoE was first recognized in the mid-1990s, it has emerged in the past few
years as the main cause of esophageal dysfunction in children and young adults.
The incidence of the disease has risen extremely fast and currently in many
countries more patients are now diagnosed with EoE than with inflammatory bowel
disorders such as Crohn*s and Colitis. This epidemic of EoE cannot be fully
explained by increasing awareness and recognition by physicians.
Although the pathophysiology of EoE is not fully understood, it has been shown
by many studies that food allergy plays an important role. The concept of EoE
being an allergic disease activated by food allergens is further supported by
the notion that EoE can be driven into remission by dietary treatment. The
allergic esophageal inflammation in EoE is probably caused by an acute
IgE-mediated and a delayed non-IgE-mediated hypersensitivity reaction.
Current pharmaceutical treatment is only moderately effective and mainly
consists of topical corticosteroids, which are prescribed off label.
Side-effects such as esophageal candidiasis preclude long-term treatment and
response is temporary since the disease recurs once the corticosteroids are
withdrawn. Without durable treatment, progressive narrowing of the esophagus
continues and repetitive endoscopic removal of food particles that got stuck in
the esophagus may be required. In more severe cases dilatations of the
esophagus are needed with the risk of perforation and bleeding. Apart from the
significant burden to the patients, these repetitive endoscopies result in
considerable costs to society.
Dietary therapy with elimination of causative allergens could potentially be
the most durable long-term solution, which is desirable since the majority of
patients are young adults or children. Elemental diets, based on
hypo-allergenic formula, showed impressive histological and clinical response
rates. Nonetheless, costs of elemental diets are high and not always reimbursed
and adherence is challenging due to the poor taste. Empiric elimination diets,
based on avoidance of most common food allergens, offer moderate response
rates, but unfortunately many foods need to be eliminated. Furthermore in both
diets a substantial number of follow-up endoscopies is required to evaluate
histological response after each step in the food reintroduction process. The
key to successful dietary treatment of EoE is thus to identify which foods are
responsible for the allergic esophagitis in individual patients. Unfortunately,
the usefulness of allergy test-directed elimination diets is questioned by low
response rates. Current tests, routinely performed on serum or skin, do not
allow identification of the responsible food allergens with acceptable
sensitivity and/or specificity.

Multiple sensitizations were found using allergy tests, but most of the EoE
patients have concurrent allergic diseases and the specific IgE found in serum
apparently does not play a role in EoE pathogenesis. This theory is supported
by the failure of a systemic humanized anti-IgE therapy in adult EoE patients.
A possible explanation for the observation that current allergy tests fail to
predict the disease triggering allergens, is that inflammatory response in EoE
is limited to the esophagus. Restricted esophageal IgE production might be
insufficient to be detected with allergy tests that require a systemic
inflammatory response. Indeed, several studies demonstrated local esophageal
mast cell and B and T cell activation, including class cell recombination to
IgE in the esophagus, local IgE production and IgE bearing mast cells in the
esophageal mucosa (25)(17). Furthermore, it has been shown that mast cells,
released during an allergic reaction, can alter enteric nerve and smooth muscle
function. This might cause esophageal hypermotility, which can be experienced
as acute dysphagia after ingestion of specific allergens. These findings
suggest that esophageal mucosa is immunologically active tissue which can
initiate an inflammatory response.

We hypothesize that the allergic inflammation in EoE is limited to local immune
activation and that only tests based on detection of local inflammation can
reveal clinically relevant sensitization patterns on which elimination diets
can be based. Therefore we aim to develop the esophageal prick test (EPT), an
endoscopic provocation test in which the esophageal mucosa is challenged with
injected food allergens.
In parallel to the in vivo endoscopic EPT, we will investigate whether an in
vitro sensitization test using esophageal tissue is feasible. An in vitro test
that could accurately identify the triggering allergens in EoE would be of
great value since more allergens can be tested after the gastroscopic
procedure. A similar in vitro test with duodenal mucosa has been shown to be
useful for identification of causative agents in intestinal food allergy. A
test using esophageal mucosal biopsies could thus potentially serve as guidance
for elimination diets in EoE.

prospective diagnostic pilot study

Upper endoscopy is a routinely performed investigation, which belongs to the
standard procedures in patients with EoE. In all EoE patients, treated with
elemental or elimination diet a gastroscopy is performed to evaluate histologic
treatment response. This is in accordance with standard care. Therefore
included patients are not exposed to additional risks, associated with the
gastroscopy. Nevertheless the duration of the procedure is extended due to the
esophageal prick test and in some patients an extra endoscopy will be performed.

Although a gastroscopy is a generally safe procedure patients should be aware
of the possible risks which include dental or mouth injury, a sore throat,
aspiration pneumonia, and esophageal injury. Patients often undergo conscious
sedation during upper endoscopy, this option is offered and recommended to the
patients included in the study. Sedation reduces discomfort during endoscopy.
However there are sedation-related complications, which are mostly transient
and of a mild degree. The general incidence of sedation-related complications
is low. Sedation can affect the cardiorespiratory system, which can increase
the risk of the procedure in patients with concurrent cardiorespiratory
diseases. Therefore patients will be connected to a monitor that checks heart
rate and oxygen level during endoscopy.

Esophageal biopsies are taken regularly during upper endoscopy. An extremely
rare but potentially severe risk of a biopsy is a perforation. In most cases
perforation can be treated expectatively or endoscopically. In a minority of
cases, surgery has to be performed to close the perforation. Another very rare
risk of an esophageal biopsy is bleeding, which can be treated endoscopically.

Allergen provocation
The skin prick test is a safe procedure and fatal side effects such as
anaphylaxis are exceedingly rare. Acute systemic anaphylactic reactions are
very rare in EoE but any patients with a history of such reactions or a severe
adverse reaction to skin prick test will be excluded from participation. Other
possible less severe side effect might include the entire range of IgE-mediated
allergic manifestations, such as urticaria, nasal congestion, sneezing,
flushing, wheezing, cough, dysphagia, diarrhea, and hypotension.
We do not expect systemic allergic reactions to the EPT. In studies with a
colonoscopic provocation test (COLAP), in which other parts of the
gastrointestinal tract were challenged with injected food allergens in a
similar way as EPT, no severe systemic reactions were observed. Nonetheless,
medications for management of acute anaphylactic will be present during and
after endoscopy.

Tissue impedance measurement
Tissue impedance is measured during upper endoscopy. A small probe is placed
against the mucosa under an angle of 30°. An electrical current of 20 µA is
injected in the mucosa through the probe. No risk is associated with this
investigation