+Model

ALLER-780; No. of Pages 6 ARTICLE IN PRESS

Allergol Immunopathol (Madr). 2016;xxx(xx):xxx---xxx

Allergologia et
immunopathologia
Sociedad Española de Inmunologı́a Clı́nica,
Alergologı́a y Asma Pediátrica
www.elsevier.es/ai

ORIGINAL ARTICLE

Primary eosinophilic gastrointestinal disorders in

children who have received food oral immunotherapy
L.Á. Echeverría-Zudaire a,∗ , S. Fernández-Fernández b , A. Rayo-Fernández b ,
C. Muñóz-Archidona c , R. Checa-Rodriguez d

a
Pediatric Allergy Unit, Severo Ochoa Universitary Hospital, Leganés, Spain
b
Pediatric Gastroenterology Unit, Severo Ochoa Universitary Hospital, Leganés, Spain
c
Pediatric Allergy Unit, Villalba General Hospital, Villalba, Spain
d
Pediatric Gastroenterology Unit, Rey Juan Carlos Universitary Hospital, Móstoles, Spain

Received 30 December 2015; accepted 4 May 2016

KEYWORDS Abstract
Eosinophilic Background: Food oral immunotherapy (OIT) involves the administration of the food allergen
esophagitis; causing the symptoms, in order to induce tolerance. Primary eosinophilic gastrointestinal disor-
Food oral ders (PEGDs) are characterised by an eosinophil-rich inflammation affecting different locations
immunotherapy; of the digestive tract. We present a series of patients with PEGDs in a group of children following
Eosinophilic OIT with milk and/or egg.
gastroenteritis; Material and methods: A prospective study during the period 2006---2014 was performed in
Eosinophilic colitis; paediatric patients subjected to OIT with milk and/or egg. When these children present persis-
Food allergy; tent gastrointestinal symptoms, they are referred to the Paediatric Gastroenterology Unit for
Desensitization; evaluation.
Immunologic or Results: Primary eosinophilic gastrointestinal disorders were diagnosed in eight of the 128 cases
immune tolerance of OIT (6.25%). The time to PEGDs development was variable: two cases showed symptoms
during OIT, and the rest with a median time of 29 months (15---48 months). Food treatment
discontinuation was not required in four of the five cases of eosinophilic oesophagitis, although
food removal was necessary in patients with eosinophilic gastroenteritis.
Conclusions: We report the highest prevalence of PEGDs in children subjected to OIT, and the
first cases of eosinophilic gastroenteritis following food OIT.
The monitoring of new digestive signs and symptoms after OIT is crucial for the diagnosis of
these disorders, and prolonged follow-up is required. The management of such patients and
the need or not to eliminate the food should be assessed on an individualised basis, according
to the severity of the condition, its evolution and response to different treatment alternatives.
© 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

∗ Corresponding author.
E-mail address: [email protected] (L.Á. Echeverría-Zudaire).

http://dx.doi.org/10.1016/j.aller.2016.05.002
0301-0546/© 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
http://dx.doi.org/10.1016/j.aller.2016.05.002
+Model
ALLER-780; No. of Pages 6 ARTICLE IN PRESS
2 L.Á. Echeverría-Zudaire et al.

Introduction Objective
The prevalence of food allergy in childhood is high, with The present study aims to describe the incidence and char-
a negative impact upon general perceived health, family acteristics of PEGDs manifested in a prospective group of
and social activities, and quality of life of both patients children with persistent IgE-mediated food allergy undergo-
and their families. Current treatment strategy in such cases ing to OIT with milk and/or egg.
is to strictly avoid the offending food, provide rescue
medication to control the adverse reactions caused by trans-
gressions, and afford adequate patient education. Despite Material and methods
such measures, however, food allergy remains one of the
most frequent causes of anaphylactic reactions in children A prospective study during the period 2006---2014 was per-
and young adults.1---3 formed in paediatric patients subjected to OIT with milk
Food oral immunotherapy (OIT) involves the administra- and/or egg due to persistent allergy to these foods as
tion of increasing doses of the food to which the patient demonstrated by clinical findings, prick testing, specific-
is allergic, with the aim of reducing the symptoms associ- IgE quantification and a positive open oral food challenge.
ated to natural exposure (desensitisation) and, if possible, During both phases, an initial dose escalation and mainte-
achieve permanent tolerance. Food oral immunotherapy nance phase, strict monitoring of new gastrointestinal signs
may be regarded as an alternative to elimination diets in and symptoms was carried out (eating problems, vomiting,
patients with IgE-mediated allergy that maintain clinical weight loss, abdominal pain, chest pain, burning sensa-
reactivity beyond the age when natural tolerance is usu- tion, persistent diarrhoea, dysphagia of oesophageal food
ally reached.3---5 The technique is fundamentally used with impaction). None of the patients presented digestive symp-
cow’s milk and egg, since in our setting it is difficult to suc- toms before starting the OIT. When such children presented
cessfully avoid these foods, and transgressions are frequent persistent gastrointestinal symptoms, they were referred to
and can be serious.6,7 Although death as a result of ana- the Paediatric Gastroenterology Unit for evaluation and they
phylaxis is infrequent in such cases, the risk must not be were first clinically evaluated, and if PEGDs was suspected
underestimated --- particularly in adolescents and asthmatic then digestive endoscopy was performed and biopsy speci-
individuals. mens obtained.
Published studies to date indicate that OIT is able to Eosinophilic gastroenteritis involves selective
achieve desensitisation to cow’s milk and egg in 84% and 81% eosinophilic infiltration of the stomach and small and/or
of the patients, respectively.8---10 However, the ability of OIT large intestine, in the absence of other possible causes of
to induce permanent or sustained tolerance has not, to date, eosinophilia of the digestive tract. It is characterised by
been extensively evaluated. The procedure is not without variable involvement of the layers of the gastrointestinal
risks, and prolonged maintenance treatment is required. wall, with different degrees of infiltration and spread which
It therefore must be accepted by the patient and/or will change the associated symptoms (eosinophilic gastroen-
family, after receiving adequate information about the teritis is defined by eosinophil-predominant inflammation
treatment. in one or more of the following locations: ≥10---30 eos/hpf
Primary eosinophilic gastrointestinal disorders (PEGDs) in the stomach and small intestine and ≥70 eos/hpf in the
are a heterogeneous group of diseases characterised by large intestine). On the other hand, eosinophilic colitis is
an eosinophil-rich inflammation affecting different loca- defined as eosinophilic infiltration limited to the colon,
tions of the digestive tract: eosinophilic oesophagitis (EoE), in the absence of other possible causes of eosinophilia.
eosinophilic gastroenteritis (EoGE) (gastritis/enteritis) and The aetiopathogenesis of both, EoGE and EoC is even
eosinophilic colitis (EoC). Eosinophilic oesophagitis is the less well known than that of EoE, although an underlying
most common form, and is a chronic oesophageal disor- allergic mechanism has also been suggested, and the
der of immune origin, mediated by antigens and clinically condition sometimes improves when an elimination diet is
and histopathologically characterised by oesophageal dys- introduced.21---23
function and a predominantly eosinophilic infiltration (≥15
eosinophils per high-power microscopy field (eos/hpf)). Statistical analysis
Eosinophilic oesophagitis mainly affects males and is
typically associated to other allergic disorders such as Proportions were expressed as percentages and 95% confi-
asthma and atopic dermatitis. Although the underly- dence intervals (CI). Continuous variables were presented
ing aetiopathogenesis is not clear, mainly food allergens as mean ± standard deviation.
and inhaled aeroallergens to a lesser extent are known
to play an important role in the development of the
disease.11---13 Results
Although the development of PEGD after OIT has been
described in the recent literature, the relationship between In the period 2006---2014, our Paediatric Allergy Unit applied
them remains controversial. All available publications refer the OIT protocol in 97 cases with cow’s milk and 31 cases
to sporadic cases of EoE.14---19 Recently, Lucendo et al. with egg. In that period, PEGDs were diagnosed in eight
have published a systematic review and meta-analysis of the global 128 cases of OIT representing 6.25% of the
demonstrating a prevalence of EoE after OIT of 2.7%.20 sample (95% CI: 2.05---10.4%). Most of the affected patients
There are no published cases of EoGE and EoC after food were males between 3 and 14 years of age. Eosinophilic
OIT. oesophagitis was diagnosed in six patients with exclusively

Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
http://dx.doi.org/10.1016/j.aller.2016.05.002
+Model
ALLER-780; No. of Pages 6 ARTICLE IN PRESS
Primary eosinophilic gastrointestinal disorders in children after food OIT 3

oesophageal involvement, while the other two patients were 128 Patients OIT
diagnosed with EoGE (one with oesophageal and duodenal
disease and the other with oesophageal and colon involve- 8 PEGDs ( 6.2%)

ment). Six of the affected patients had undergone OIT with

6 EoE 2 EoGE
cow’s milk, one with egg, and one with both foods.
All the patients had a history of allergic disorders
5Continued OIT 3 Discontinued OIT
(asthma, rhinoconjunctivitis, atopic dermatitis or allergy 1 EoE∗
to different foods). The previous total IgE and specific IgE 3 PPIs 2 PPIs + SF 2 EoGE
(ImmunoCAP) titres corresponding to each of the implicated Follow-up Follow-up
endoscopy endoscopy
foods are shown in Table 1.
The time of onset of digestive disorders after OIT var- 2 Histological Parental refusal 1 Histological 3 Histological
ied according to the different cases. Six of eight patients 1 EoE
remission for endoscopy remission remission
developed PEGDs after OIT (all with cow’s milk), with a
All remained asymptomatic ∗ Very symptomatic with medical treatment
median time of 29 months (15 months---4 years). In one of
Abbreviations: OIT: oral immunotherapy. PEGDs: primary eosinophilic
these patients, OIT with egg was performed after finishing gastrointestinal disorders. EoE: eosinophilic esophagitis.
OIT with cow’s milk (case 6). In the remaining two patients EoGE: eosinophilic gastroenteritis. PPIs: proton pump inhibitors.
the diagnosis of PEGDs was established in the course of OIT. SF: swallowed fluticasone
The most common initial symptom was abdominal pain (in Figure 1 Evolution of eight patients with primary eosinophilic
six of the eight cases), followed by vomiting (in five cases) gastrointestinal disorders after food oral immunotherapy.
and dysphagia (in three cases). The two patients with EoGE
experienced more intense symptoms, with greater clinical published by Lucendo et al.20 found that the prevalence of
repercussion (diarrhoea and constitutional syndrome in the this disorder after OIT (egg, milk, peanut or wheat) was 2.7%
patient with colon involvement). One of the patients (case (95% CI: 1.7---4%). This is considerably lower than our own fig-
3) was asymptomatic, and EoE was detected on occasion ure, which may be explained because the systematic review
of the endoscopic study carried out due to the suspicion of only included EoE patients and not other PEGDs.
celiac disease. There may be a number of explanations for the higher
The five patients with EoE received treatment with prevalence found in our study. In our opinion, the most
proton pump inhibitors with or without swallowed cor- important factor is the close clinical monitoring performed
ticosteroids (fluticasone 500---750 ␮g/daily), and OIT was during follow-up. In this regard, we compiled a detailed clin-
maintained. The two patients who were diagnosed recently ical history and conducted a physical examination on each
received a double dose of proton pump inhibitors [PPIs] visit in order to detect signs and symptoms suggestive of gas-
(1 mg/kg per dose, twice daily for 8---12 weeks), with trointestinal disease. When such disease was suspected, the
histological response. These patients were diagnosed as PPI- patients were referred to the Paediatric Gastroenterology
responsive oesophageal eosinophilia. Four patients had a Unit for evaluation. On the other hand, there is no sign,
good clinical response, and only one (case 5) required OIT symptom or laboratory test parameter pathognomonic of
discontinuation in order to control the symptoms. In the PEGDs. Furthermore, in the specific case of EoE, there is a
patient with celiac disease, medical treatment was pre- known lack of correlation between clinical and histological
scribed in view of the persistence of eosinophilic infiltration findings.24
after eliminating gluten from the diet. Endoscopic controls Gastrointestinal symptoms are common in the context
after treatment were performed in four of the five patients, of food OIT. However, while the symptoms associated to
with endoscopic improvement or normalisation in three of IgE-dependent mechanisms tend to manifest immediately
them. Due to the greater digestive tract involvement in the after food exposure (in under 2 h), the manifestations of
two patients with EoGE, the food used in OIT was eliminated PEGDs in relation to OIT usually exhibit no such sequen-
and treatment was started with proton pump inhibitors tial relationship --- although they characteristically persist
and corticosteroids. Clinical and histological remission was over time. In the case of younger patients, vomiting is usu-
achieved in both cases (Fig. 1). ally the most prevalent symptom in both scenarios --- this
sometimes makes it difficult to establish a correct differen-
tial diagnosis.25 However, in the case of dysphagia or food
Discussion impaction---more characteristic of EoE12 --- a high degree of
suspicion must be established, since such manifestations are
In our experience, the prevalence of primary eosinophilic not commonly reported by the patients during OIT.26 In our
gastrointestinal disorders (PEGDs) in patients who have series, the most frequent symptom was abdominal pain, fol-
received food OIT is 6.25% (95% CI: 2.05---10.4%). Very few lowed by vomiting, dysphagia or food impaction (present in
studies are available on the development of EoE or other only three of our patients, specifically cases 5---7).
eosinophilic digestive disorders in patients who undergo Oral immunotherapy is a novel form of treatment, and
food OIT, and most of the existing publications correspond long-term safety of OIT is nowadays poorly reported, so
to retrospective studies14---16 and case reports.17,18 The series it remains unknown if long-term adverse effects can be
described in our study is the largest published to date, induced. Consequently, patient monitoring must be pro-
and reports a higher frequency of PEGD than other studies, longed over time. This may also be one of the reasons why
where the prevalence ranges between 2.5%6,9 and 3.5%.3 On the prevalence of PEGDs in our series was higher than in
the other hand, a recent systematic review on the evidence other studies, since follow-up in our case covered periods
of an association between newly manifesting EoE and OIT of up to nine years.

Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
http://dx.doi.org/10.1016/j.aller.2016.05.002
 4

ALLER-780; No. of Pages 6

+Model
http://dx.doi.org/10.1016/j.aller.2016.05.002
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal

Table 1 Case summary.

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8
Age (years)/sex 14/male 14/male 9/female 11/female 3/male 9/male 14/male 13/male
Personal history Asthma and Peach Asthma AD and RCJ Asthma, AD. Asthma, AD Asthma, RCJ Asthma AD
RCJ allergy Egg and Kiwi Egg and nut Multiple food AD, Egg allergy Multiple food
allergy allergy allergies allergies
Total IgE (UI/ml) 752 559 527 52.6 664 171 287 77.5
Specific IgE ALA 8.6 Egg white ALA 10.3 ALA 2.77 ALA >100 Egg white ALA 5.1 ALA 0.5
(KU/L) 12.1
BLG 4 >100 BLG 8.7 BLG 3.4 BLG 90.7 OVA 6.5 BLG 2.2 BLG <0.35
Cas 21.1 OVA 71.1 Cas 20.1 Cas 13.4 Cas 79.9 OVM 9.5 Cas 68.4 Cas 1.06
OVM 38.4 ALA 23.5
BLG 1.15

ARTICLE IN PRESS
Cas 10.3
OIT Milk/112 Egg/315 Milk/130 Milk/149 Milk/discontinued Milk/222 Milk/112 Milk/160
food/induction OIT Egg/338
phase (days)
Time to 16 months In induction 24 months 47 months In induction Milk 24 15 months 48 months
development OIT OIT months
PEGDs after Egg 1 month
OIT
Clinical Abdominal Abdominal Asymptomatic Abdominal Dysphagia Dysphagia Dysphagia Abdominal Pain
characteristics pain pain pain
Pyrosis Vomiting Vomiting Abdominal pain Abdominal pain Vomiting
Vomiting Vomiting Diarrhoea
Constitucional
syndrome
Diagnostic EoE EoE EoE EoE EoE EoE Eosinophilic Eosinophilic
Celiac gastroenteritis gastroenteritis
disease (Esophageal and (Esophageal and
duodenal disease) colon disease)
Treatment PPIs PPIs PPIs PPIs PPIs PPIs PPIs PPIs
Topical Topical Topical steroid Topical steroid Oral steroids

L.Á. Echeverría-Zudaire et al.

steroid steroid therapy therapy
therapy therapy
Discontinued OIT Discontinued OIT
Abbreviations
1 RCJ: rhinoconjunctivitis. 2 AD: atopic dermatitis. 3 IgE: immunoglobulin E.
4 ALA: alpha-lactalbumin, BLG: beta lactoglobulin, CAS: casein.
OVA: ovalbumin; OVM: ovomucoid, 6 OIT: oral immunotheraphy.
7 PEGDs: primary eosinophilic gastrointestinal disorders.
8 EoE: eosinophilic oesophagitis.
9 PPI: protom pump inhibitor.
+Model
ALLER-780; No. of Pages 6 ARTICLE IN PRESS
Primary eosinophilic gastrointestinal disorders in children after food OIT 5

All our patients reported other concomitant allergic treatment, followed by symptoms resolution in all cases.
conditions such as asthma, rhinoconjunctivitis or atopic der- Three of these five children had normal histological findings,
matitis. The relationship between PEGDs (particularly EoE) despite not having eliminated the food. Regarding the other
and these allergic diseases is known.11,13 The prevalence two cases (also with disappearance of the symptoms fol-
of EoE in the general population is estimated at 1.1%,27 lowing medical treatment), one rejected control endoscopy
although the prevalence of PEGD in high risk allergic popu- (case 1), and the other showed persistent endoscopic abnor-
lations is not clear. A recent study recorded a prevalence malities (case 3). Morais et al.18 recommend to discontinue
of EoE of 8.3% in allergic children28 --- a figure which comes OIT when EoE is diagnosed in the dose-scaling phase, and
closer to that found in our series. Consequently, since all other authors advise the removal of the food in patients
our patients suffered such allergic disorders, they appear to who have developed EoE after OIT.16,17 In our series we
conform a high risk group for PEGD --- and this may also help found both, endoscopic healing and disappearance of the
explain our recorded higher prevalence of 6.25%. symptoms to be possible despite maintenance of the food
Our series also describes the first published cases of EoGE introduced in OIT. In our opinion, in the case of allergic
following food OIT. Eosinophilic gastroenteritis is less com- patients with EoE, the important improvement in their qual-
mon than EoE, and few references of the disease can be ity of life represented by the possibility of consuming a food
found in the literature. As a result, establishing the diagno- without the risk of serious reactions,29 and the fact that the
sis may be more complicated.14 The symptoms are usually removal of the food does not guarantee the resolution of
confusing, with a broad variety of signs and symptoms, EoE, implies that the decision to eliminate it or not should
depending both on the affected zone of the digestive tract be made on an individualised basis, depending on the diag-
and on the intestinal wall layers infiltrated by eosinophils. In nosis, symptoms, evolution and response to other available
our series, case 7 was characterised by vomiting, abdominal treatments. However, in the case of EoGE, we consider that
pain and intermittent dysphagia approximately 15 months the food introduced in OIT should be removed, due to the
after OIT with cow’s milk, while case 8 involved intense severity of the clinical condition.
abdominal pain, diarrhoea and important anorexia, with In conclusion, the series of primary eosinophilic gas-
weight loss altering normal life and even preventing the trointestinal disorders described in our study is the largest
child from attending school, four years after the adminis- published to date in children who have undergone food oral
tration of OIT, also with cow’s milk. Thus, our two cases immunotherapy. We underscore the need for correct and
were not characterised by a common clinical picture, and prolonged patient gastrointestinal follow-up, maintaining a
the diagnosis could only be established after performing high degree of suspicion in individuals with persistent diges-
endoscopic studies. tive tract symptoms. The decision to eliminate the food from
In view of the relationship between PEGDs (fundamen- OIT should be agreed with the patients and their families
tally EoE) and allergic disease, it could be postulated that on an individualised basis, depending on the severity of the
introduction of the food in our patients was possibly not the condition, the symptoms, evolution and response to other
only cause involved in the development of gastrointestinal possible treatment alternatives.
pathology. Since endoscopic study before OIT is not indi-
cated in asymptomatic patients, digestive manifestations
coinciding with introduction of the food, suggest the onset Ethical disclosures
of PEGDs, although without being able to confirm its pre-
vious existence. We were only able to confirm the absence Confidentiality of data. The authors declare that they have
of previous eosinophilic digestive disease in case 3, since followed the protocols of their work centre on the publi-
in that patient an endoscopic study had been made before cation of patient data and that all the patients included
administering OIT, due to the presence of celiac disease. in the study have received sufficient information and have
In three of our cases, EoE was diagnosed in the course given their informed consent in writing to participate in that
of OIT, which may point to the introduction of the food in study. The authors declare that no patient data appears in
the diet as the underlying causal factor. In the rest of the this article.
series, the time between OIT and the diagnosis exceeded
one year, with a range of 15 months to over four years. Thus,
Right to privacy and informed consent. The authors
in these cases a possible causal relationship between OIT and
declare that no patient data appears in this article.
PEGDs is more difficult to establish. Such a long time interval
once again underscores the need for prolonged monitoring
of these patients. Protection of human subjects and animals in research.
Regarding treatment, exclusion of the cow’s milk The authors declare that no experiments were performed
introduced in the context of OIT was decided in the two on humans or animals for this investigation. The authors
patients with EoGE, followed by a favourable clinical and declare that the procedures followed were in accordance
histological course that remains long term. with the regulations of the responsible Clinical Research
In the six patients with EoE, food elimination was decided Ethics Committee and in accordance with those of the World
as the first treatment option only in one patient (case 5) Medical Association and the Helsinki Declaration.
in which the clinical manifestations appeared in the dose
scaling phase of OIT, since the parents rejected medical
treatment. After removal of food, symptoms disappeared Conflict of interest
and normal histological findings were shown. In the other
five patients the food was not eliminated, establishing drug The authors have no conflict of interest to declare.

Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
http://dx.doi.org/10.1016/j.aller.2016.05.002
+Model
ALLER-780; No. of Pages 6 ARTICLE IN PRESS
6 L.Á. Echeverría-Zudaire et al.

References immunotherapy for IgE-mediated cow’s milk allergy. J Allergy

Clin Immunol. 2009;124:610---2.
1. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, 16. Sánchez-García S, Rodríguez Del Río P, Escudero C, Martínez-
Garcez T, et al. Increase in anaphylaxis-related hospitalizations Gómez MJ, Ibáñez MD. Possible eosinophilic esophagitis
but no increase in fatalities: an analysis of United Kingdom induced by milk oral immunotherapy. J Allergy Clin Immunol.
national anaphylaxis data, 1992---2012. J Allergy Clin Immunol. 2012;129:11551157.
2015;135:956---63. 17. Ridolo E, De Angelis GL, Dall’aglio P. Eosinophilic esophagi-
2. Cianferoni A, Muraro A. Food-induced anaphylaxis immunol. tis after specific oral tolerance induction for egg protein. Ann
Allergy Clin North Am. 2012;32:165---95. Allergy Asthma Immunol. 2011;106:73---4.
3. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas 18. Morais P, Antunes J, Chambel M, Prtaes S, Leiria P. Diagnosis
M, Cardona V, et al. First European data from the network of of eosinophilic esophagitis in an infant undergoing milk oral
severe allergic reactions (NORA). Allergy. 2014;69:1397---404. immunotherapy --- a case report. Eur Ann Allergy Clin Immunol.
4. Martorell A, García Ara MC, Plaza AM, Boné J, Nevot S, Echev- 2014;46:154---6.
erria L, et al. The predictive value of specific immunoglobulin 19. Fuentes-Aparicio V, Alvarez-Perea A, Infante S, Zapatero L,
E levels in serum for the outcome of the development of tol- D’Oleo A, Alonso-Lebrero E. Specific oral tolerance induc-
erance in cow’s milk allergy. Allergol Immunopathol (Madr). tion in paediatric patients with persistent egg allergy. Allergol
2008;36:325---30. Immunopathol (Madr). 2013;41:143---50.
5. Boyano-Martinez T, Garcia-Ara C, Diaz-Pena JM, Martin-Esteban 20. Lucendo AJ, Arias A, Tenias JM. Relation between eosinophilic
M. Prediction of tolerance on the basis of quantification of esophagitis and oral immunotherapy for food allergy: a system-
egg white-specific IgE antibodies in children with egg allergy. atic review with meta-analysis. Ann Allergy Asthma Immunol.
J Allergy Clin Immunol. 2002;110:304---9. 2014;113:624---9.
6. Alonso Lebrero E, Fernández Moya L, Somoza Álvarez ML. 21. Busonia V, Lifschitz C, Christiansen S, de Davila MTG, Orsia
Alergia a leche y huevo en niños. Allergol Immunol Clin. M. Gastroenteropatía eosinofílica: una serie pediátrica. Arch
2001;16:96---115 (Extraordinario 2). Argent Pediatr. 2011;109:68---73.
7. Boyano-Martínez T, García-Ara C, Pedrosa M, Díaz-Pena JM, 22. Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Samp-
Quirce S. Accidental allergic reactions in children allergic to son HA, Sicherer SH. Allergic eosinophilic gastroenteritis
cow’s milk proteins. J Allergy Clin Immunol. 2009;4:883---8. with protein-losing enteropathy: intestinal pathology, clinical
8. Begin P, Chinthrajah RS, Nadeau KC. Oral immunotherapy course, and long-term follow-up. J Pediatr Gastroenterol Nutr.
for the treatment of food allergy. Hum Vaccin Immunother. 2006;42:516---21.
2014;10:2295---302. 23. Lucendo AJ, Serrano-Montalbán B, Arias Á, Redondo O, Tenias
9. Yeung JP, Kloda LA, McDevitt J, Ben-Shoshan M, Alizadehfar R. JM. J Pediatr Gastroenterol Nutr. 2015;61:56---64.
Oral immunotherapy for milk allergy. Cochrane Database Syst 24. Pentiuk S, Putnam PE, Collins MH, Rothenberg ME. Dis-
Rev. 2012;11. CD009542. sociation between symptoms and histological severity in
10. Romantsik O, Bruschettini M, Tosca MA, Zappettini S, Della Casa pediatric eosinophilic esophagitis. J Pediatr Gastroenterol Nutr.
Alberighi O, Calevo MG. Oral and sublingual immunotherapy for 2009;48:152---60.
egg allergy. Cochrane Database Syst Rev. 2014;11. CD010638. 25. Chadha SN, Wang L, Correa H, Moulton D, Hummell DS. Pediatric
11. Papadopoulou A, Koletzko S, Heuschkel R, Dias JÁ, Allen eosinophilic esophagitis: the Vanderbilt experience. Ann Allergy
KJ, Murch SH, et al. Management guidelines of eosinophilic Asthma Immunol. 2014;113:445---51.
esophagitis in childhood. J Pediatr Gastroenterol Nutr. 26. Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L,
2014;58:107---18. et al. Specific oral tolerance induction in children with very
12. Kagalwalla AF, Amsden K, Shah A, Ritz S, Manuel-Rubio M, Dunne severe cow’s milk-induced reactions. J Allergy Clin Immunol.
K, et al. Cow’s milk elimination: a novel dietary approach to 2008;121:343---7.
treat eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 27. Ronkainen J, Talley NJ, Aro P, Storskrubb T, Johansson SE, Lind
2012;55:711---6. T, et al. Prevalence of oesophageal eosinophils and eosinophilic
13. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis oesophagitis in adults: the population based Kalixanda study.
PA, et al. Eosinophilic esophagitis: updated consensus recom- Gut. 2007;56:615---20.
mendations for children and adults. J Allergy Clin Immunol. 28. Kim JS, Nowak-Wegrzyn A, Sicherer AH, Noone S, Moshier
2011;128:3---20, e6. EL, Sampson HA. Dietary baked milk accelerates the resolu-
14. Hofmann AM, Scurlock AM, Jones SM, Palmer KP, Lokhnygina Y, tion of cow’s milk allergy in children. J Allergy Clin Immunol.
Steele PH, et al. Safety of a peanut oral immunotherapy pro- 2011;128:125---31.
tocol in children with peanut allergy. J Allergy Clin Immunol. 29. Vazquez-Ortiz M, Alvaro M, Piquer M, Dominguez O, Giner
2009;124:286---91. MT, Lozano J, et al. Impact of oral immunotherapy on qual-
15. Narisety SD, Skripak JM, Steele P, Hamilton RG, Matsui EC, ity of life in egg-allergic children. Pediatr Allergy Immunol.
Burks AW, et al. Open-label maintenance after milk oral 2015;26:291---4.

Please cite this article in press as: Echeverría-Zudaire LÁ, et al. Primary eosinophilic gastrointestinal
disorders in children who have received food oral immunotherapy. Allergol Immunopathol (Madr). 2016.
http://dx.doi.org/10.1016/j.aller.2016.05.002