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Eosinophilic Gastrointestinal Disorders
1. Eosinophilic Gastrointestinal
Disorders (EGID)
Tharida Khongcharoensombat, MD
Division of Pediatric Allergy, Immunology and Rheumatology unit
Department of Pediatrics, Faculty of Medicine
King Chulalongkorn Memorial Hospital
27 January 2023
3. Definition
• Eosinophilic gastrointestinal disorders (EGIDs) are defined as
• Disorders that selectively affect the gastrointestinal (GI) tract with eosinophil-
rich inflammation in the absence of known causes of eosinophilia.
• EGIDs arise secondarily to the interplay of genetic, immune, and
environmental factors.
• Eosinophilic esophagitis
• Eosinophilic gastritis
• Eosinophilic gastroenteritis
• Eosinophilic colitis
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
4. • The umbrella term for disorders of GI tract eosinophilic inflammation in the absence of
secondary causes should be “eosinophilic gastrointestinal disease” (EGID)
• It is desirable, but not required, to name specific locations of small bowel involvement, if these
are known
• Eosinophilic duodenitis
• Eosinophilic jejunitis
• Eosinophilic ileitis
• The term “eosinophilic gastroenteritis” should be redefined and only used to indicate gastric
AND small bowel involvement
• When more than 2 GI tract areas (outside of the esophagus) are involved, the name should
reflect the involved areas
• The GI wall layer of involvement (or if this is unknown) should be noted.
• Complications of EGIDs should be noted.
Dellon ES, et al. Clin Gastroenterol Hepatol. 2022 Nov;20(11):2474-2484.e3.
6. Eosinophil levels in the GI tract in
apparently normal endoscopic biopsies.
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
7. Differential diagnosis
• Intestinal infections are the
most frequent cause of
secondary eosinophilic
gastrointestinal inflammation.
• Especially in children with
recurrent abdominal pain
+ peripheral eosinophilia
• Colonic spirochetosis
• Helicobacter pylori infection
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
9. • EoE being the most common.
• Incidence rates have been increasing.
• A meta-analysis¹ estimated an overall
pooled EoE prevalence of 22.7/100,000
• Significantly higher in
• Male
• Adult population (18–65 years of age)
• Whites > Asians and African
American
Epidemiology
1. Dellon ES, et al. Gastroenterology. 2018;154(2):319-332.e3
Khokhar D, et al. Clin Exp Allergy. 2022 Oct;52(10):1142-1156.
10. • Prevalence of eosinophilic gastritis: 1.5 – 6.4/100.000
• Prevalence of eosinophilic gastroenteritis: 2.7 – 8.3/100.000
• Prevalence of eosinophilic colitis: 1.7 to 3.5/100.000
• The age at onset of EGIDs: vary
• Children
• Adults: 3rd – 5th decade
Epidemiology
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
11. Regulation of
gastrointestinal eosinophils
• Eosinophil from BM → Lamina propria
(CCR3/Eotaxin-1)
• ILC-2 → IL-5, IL-13
• Eosinophil express a broad range of
PRRs and FcγR
• Eosinophils stimulated by Th2-type
cytokines and epithelium-derived IL-33
mediate tissue inflammation in a
variety of primary EGIDs.
• Eosinophils may also modulate T cell–
mediated immune responses, IgA
class switching, and glucose
homeostasis
Pathogenesis
Jung Y, et al. J Immunol. 2014 Aug 1;193(3):999-1005.
12. Pathogenesis
• EGIDs shared mechanisms with allergic diseases.
• About 75% of patients with EGIDs have atopy.
• The prevalence of atopic disease such as allergic rhinitis, bronchial asthma,
IgE-mediated food allergies, and eczema is far higher in patients with EoE
than the general population.¹
• EGID mechanisms: fall between pure immunoglobulin E (IgE)–mediated and T
helper cell type 2 (Th2) responses
• Contributory roles for food antigens, IL-5, IL-13, eotaxin (Th2 predominate)
• Only a minority have IgE-mediated clinical reactions to these foods, such as
food-induced anaphylactic responses.
• In one pediatric study², children with EoE were found to have more than 60%
with food allergies.
• > 50% of patients, EGIDs occur independent of peripheral blood
eosinophilia
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
1. Gonzalez-Cervera J, et al. Ann Allergy Asthma Immunol 2017;118:582-590.e2
2. C. A. Liacouras, et al. Clinical Gastroenterology and Hepatology, vol. 3, no. 12, pp. 1198–1206, 2005
13. Proinflammatory Role of Eosinophils
• Activate eosinophil → produce highly bioactive inflammatory mediators
• Trigger degranulation of mast cells, release of chemokines, cytokines, lipid
mediators and neuro-mediators
• Inducing the Th2-type immune response
• Tissue damage - bowel inflammation
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
14. Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
• EoE is frequently associated with atopic diseases (AR, asthma, AD)
• EoE is a chronic inflammatory disease of the esophagus driven by food allergen exposure which triggers esophageal eosinophilia
and esophageal epithelial remodeling
Genetic susceptibility Early life factor Barrier formation
- DSG1
- Desmoplakin
- SPINK5
- FLG
0
Pathogenesis (EoE)
15. Pathogenesis: genetic (EoE)
• Hereditability pattern
• Increased risk of EoE in
first-degree relatives (10- to
64-fold) compared with that
of the general population.
• Multiple genes are likely
contributing to the
development of EoE.
O'Shea KM, et al. Gastroenterology. 2018 Jan;154(2):333-345.
Khokhar D, et al. Clin Exp Allergy. 2022 Oct;52(10):1142-1156.
17. Pathogenesis: possible triggers
• Genetic predisposition
• Environmental triggers (ingested or inhaled allergens)
• Gastrointestinal dysbiosis
• Anatomical malformations
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
Induce eosinophilic inflammation in EGIDs patients
18. Disease Etiology
Eosinophilic esophagitis • Genetic, host immune system
• Environmental factors (food, aeroallergen)
• Coexisting atopic disease, Th2 response
Eosinophilic gastritis/gastroenteritis Same as eosinophilic esophagitis (atopic: asthma, AR - less
convincing evidence compared to EoE)
• Increased secretion of IL-4 and IL-5 by peripheral blood T cells
• Increased IL-4, IL-5, IL-13, IL-17, CCL26
• Increased mast cell–specific gene expression in gastric tissue
• Increased number of mast cells in gastric and intestinal biopsies
Eosinophilic colitis • Usually a non–IgE-associated disease
• T cell–mediated process (but the exact immunologic
mechanisms have not been identified.)
• Infant: FPIES, Elderly: helminth, IBD, EGPA
• Idiopathic (when secondary causes have been excluded)
Pathogenesis: possible triggers
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
19. • The prevalence of IgE‐mediated food allergy varies between 25% and nearly 70%.
• The most frequently implied foods are milk, wheat, soy, egg, nuts, and shellfish.
• Eczema was also significantly more frequent in patients than controls, (OR 2.85, 95% CI
1.87–4.34)
• In a large cross‐sectional, population‐based survey conducted in the US, a high prevalence
of allergic disorders was observed among 74 EoE children and 89 EoE adults
• 32.4 and 37.3% had ≥ 1 current IgE ‐food allergy
• 27.8% and 47.8% had asthma
• 27.5% and 22.9% had atopic dermatitis/eczema
• 43.5% and 41.6% had seasonal rhinitis. Rossi CM, et al. Clin Transl Allergy. 2022 May 23;12(5):e12146.
Pathogenesis:
Food allergy and atopic disease in EoE
20. Clinical manifestation
• The clinical presentation of EGIDs varies based on the affected area and
layer of the GI wall involved.
• Coexistence of EoE in children with EGE has been reported.
• It is widely described that EGIDs are associated with allergic diseases
• Prevalent allergy comorbidities are food allergy, asthma and allergic rhinitis
• Compared to adults, children and adolescents may develop growth
retardation, failure to thrive, delayed puberty and amenorrhea
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
21. Eosinophilic esophagitis
• Feeding problems
• Vomiting
• Abdominal pain
• Epigastric or chest pain
• Dysphagia
• Food impactions
Clinical manifestation
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
O'Shea KM, et al. Gastroenterology. 2018 Jan;154(2):333-345.
Symptoms occur in chronologic order →
if left untreated: progressive esophageal scarring and dysfunction
22. Eosinophilic gastritis
• Nausea, vomiting, early satiety, abdominal pain, chest pain and throat pain
(10.2% concurrent EoE)
• Isolated ulcer that might perforate, not responsive to proton pump
inhibitors.
Eosinophilic gastroenteritis
• Diarrhea, vomiting, and abdominal pain
• Malnutrition, anemia, and protein losing enteropathy
Clinical manifestation:
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
23. Eosinophilic gastritis and gastroenteritis
Symptoms that are related to the degree and area of the GI tract affected.
• The mucosal form: nausea, vomiting, and abdominal pain (an mimic acute appendicitis), bloating,
diarrhea, blood loss via stool, iron deficiency anemia, malabsorption, protein-losing enteropathy, and
failure to thrive,
• The muscularis form → leading to thickening of the bowel wall and decreased motility → bowel
obstruction
• The serosal form (minority): exudative ascites with higher peripheral eosinophil counts compared with
the other forms.
Gastric ulcer disease is not a common feature but has been reported.
• It responds to either topical or systemic corticosteroids but not to PPI therapy.
Clinical manifestation
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
24. Eosinophilic colitis
• It has a bimodal age presentation
• Infancy (at approximately 60 days of age)
• Adolescence and early adulthood
• Abdominal pain, diarrhea (bloody or nonbloody), tenesmus, anorexia, and/or
weight loss.
Clinical manifestation
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
25. EoE EG, EGE EC
Feeding problems
Nausea, Vomiting
Chest pain, Throat pain
Abdominal pain
Dysphagia
Food impact
Isolated ulcer Not response PPI
Diarrhea Mucosal form
Malnutrition, PLE, IDA, FTT,
hypoalbuminemia
Mucosal form
Gut obstruction Muscular form
Exudate ascites Serosal form
Hematochezia, weight loss,
anorexia
26. Diagnosis
• A diagnostic evaluation for EGIDs
• All with refractory problems
• Especially in; strong history of atopy, peripheral blood eosinophilia, FH of EGIDs
• No pathognomonic symptoms or laboratory tests
• Clinical + histopathologic findings + absence of secondary causes of gastrointestinal
eosinophilia
• No accepted diagnostic criteria have been established for EGIDs (except EoE)
• Symptoms may correlate poorly with histology.
• The diagnosis of EGIDs depends on the microscopic evaluation of endoscopic biopsy samples
• Quantity, location, characteristics of the eosinophilic inflammation
• Negative endoscopic mucosal biopsies do not definitively rule out muscular or subserosal
tissue involvement Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
27. Abnormal Eosinophil levels for diagnosis EGIDs
• Stomach 30/HPF
• Duodenum and ileum 28/HPF
• Large intestine 50/HPF
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
28. • Peripheral eosinophilia (not required for the
diagnosis)
• More than 70% of patients with EGE have
transient peripheral blood eosinophilia (>500)
• Not an index of disease activity and response to
therapy
• Allergy tests (SPT, sIgE, Total IgE) are not specific
markers for EGIDs
• SPT for food and aeroallergen
• Utility is low in adult and variable in children
Diagnosis
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
29. Food Allergy Testing
Children
• Retrospective study of all children with EoE seen at Children’s Hospital of Philadelphia between
2000 and 2011 (n=793)
• Milk, egg, wheat, and soy were found to be the most common food allergens
• Approximately 70% of children had at least 1 positive SPT result to foods.
• SFED or testing-directed diets (via APT or SPT) both yielded 53% success rates.
• In addition, removal of dietary triggers via allergy testing plus empiric elimination of milk
led to resolution in 77% of patients.
Adult: limited studies
• Recent comprehensive systematic review and meta-analysis that included 33 studies and 1317
patients with EoE
• Only 45.5% of allergy testing–directed diets were shown to have an effective outcome
Anyane-Yeboa A, et al. Gastroenterol Hepatol (N Y). 2018 Aug;14(8):463-469.
30. • Milk is the most common food that causes EoE.
• Milk elimination–only studies, the rate of success has been around 65%
Spergel J, et al. J Allergy Clin Immunol. 2018 Jul;142(1):1-8.
31. Aeroallergens as antigens in patients with EoE
• Intranasal instillation of aeroallergen antigens, including dust mite,
Aspergillus fumigatus, and cockroach, causes onset of experimental EoE
• Ram G, et al. Ann Allergy Asthma Immunol 2015 (N=1180 children with EoE)
• 20% of those suspected to have a pollen trigger showed biopsy-proved
esophageal eosinophilic exacerbations that occurred during a pollen
season for which they had specific pollen sensitization
• SLIT and OIT can drive esophageal eosinophilia. Spergel J, et al. J Allergy Clin Immunol. 2018 Jul;142(1):1-8.
32. • Serum sIgG4 levels to food and aeroallergen proteins were higher in patients with EoE than non-EoE controls
• Whether sIgG4 plays a pathogenic role in EoE or could be used as an EoE biomarker remains unknown and
warrants further study. McGowan EC, et al. Clin Exp Allergy. 2022 Aug 18.
33. EoE diagnostic criteria (ACG 2013)
• Symptoms related to esophageal dysfunction
• Eosinophil-predominant inflammation on
esophageal biopsy, (peak value of ≥ 15 eo/HPF)
• Mucosal eosinophilia is isolated to the
esophagus and persists after a PPI trial
• Secondary causes of esophageal eosinophilia
excluded
• A response to treatment (dietary elimination;
topical corticosteroids) supports, but is not
required for diagnosis.
Dellon ES, et al. Am J Gastroenterol. 2013 May;108(5):679-92; quiz 693.
34. 2018 Removal of the PPI trial requirement
Dellon ES, et al. Gastroenterology. 2018 Oct;155(4):1022-1033.e10.
36. Eosinophilic gastroenteritis
• Peripheral blood eosinophilia is present
in about 70% of cases, with higher levels in
patients with mucosa-predominant pattern
and at greater risk of relapse.
• Iron-deficiency anemia may be evident
and hypoalbuminemia present, especially
in patients with mucosal involvement.
• Total serum IgE ≥100 IU/mL is reportedly
present in about two-thirds of EGE cases.
• Elevated ESR in a few cases.
Sunkara T, et al. Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
• Fecal protein loss (α1-antitrypsin) in a 24-hour
feces collection: highly increased
• Stool examination should be performed to rule out
parasitic infections (ie, Strongyloides, Ascaris,
Ancylostoma, Anisakis, Capillaria, Toxicara,
Trichiura, andTrichinella spp.)
• Mild–moderate steatorrhea is present in about
30% of patients.
• Some presence of exudative fluid with net
eosinophilic predominance reaching about 90% of
white blood cells in the peritoneal fluid
37. Eosinophilic enteritis
• Wireless capsule
endoscopy is useful to
explore the entire small
intestine and to reveal
lesions not seen by
conventional
endoscopy
Pineton de Chambrun G, et al. Curr Gastroenterol Rep. 2018 Jul 2;20(8):37.
38. Eosinophilic esophagitis
• Normal
• Longitudinal furrows
• Esophageal rings (concentric rings or
trachealization in the esophagus), fold
thickening
• White exudate (white spots, papules or
plaques)
• Ulcerations
• Edema (decreased vascularity or pallor of the
esophageal mucosa), erythema
• Polyps, nodules, strictures
• Mucosal fragility
Diagnosis: Endoscopic finding
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Sunkara T, et al. Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Nguyen N, et al. Front Pediatr. 2021 Aug 24;9:713027.
Eosinophilic gastroenteritis/enteritis/colitis
• Normal
• Edema, erosion, reddening
• Ulcers
• Micronodules/ polyps/ pseudo-polyp (often
contain marked aggregates of lymphocytes
and eosinophils)
• Diffuse inflammation
• Complete loss of villi
• Submucosal edema
• Fibrosis
39. Diagnosis:
Additional diagnostic modalities
• Endoscopic functional luminal imaging probe (endoFLIP) has demonstrated
altered esophageal wall compliance in adults and children with EoE, further
supporting the concern for esophageal remodeling.
• 2 pediatric studies: Esophageal cross-sectional area and compliance can
align with eosinophilic inflammation, epithelial remodeling, and subepithelial
fibrosis.
• endoFLIP: adjunctive tool in both stricture identification and assessment when
planning for esophageal dilation in adults (Gonsalves, unpublished data)
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
41. Ashitani K, et al. Intern Med. 2019 Aug 1;58(15):2167-2171.
Fujiwara Y, et al. Endosc Int Open. 2020 Dec;8(12):E1817-E1825.
Nguyen N, et al. Front Pediatr. 2021 Aug 24;9:713027.
42. CT scan
• Eosinophilic gastroenteritis
• Non-specific radiological findings; wall thickening, polyps, ulcers, strictures,
ascites, omental thickening, and lymphadenopathy
• Eosinophilic colitis
• Wall thickening, isolated haustral thickening, and circumferential thickening
• The differential diagnosis of these radiological findings: IBD eg. Crohn’s disease
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
Diagnosis: Radiology
43. Diagnosis: Histology
• Stomach 30/HPF
• Duodenum and ileum 28/HPF
• Large intestine 50/HPF
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Collins MH, et al. Front Med (Lausanne). 2018 Jan 15;4:261.
Licari A, et al. Curr Pediatr Rev. 2020;16(2):106-114.
44. Eosinophilic
esophagitis
Eosinophilic
gastritis
Eosinophilic
enteritis
Eosinophilic
colitis
Eosinophil count/HPF (number of HPF) ≥15 • ≥30 (≥5)
• ≥70 (≥3 )
• 26 (x2) or 52 (x1)
in duodenal
mucosa
• 28 (x2) or 56 (x1)
in ileum
• 50 (x2) or 100
(x1) in cecum
and ascending
colon
• 42 (x2) or 84 (x1)
in transverse and
descending
colon
• 32 (x2) or 64(x1)
in rectosigmoid
mucosa
Basal zone hyperplasia, papillary lengthening
Crypt hyperplasia or abscess
Dilated intercellular spaces
Dyskeratotic epithelial cells
Degranulation of eosinophils (deposit of granules)
Eosinophil in expanded lamina propria, lamina
propria fibrosis
Eosinophil in muscularis mucosa and submucosa
Excess intraepithelial eosinophils
Villous atrophy
Collins MH, et al. Front Med (Lausanne). 2018 Jan 15;4:261.
45. Collins MH, et al. Front Med (Lausanne). 2018 Jan 15;4:261.
Esophagus Gastric mucosa
46. Collins MH, et al. Front Med (Lausanne). 2018 Jan 15;4:261.
Duodenum Colon
47. EoE monitoring
• There can be a disconnect between EoE symptoms and endoscopic or histologic
measures of disease activity.
• Close clinical follow-up of patients is required
• Histopathology remains necessary for monitoring EoE disease activity.
• However, studies have used varying thresholds of eos/hpf to determine
treatment response.
• < 15 eos/hpf: modestly predictive of gross endoscopic or symptomatic
improvement
• < 5 eos/hpf correlates with combined improvement in both of these parameters
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
48. Treatment: Eosinophilic esophagitis
• Chronic disease that requires chronic therapy
• Goals: Not only to improve clinical symptoms but also to prevent
disease progression and ensuing complications.
• Both medical and dietary therapy can accomplish these goals.
• Critical areas that need to be further defined in this field are
• Understanding the natural history and predictors of the different
phenotypes of the disease
• Identification of better food trigger identification tools
• Development of noninvasive assessments of the esophagus.
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
51. Treatment: Eosinophilic esophagitis
Dietary therapy
1. Elemental diet (or amino acid–based diet )
• Kelly KJ, et al. Gastroenterology 1995;109:1503-12.
• Administration of an elemental diet led to symptom and inflammatory
resolution in children in whom acid blockade had failed.
• Pediatric series from several institutions confirmed an overall greater
than 90% histologic remission in EoE using an amino acid formula.
• Adult: lower histologic response of approximately 75%
• An overall meta-analysis showed the superiority of the elemental diet
over specific food elimination diets.
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
52. 2. Allergy testing–directed elimination diet
• Combination of skin prick, sIgE and atopy patch tests to detect potential
EoE triggers
• Identification of food triggers in EoE is consistently low in adults
and variable in children.
• Skin prick testing to foods should be considered, especially in children.
• Empiric removal of a food in a specific food antigen IgE-sensitized child
can result in immediate hypersensitivity reactions on food reintroduction.
• The presence of food allergy/sensitization can align with more severe
histologic disease in the context of TGF-b1 genotype.
Treatment: Eosinophilic esophagitis
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
53. 2.1 Environmental allergy testing and control of concurrent atopic
diatheses
• Abundant data demonstrate the ability of aeroallergens to trigger and/or
exacerbate EoE.
• It is reasonable to test patients with EoE for aeroallergen
sensitization and to educate patients about simple avoidance
measures.
• Case reports document the success of aeroallergen immunotherapy for
EoE¹ → Aeroallergen immunotherapy could be a reasonable adjuvant
EoE therapy.
• It is reasonable to speculate that EoE control might be improved by
optimizing the management of concurrent asthma, allergic rhinitis, and
eczema.
Treatment: Eosinophilic esophagitis
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
1. Ramirez RM, et al. J Allergy Clin Immunol 2013;132:503-4.
54. 3. Empiric elimination diet: 1-, 2-, 4-, 6- food empirical diet
• 6-food elimination diet (SFED) (cow’s milk, egg, soy, wheat, peanuts/tree nuts,
and fish/shellfish)
• SFED effectiveness: histologic remission in 74% (children)
• 4-food elimination (milk, wheat, egg, and soy)
• Histologic remission in 54% (adult), 64% (children)
• 2-food elimination (milk, wheat)
• Histologic remission in 43% (adult and children)
• 65% to 85% of patients had a single food trigger.
• Step-up approach, clinicohistologic remission was achieved in 43%, 60%, and
79% of patients on the TFED, FFED, and SFED, respectively.
• Potential to decrease the number of endoscopies by 20% and time to identification of food
trigger(s) by 30% when compared with an SFED.
Treatment: Eosinophilic esophagitis
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
55. 3. Empiric elimination diet (continue)
• Allow fruits, vegetables, meat, poultry, rice, beans, and non-wheat grains
• Elimination duration 6-8 weeks
• Reintroduce: less allergenic foods first, age-appropriate form and
serving size, most of the days of the week
• Repeat endoscopy after introduction 1-2 foods (each food: 2 weeks)
• If a patient develops recurrence of symptoms with food reintroduction →
washout period of 6 weeks before reintroduction of the next food group
• Long term remission
• Adult: up to 3 years without the need for pharmacologic therapy
• Long-term compliance can be difficult, and lower long-term “real-
world” response rates
• To improve success: dietician + allergist
Treatment: Eosinophilic esophagitis
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
56. Anti-inflammatory medications
Topical corticosteroids (first-line treatment)
• Asthma metered-dose inhalers with a puff-and-swallow technique for
esophageal deposition.
• Fluticasone propionate, viscous budesonide.
• Symptom improvement and histologic normalization within several weeks.
• Long-term TCS therapy is indicated in patients with EoE because of frequent
recurrence with TCS removal.
• Side effects from TCSs can include oral and/or esophageal candidiasis (4-5%
among children, 5-15% in adult) and adrenal insufficiency (significant adrenal
crisis is rare), bone demineralization
• No reported adverse effects on pediatric patients height.
Treatment: Eosinophilic esophagitis
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
58. • Budesonide effervescent tablets (BET) were effective in inducing
histologic remission in 100% and 94% of patients receiving 1 mg BET twice
daily or 2 mg BET twice daily, respectively, and have recently been
approved for EoE treatment in Europe. Miehlke S, et al. Therap Adv Gastroenterol. 2020 Jun 10;13:1756284820927282.
59. • Duration of STC for induction
remission: 2-12 weeks
• Duration of STC for maintenance
of remission: 48-50 weeks
• May decrease the dose to the
lowest effective level to minimize
medication side effects.
Miehlke S, et al. Therap Adv Gastroenterol. 2020 Jun 10;13:1756284820927282.
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
60. Evidence of continue or decrease dosing
Topical corticosteroids (continue)
• In one study, high-dose FP (1760 mcg/ day: 4 puffs of the 220 mcg MDI
twice daily) for 12 weeks induced histologic remission in 65% to 77% of
patients with EoE.
• 50% dose reduction (4 puffs of the 220 mcg MDI once daily) was
effective at maintaining histologic remission in 73% to 93% of patients.
• Intermittent dosing is not supported by a small study of budesonide
slurry every Monday-Wednesday-Friday, which found that the majority of
patients relapsed.
• Loss of response or corticosteroid resistance in some patients during
an extended treatment course. Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
61. PPI
• Inexpensive, effective and safe for long-term use.
• A novel anti-inflammatory/anti-eosinophil mechanism of PPIs is
independent of acid suppression.
• The presence of acid reflux does not predict who with EoE will respond
to PPI treatment.
• No clinical features that clearly discern a patient who will respond to
PPI monotherapy.
• Genetic: Molecular transcriptomics
• Expression of transcript for the potassium channel Kir2.1 (KCNJ2
gene) is lower in patients with PPI-responsive EoE.
• Patients with allergic rhinitis and CYP2C19 rapid metabolizers are at
greater risk for loss of EoE control despite continued PPI therapy
Treatment: Eosinophilic esophagitis
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
62. PPI (continue)
• Remission
• Meta-analysis¹ induced histologic remission in up to 50% and
symptomatic improvement in up to 60% of adults and children.
• Sustained remission > 75% and a majority of those who relapse on
maintenance dosing can achieve remission at a higher treatment dose.
• Comparative efficacy of PPIs, corticosteroids, and diet is not known.
• Dose: High-dose PPI is now considered an EoE-directed therapy. (even if
GERD is not present, no FDA-approved dosage)
• Omeprazole 20-40 mg twice daily or its equivalent in adults, or 1
mg/kg/day (maximum 40 mg once daily)
• Twice daily dosing is more effective at inducing histologic response
than once daily dosing
Treatment: Eosinophilic esophagitis
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
1. Lucendo AJ, et al. Clin Gastroenterol Hepatol 2016; 14: 13–22.
64. Esophageal dilation
• EoE progresses to esophageal remodeling and stricture when left
untreated or when the patient is unresponsive to therapy
• Adult EoE → stricture 30-80%, increases proportionally with age and delay
in time to diagnosis
• Indication (no definite guideline): clinical impaction, dysphagia, strictures
• Endoscopic dilatation does not alter the underlying inflammatory
process in EoE and does not improve histologic changes → treatment
with concomitant pharmacologic therapy or elimination diet reduces the
risk of needing subsequent dilations.
• For those patients with a stricture at diagnosis, therapy can be difficult with
poor response to TCSs and requirement for repeated dilation.
Gonsalves NP, et al. J Allergy Clin Immunol. 2020 Jan;145(1):1-7.
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
Treatment: Eosinophilic esophagitis
65. Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
First step to consider
• Patient nonadherence
• Suboptimal medication dose
• Ineffective delivery or inappropriate
administration of the medication
• Continued exposure to allergen
• Concomitant infection
• Esophageal stricture
• Inappropriate diagnosis of EoE
Refractory EoE
Second line:
• Corticosteroids
• LTRA
• Mast cell
stabilizers
• Immunomodulators
• Biologic agents
66. Hirano I, et al. Ann Allergy Asthma Immunol. 2020 May;124(5):416-423.
67. • Immunomodulators (e.g., azathioprine, 6-mercaptopurine), LTRA,
mast cell stabilizers, biologics, and monoclonal antibodies
(Infliximab, omalizumab) - poor effect in achieving remission.
• CRTH2 antagonist, OC000459, and anti–IL-5 monoclonal antibodies
(e.g., mepolizumab and reslizumab) - partial efficacy in reducing
eosinophilic inflammation characteristic of EoE.
• Anti–IL-13 and anti–IL-4-Rα monoclonal antibodies (QAX576 and
RPC4046) have demonstrated compelling results in early clinical trials.
❖ Current consensus guidelines do not recommend the use of these
various drugs because there are limited data in support of them.
Treatment: Refractory EoE
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
68. • Dietary elimination
• Later EGE appears during childhood, the worse it responds to dietary
modification
• Anti-inflammatory medications (e.g., topical steroids, systemic steroids)
• Systemic corticosteroids are a mainstay of therapy, first-choice,
effective > 90% of case
• But side effects limit long-term use and disease typically recurs after
corticosteroid discontinuation.
• Others: Immunomodulators, LTRA and mast cell agents (cromolyn;
ketotifen), Biologic (Anti-IgE, Anti-IL5)
• There is no consensus as to ideal treatment, because no large-scale
studies have been performed, but response to corticosteroids is well
known. Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
Sunkara T, et al.Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Treatment: Eosinophilic gastroenteritis
69. Sunkara T, et al.Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Treatment: Eosinophilic gastroenteritis
Budesonide
• Slow-release enteric-coated capsules
(enteritis and proximal colitis)
• Reed C, et al. Dig Liver Dis.
2015;47(3):197–201.
• Budesonide (viscous slurry or
enteral release): induced
remission in 61% of patients
• The usual dose is 9 mg/day → can
be tapered to 6 mg/day for prolonged
use, as well as for maintenance
therapy.
Prednisolone
• Initial dose of 30–40 mg/day for 6–8
weeks → dose tapering
• Complete remission of symptoms
within 2-3 weeks of treatment,
reducing eosinophilic tissue infiltration,
blood hypereosinophilia, and
controlling ascites.
• Highest response rate: serosal type
• Relapses can occur → require low
maintenance doses (1–10 mg/day) of
prednisolone for a longer time or
substitution of prednisolone with
budesonide
70. Montelukast
• The usual dose is 5–10 mg/day
• Alone or combination with TCS
• Clinical and histological responses
2-4 weeks of treatment with
remission of at least 12 months.
• More randomized trials are required
to assess the long-term benefits and
side effects of LT antagonists in
EGE
Sunkara T, et al.Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Treatment: Eosinophilic gastroenteritis
Cromolyn
• Dose: 100-300 tid-qid
• Duration: 10 weeks-over a year
• Studies of efficacy are controversy
• Alternative/combination to steroids
71. Ketotifen
• Dose: 1–2 mg twice daily bid.
• Studies of efficacy are controversy
• Adjunct to steroids and montelukast
for treating refractory EGE in
pediatric patients.
Sunkara T, et al.Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Treatment: Refractory Eosinophilic gastroenteritis
6-MP (Mercaptopurine)
• 1 study: patient achieved clinical and
histological remission that was maintained
for >3 year
Azathioprine
• Dose: 50 mg/day
• Studies of efficacy are controversy
• Use in steroid-dependent and refractory EGE
• Complete clinical and histological remission
that was maintained for >3 years.
• Combination with prednisolone more
effective in 1 study
• Need further study
72. • Reslizumab
• Infliximab
• Limit by development of resistance and secondary loss of response →
can be managed by switching to adalimumab, which allows sustained
remission and endoscopic improvement
• Omalizumab
• Foroughi et al reported success in an open-label study of 9 patients
treated with omalizumab (maximum dose of 375 mg SC q 2 weeks x 8
doses)
• Outcome: well tolerated, drop in AEC, decrease symptoms, significant
decrease in allergen-specific basophil activation
Sunkara T, et al.Clin Exp Gastroenterol. 2019 Jun 5;12:239-253.
Treatment: Refractory Eosinophilic gastroenteritis
73. Abou Rached A, et al.World J Gastrointest Pharmacol Ther. 2016 Nov 6;7(4):513-523.
74. • Dietary elimination
• Effective only in children (no clear evidence in adults)
• Anti-inflammatory medications (e.g., topical steroids, systemic steroids)
• Based on case series and clinical experiences
• Systemic corticosteroids if dietary approach is impractical or failed to
achieve a valid response
• Others: Immunomodulators in severe cases (6MP, AZA, Infliximab), LTRA,
Mast cell stabilizer (limited data on the efficacy), FMT, Surgery
Treatment: Eosinophilic colitis
Giudici G, et al. Minerva Gastroenterol Dietol. 2020 Jun;66(2):157-163.
75. Anti-inflammatory medications: Corticosteroid
• No randomized controlled trials to date on the efficacy of steroids in EC.
• Oral prednisone
• 20- 40 mg per day or (0.5-1 mg/kg) x 2 weeks has been shown to induce
clinical remission in most patients
• Maintenance: 5-10 mg prednisone/day
Refractory or Steroid-spare agents
• Mesalazine, azathioprine/6-mercaptopurine or anti-TNF agents (i.e. infliximab,
adalimumab)
• Antibody directed against CCR3: decrease eosinophilic inflammation and
diarrhea in a mouse model of eosinophilic gastroenteritis
Treatment: Eosinophilic colitis
Giudici G, et al. Minerva Gastroenterol Dietol. 2020 Jun;66(2):157-163.
76. Emerging therapy for EGIDs
• Novel topical corticosteroid formulations
• Anti IL 5: mepolizumab and reslizumab in phase 2 RCTs in EoE with a
moderate impact on tissue eosinophilia.
• Anti IL-13: a phase 2 study with RPC4046 showing promising results.
• Anti IL-4: dupilumab is in a phase 2 trial of EoE with promising results.
• A small molecule antagonist of the chemoattractant receptor-homologous
molecule on Th2 cells shows some beneficial effect in a small study.
• Notably, omalizumab and infliximab have not shown efficacy in EoE.
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
77. Pitlick MM, et al. World Allergy Organ J. 2022 Jul 31;15(8):100676.
78. Pitlick MM, et al. World Allergy Organ J. 2022 Jul 31;15(8):100676.
79. Rossi CM, et al. Clin Transl Allergy. 2022 May 23;12(5):e12146.
80. Rossi CM, et al. Clin Transl Allergy. 2022 May 23;12(5):e12146.
Peterson K, et al. J Allergy Clin Immunol Pract. 2021 Sep;9(9):3276-3281.
81. • Today, the U.S. Food and Drug Administration approved Dupixent
(dupilumab) to treat eosinophilic esophagitis (EoE) in adults and
pediatric patients 12 years and older weighing at least 40 kilograms (which
is about 88 pounds).
• Today’s action marks the first FDA approval of a treatment for EoE.
Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-eosinophilic-esophagitis-chronic-immune-disorder, Assessed Jan 21, 2023
82. The efficacy and safety of Dupixent in EoE
• Randomized, double-blind, parallel-group, multicenter,
placebo-controlled trail
• N = 321, 24 weeks Part A and B
• 2 arms: Placebo or 300 milligrams of Dupixent every
week.
• Primary outcome:
• Proportion of patients who achieved a certain level
of reduced eosinophils in the esophagus at week
24, as determined by assessing patients’
esophageal tissue under a microscope
• Change in the patient-reported Dysphagia
Symptom Questionnaire (DSQ) score from
baseline to week 24.
The efficacy and safety of Dupixent in EoE
Result
• In Part A of the trial (Treatment Vs Placebo)
• Reduced eosinophil level: 60% Vs 5%
• DSQ: improvement 22 points Vs 10 points
• In Part B of the trial (Treatment Vs Placebo)
• Reduced eosinophil: 59% Vs 6%
• DSQ: improvement 24 points Vs 14 points
• The most common side effects: injection site
reactions, upper respiratory tract infections, joint
pain, and herpes viral infections.
Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-eosinophilic-esophagitis-chronic-immune-disorder, Assessed Dec 31, 2022
83. The natural history of EoE
• Progress from an inflammatory to fibrostenotic phenotype
• But subepithelial fibrosis is detected even in children, suggesting that
esophageal remodeling occurs early in the disease process.
• Esophageal remodeling → esophageal dysmotility
• The treatment of esophageal inflammation, either with topical
corticosteroids (tCS) or elimination diets, likely prevents long-term
fibrostenotic changes and improves impaired barrier integrity in patients
with EoE.
• Spontaneous resolution of esophageal eosinophilia is uncommon in
EoE, although the degree of eosinophilia may wane even in the absence
of active therapy
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
Dellon ES, et al. Gastroenterology. 2018 Jan;154(2):319-332.e3.
84. Prognosis: Eosinophilic esophagitis
• Symptom-focused outcome studies
• Relatively benign course of the disease
• Several years after a diagnosis: 30%–50% of children → dysphagia
• Modification in eating behaviors, avoidance of specific food textures
(meat, crusty bread), increased use of liquids with meals, prolonged
meal times, and meticulous mastication can reduce the occurrence of
dysphagia from esophageal strictures.
• Endoscopic-focused outcomes studies
• Progression of significant fibrostenoses in most patients with over a
decade of untreated EoE
Steinbach EC, et al. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1483-1495.
Dellon ES, et al. Gastroenterology. 2018 Jan;154(2):319-332.e3.
85. • Requires prolonged treatment
• Ongoing symptoms from childhood into adulthood
• Longer periods of untreated EoE are associated with long-term
sequelae including fibrostenotic complications.
• Esophageal eosinophilia (not necessarily EoE) has been associated with
Barrett esophagus, but there is no evidence to date that EoE is
premalignant.
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Prognosis: Eosinophilic esophagitis
86. • Wax and wane chronically
• Regular endoscopic evaluation and symptom
monitoring is needed.
• In patients with coexisting peripheral blood
eosinophilia, AEC often serve as markers for tissue
involvement.
Prognosis: Eosinophilic gastritis
and gastroenteritis
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
Pineton de Chambrun G, et al. Clin Gastroenterol Hepatol. 2011 Nov;9(11):950-956.e1.
42%
37%
21%
Predominant mucosal disease
• Continuous course
Predominant muscle layer disease
• Recurring course
Predominant subserosal disease
• Single flare and no continuous
chronic course
87. • Chronic waxing-and-waning
• Can often be a manifestation of other primary disease processes, routine
surveillance of other organ systems and regular upper and lower GI
endoscopy is recommended.
• In general, eosinophilic colitis tends to be more aggressive in adolescent
and adults, while in infants is rather more benign and usually resolves
within days after removing the food-allergen implicated.¹
Chen E. Rosenberg, et al, Middleton’s Allergy 9th ed
1. Giudici G, et al. Minerva Gastroenterol Dietol. 2020 Jun;66(2):157-163.
Prognosis: Eosinophilic colitis