Eosinophilic gastrointestinal disorders (part II)

Eosinophilic Gastrointestinal
disorders (Part II)
Yoavanit Srivaro M.D.

Outline
• Eosinophilic Gastritis and Gastroenteritis
• Eosinophilic Colitis

Eosinophilic Gastritis and
Gastroenteritis

Eosinophilic Gastritis and Gastroenteritis
• Definition
• Classification
• Epidemiology
• Etiology
• Clinical Presentation
• Diagnostic evaluation
• Treatment

Definition
• characterized by selective
infiltration of eosinophils
in
• stomach, small intestine,
or both with variable
involvement of esophagus,
large intestine, or both.
Simon D, Wardlaw A, Rothenberg ME. Organ-specific eosinophilic disorders of the skin, lung, and
gastrointestinal tract. The Journal of allergy and clinical immunology. 2010;126(1):3-13.

Classification
Primary subtypes
• Atopic
• Nonatopic
• Familial primary subtypes
Secondary subtypes
Eosinophilic disorders
• Hypereosinophilic syndrome
Noneosinophilic disorders
• Celiac disease
• Connective tissue disease
(scleroderma)
• Iatrogenic
• Infection
• Inflammatory bowel disease
• Vasculitis (Churg-Strauss
syndrome)
Mucosal, Muscularis,Serosal

Epidemiology
• Wide age range
Infancy Seventh decades
• Most commonly
Third Fifth decades
Ingle SB, Hinge Ingle CR. Eosinophilic gastroenteritis: an unusual type of gastroenteritis. World journal of
gastroenterology : WJG. 2013;19(31):5061-6.
Prussin C. Eosinophilic gastroenteritis and related eosinophilic disorders. Gastroenterology clinics of North
America. 2014;43(2):317-27.

Epidemiology
• An electronic survey sent to North American
Allergists and Pediatric Gastroenterologists indicate
prevalence for EGE of 22 to 28 per 100,000 persons
America. 2014;43(2):317-27.
Spergel JM, Book WM, Mays E, Song L, Shah SS, Talley NJ, et al. Variation in prevalence, diagnostic criteria,
and initial management options for eosinophilic gastrointestinal diseases in the United States. Journal of
pediatric gastroenterology and nutrition. 2011;52(3):300-6.

Etiology
• Idiopathic
• Allergic mechanism
1. Increased total IgE and Food specific IgE
levels
2.Increased T helper 2 associated cytokines

Etiology
• Data from clinical studies suggest that patients with
eosinophilic gastroenteritis have increased secretion
of IL-4 and IL-5 by peripheral blood T cells.
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106

Etiology
• T cells derived from the lamina propria of the
duodenum of patients with EGID preferentially
secrete Th2 cytokines (especially IL-13) when
stimulated with milk proteins

Etiology
• Mast cells are also increased in EGID.
• Recent murine model of oral allergen–induced
diarrhea has indicated that mast cells have a critical
role in the pathogenesis of allergic diarrhea in EGID.
Brandt EB, Strait RT, Hershko D, et al. Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest
2003;112:1666-77.

Hogan SP, Mishra A, Brandt EB, Foster PS, Rothenberg ME. A critical role for eotaxin in experimental oral antigen-induced eosinophilic
gastrointestinal allergy. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(12):6681-6.
Allergen sensitized
mice
Challange with Oral allergen
•Marked allergen-specific IgG1
and IgE, Th2-type (IL-4 and IL-5)
cytokine production
•Eosinophil accumulation in the
blood and small intestine
Genetic absence
of eotaxin mice
(se (sensitized mice)
•Eosinophil recruitment into
small intestine was ablated
•Enhanced eosinophil
accumulation in the blood
compared with wild-type mice.
Genetic absence
of IL-5 mice
(sensitized mice)
• Partial eosinophil
accumulation small
intestine
•Decline in circulating
eosinophil levels

Hogan SP, Mishra A, Brandt EB, Foster PS, Rothenberg ME. A critical role for eotaxin in experimental oral antigen-induced eosinophilic
gastrointestinal allergy. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(12):6681-6.
Allergen sensitized
mice
•Marked allergen-specific IgG1
and IgE, Th2-type (IL-4 and IL-5)
cytokine production
•Eosinophil accumulation in the
blood and small intestine
•Eosinophil recruitment into
small intestine was ablated
•Enhanced eosinophil
accumulation in the blood
compared with wild-type mice.
• Partial eosinophil
accumulation small
intestine
•Decline in circulating
eosinophil levels
These results establish that the accumulation of
gastrointestinal eosinophils is antigen induced, can occur
independent of IL-5.
Genetic absence
of eotaxin mice
(se (sensitized mice)
Genetic absence
of IL-5 mice
(sensitized mice)

Eotaxin
CC Chemokine Original name Chemokine
receptor
Major function
CCL 11 Eotaxin CCR3 Eosinophil,
Basophil,TH2
recruitment
CCL 24 Eotaxin-2 CCR3 Eosinophil,
Basophil,TH2
recruitment
CCL 26 Eotaxin-3 CCR3 Eosinophil,
Basophil,TH2

Hogan SP, Mishra A, Brandt EB, Royalty MP, Pope SM, Zimmermann N, et al. A pathological function for eotaxin and eosinophils in
eosinophilic gastrointestinal inflammation. Nature immunology. 2001;2(4):353-60.
•(OVA)-alum–sensitized mice were challenged with 2 doses of oral OVA
in the form of enteric-coated beads
•Mice developed eosinophil-associated GI dysfunction, including
gastromegaly, delayed food transit, and weight loss, all strongly
dependent on the chemokine eotaxin-1

Hogan SP, Mishra A, Brandt EB, Royalty MP, Pope SM, Zimmermann N, et al. A pathological function for eotaxin and eosinophils in
eosinophilic gastrointestinal inflammation. Nature immunology. 2001;2(4):353-60.
•(OVA)-alum–sensitized mice
were challenged with 2 doses
of oral OVA in the form of
enteric-coated beads
•Mice developed eosinophil-
associated GI dysfunction,
including gastromegaly,
delayed food transit, and
weight loss, all strongly
dependent on the chemokine
eotaxin-1
Placebo

Clinical Presentation
• Approximately 80% have symptoms for several years
• Occasionally, the disease may manifest itself as an
acute abdomen or bowel obstruction

Children & Adolescent
• Growth retardation
• Failure to thrive
• Delayed puberty or
amenorrhea.
Adults
• Abdominal pain
• Diarrhea
• Dysphagia

• Present with a constellation of symptoms that are
related to the degree and area of the GI tract
affected
1. Mucosal layer
2. Muscularis layer
3. Serosal layer

Mucosal disease
• Vomiting
• Abdominal pain
• Diarrhea
• Blood loss in stools
• Iron deficiency anemia
• Malabsorption
• Protein-losing enteropathy
• Failure to thrive
Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. Allergic eosinophilic
gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-
up. Journal of pediatric gastroenterology and nutrition. 2006;42(5):516-21.

Muscle layer disease
Bowel wall thickening & Intestinal obstruction
Cramping & abdominal pain associated with nausea
and vomiting

Subserosal disease
• Eosinophilic exudate ascites
• Abundant peripheral eosinophilia
• Serosal and visceral peritoneal inflammation leads to
leakage of fluids

• EGE can occasionally involve the hepatobiliary
tree.
: Pancreatitis
: Cholangitis
America. 2014;43(2):317-27.

Diagnostic evaluation
• Laboratory
• Allergic evaluation
• Radiographic evaluation
• Endoscopic and Pathology

Laboratory
• Complete blood count
• Serum albumin
• Fecal protein
• Stool examination

Complete Blood Count
Peripheral blood eosinophilia Iron deficeicy anemia

Complete Blood Count
Peripheral blood eosinophilia
Layer Average count
eosinophil/microltr
Mucosal 2,000
Muscular 1,000
Serosa 8,000
• Found in 20%-80% of cases

Fecal protein
• Alpha1-antitrypsin in a 24-h feces collection
• Identify the inability to digest and absorb proteins in
GI tract.
• The normal value is 0-54 mg/dL.
• Patients with eosinophilic gastroenteritis have
elevated alpha1- antitrypsin in their feces.

Stool examination
•Should be performed to rule out parasitic infestation.
•Mild-to-moderate steatorrhea is present approximately
30% of patients.

Allergic evaluation
• Skin prick test
• Specific IgE antibody to inhaled & oral allergen
• Atopic patch testing
• Diagnostic trials of therapy with
1. Elimination
2. Oligoantigenic diets
3. Elemental (amino-acid based) diets
Khan S. Eosinophilic gastroenteritis. Best practice & research Clinical gastroenterology.
2005;19(2):177-98.

Radiographic evaluation
Chen MJ, Chu CH, Lin SC, Shih SC, Wang TE. Eosinophilic gastroenteritis: Clinical experience with 15 patients.
World JGastroenterol 2003; 9(12): 2813-2816

Endoscopic and Pathology

America. 2014;43(2):317-27.

Histology of The Stomach
higheredbcs.wiley.com

Histology of The Stomach
Pathologyoutlines.com
Submucosa
Mucosa
Lamina propia

Histology of The Intestine
The organized tissues of the Peyer's patches and mesenteric lymph nodes (MLNs) are involved in the
induction of immunity and tolerance, whereas the effector sites are scattered throughout the lamina propria
and epithelium of the mucosa. Both the Peyer's patches and villus lamina propria are drained by afferent
lymphatics that go to the MLNs. SED, subepithelial dome; TDA, thymus-dependent area.

Gastrointestinal Eosinophils Under Homeostatic
Healthy States
• Eosinophils are present at low levels in
numerous tissues
• In biopsy and autopsy specimens, organs that
normally demonstrate tissue eosinophils at
substantial levels are
- GI tract - Lymph nodes
- Spleen - Thymus
DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME. Quantity and distribution of eosinophils in
the gastrointestinal tract of children. Pediatric and developmental pathology : the official journal of the
Society for Pediatric Pathology and the Paediatric Pathology Society. 2006;9(3):210-8.

Gastrointestinal Eosinophils Under Homeostatic
Healthy States
• Eosinophils throughout the GI tract of
conventional healthy mice : normally present
in the lamina propria of the stomach, small
intestine, cecum, and colon.
• Eosinophils are not normally present in Peyer
patches or intraepithelial locations.
• Eosinophils are frequently infiltrate in Peyer
patches regions in EGID.
Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin
Invest 1999;103: 1719-27
Rothenberg ME, Mishra A, Collins MH, et al. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin
Immunol 2001;108:891-4.

DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME. Quantity and distribution of eosinophils in
the gastrointestinal tract of children. Pediatric and developmental pathology : the official journal of the
Society for Pediatric Pathology and the Paediatric Pathology Society. 2006;9(3):210-8.

Normal Duodenum histology

Normal Colon histology

Embryology.med.unsw.ed

Dense eosinophilic
infiltrates in the lamina
propria and mucosae

No standards exist for diagnosis
The following findings support the diagnosis
1.Presence of elevated eosinophils in
biopsy specimens from the GI tract
wall
2. Infiltration of eosinophils within
intestinal crypts and gastric glands
3. Lack of involvement of other organs
4. Exclusion of other causes of
eosinophilia

g
•Gross Endoscoopic finding
are often normal
•Endoscopic bx should be
obtained from 5-6 site of
afffected organ
•In stomach eosinophil
levels>30 eo/HPF
differrentiate eosinophilic
gastritis from normal adult
control
America. 2014;43(2):317-27.

No standards exist for diagnosis
Four criteria are required for the diagnosis
1. Presence of gastrointestinal
symptoms
2. Eosinophilic infiltration of
gastrointestinal tract
3. Exclusion of parasitic disease
4. Absence of other systemic
involvement

Treatment
• Eliminating the dietary intake of foods
implicated by skin-prick tests
• Drugs

Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. Allergic eosinophilic gastroenteritis with
protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up. Journal of pediatric
gastroenterology and nutrition. 2006;42(5):516-21.
6 6 Pts with AEG
with PLE
6 Pts with
AEG
5 Pts with
Abd S/S
with Bx -ve
Medical records of patients were reviewed for
clinical history, physical ,laboratory values.

6 Pts with AEG
with PLE
•Pts had excellent response to therapy with amino
acid based formula and tolerated gradual
introduction of some foods with time.

Eliminating the dietary intake of
foods
Dietary modification
Disease remission
Specific food groups are slowly reintroduced, at
about 3-week intervals for each food group
Endoscopy is performed every 3 months to
identify either sustained remission or disease
flare-up

Treatment
• Cromoglycate
• Montelukast
• Ketotifen
• Suplatast tosilate
• Mycophenolate mofetil (inosine
monophosphate dehydrogenase inhibitor)
• Alternative Chinese medicines

Treatment
• Cromoglycate
• Montelukast
• Ketotifen
• Mycophenolate mofetil (inosine
monophosphate dehydrogenase inhibitor)
• Alternative Chinese medicines
Generally unsuccessful

Treatment
:Anti-Th2 drug
:Inhibits the expression of Th2 cytokines, such
as IL-5.
:Successful treatment of EGE with suplatast
has been described in 2 single patient case
reports.
America. 2014;43(2):317-27.

Treatment
• Anti-inflammatory drugs
:Systemic steroids
:Topical steroids
• Anti–IL-5
• Anti-IgE
• Azathioprine or 6-mercaptopurine

Antiinflammatory drugs
• If diet restriction is not feasible or has failed to
improve the disease.
• As with treatment for asthma, topical steroids have a
better benefit-to-risk effect than systemic steroids.

Anti-inflammatory drugs
• Systemic steroid therapy
: A course of 2 to 6 weeks with relatively low doses
seems to work better than a 7-day course of burst
glucocorticoids.

Anti-inflammatory drugs
• Topical glucocorticoids
:Budesonide tablets (Entocort EC) are designed to
deliver the drug to the ileum and proximal colon.
:As with treatment for asthma, topical steroids have
a better benefit-to-risk effect than systemic steroids.

Patient profile: A 32-year-old Caucasian woman
Present illness: Admitted to hospital with complaints of recurrent
cramping pain in the upper abdomen associated
with nausea and non-bloody diarrhoea. She had
lost 4 kg in weight.
Past history : No history of food intolerance, allergy, travel
to tropical areas, or prior medication
Tan AC, Kruimel JW, Naber TH. Eosinophilic gastroenteritis treated with non-enteric-coated budesonide
tablets. European journal of gastroenterology & hepatology. 2001;13(4):425-7.

Physical examination:
Slightly enlarged belly with normal bowel sounds.
Laboratory data:
Hb 8.1 mmol/l
WBC 29x109/l Eosinophil 69%.
Total serum protein 67.3 g/l.
Immunoglobulins:normal.
Echography : ascitic fuid.
Upper gastrointestinal endoscopy (biopsies):normal

Problem list: Eosinophilia and Ascitic fuid
Strong suspicious :Eosinophilic gastroenteritis of the serosal
type
Treatment: Prednisolone 40 mg/day was initiated

Clinical course:
- A rapid dissolution of complaints and a decrease in the
eosinophilic count.
- After tapering and eventually stopping the prednisone
medication, the patient remained without complaints for
over 1 year.
- Then she experienced more complaints of diarrhoea
and ascites. Total eosinophilic count was markedly
increased

Clinical course:
- To ascertain the diagnosis of eosinophilic gastroenteritis
- A full-thickness surgical antrum biopsy was taken.
- Histology revealed eosinophilic granulocytic infiltration in
the muscular mucosa .
- In the ascitic fuid, an inflammatory response with
eosinophilic granulocytes

Clinical course:
-Prednisone was started at a dose of 25 mg, with rapid
dissolution of complaints and peripheral eosinophilia.
-When the prednisone dose was tapered to 5 mg/day, the
patient complained of crampy abdominal pain and
diarrhoea.

Clinical course:
-We gave budesonide tablets, normally used for the
preparation of the budesonide clysma.
-Starting dose was 4 mg daily, with a good clinical effect.
- With this treatment regimen, the patient has been in
remission for more than 2 years.

Prussin C. Eosinophilic gastroenteritis and related eosinophilic disorders. Gastroenterology clinics of North America.
2014;43(2):317-27.
Initiated using prednisone at 0.4 to
0.8 mg/kg each morning
+
Solubilized budesonide is begun at 9
mg orally daily, taken at bedtime on
an empty stomach
Prednisone is tapered
over the next 2 or more
weeks
clinical symptoms
are controlled
•One to 2 months after the
prednisone has been stopped
•Budesonide dose is slowly tapered
over an additional 2 to 4 months to
the minimum required dose.
clinical symptoms
are controlled

2014;43(2):317-27.
Initiated using prednisone at 0.4 to
0.8 mg/kg each morning
+
Solubilized budesonide is begun at
9mg orally daily, taken at bedtime
on an empty stomach
Prednisone is tapered
over the next 2 or more
weeksclinical symptoms
are controlled
•One to 2 months after the
prednisone has been stopped
•Budesonide dose is slowly tapered
over an additional 2 to 4 months to
the minimum required dose.
clinical symptoms
are controlled

Foroughi S, Foster B, Kim N, Bernardino LB, Scott LM, Hamilton RG, et al. Anti-IgE treatment of eosinophil-associated
gastrointestinal disorders. The Journal of allergy and clinical immunology. 2007;120(3):594-601.
Nine EGE pts
3 wks pre
Omalizumab
baseline screen
16 wks
Omalizumab q 2 wks
Repeat all
baseline study

Omalizumab was
associated with decrease
in absolute eosinophil
count
:at week 16 (34%, P = 0.004)
: combined weeks 12 to 16
(42%, P = 0.012)

Tissue eosinophils decreased in the duodenum (59%)
and gastric antrum (69%) but did not reach statistical
significance (P 0.074 and 0.098, respectively).

Symptom scores were
decreased at both the
midstudy (63%) and end
of study (70%) time points
(P < .005 for both)

Anti–IL-5
2014;43(2):317-27.
Reslizumab
• an open-label clinical trial of
reslizumab (SCH55700) was
undertaken in 4 subjects
with EGE.
• Reslizumab suppressed blood
eosinophilia in a significant
manner.
• tissue eosinophilia was only
modestly suppressed
•EGE symptoms were minimally
affected.

Eosinophilic Colitis
• Introduction
• Classification
• Epidemiology
• Etiology
• Clinical Presentation
• Diagnostic evaluation
• Treatment

Introduction
• Eosinophils accumulate in the colon of patients with
a variety of disorders
: Eosinophilic gastroenteritis
: Allergic colitis of infancy
: Infections (e.g., pinworms, dog hookworms)
: Drug reactions
: Vasculitis (e.g., Churg-Strauss syndrome)
: IBD
Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). The Journal of allergy and clinical
immunology. 2004;113(1):11-28.

Classification
Primary subtypes
• Atopic
• Nonatopic
Secondary subtypes
Eosinophilic disorders
• Hypereosinophilic syndrome
Noneosinophilic disorders
• Celiac disease
• Connective tissue disease
(scleroderma)
• Iatrogenic
• Infection
• Inflammatory bowel disease
• Vasculitis (Churg-Strauss
syndrome)
immunology. 2004;113(1):11-28.

Allergic colitis in infancy
• Cow’s milk and soy proteins are the foods most
frequently implicated in allergic colitis of infancy
• This condition may occur more often in infants
exclusively breastfed and can even occur in infants
fed with protein hydrolysate formulas
immunology. 2004;113(1):11-28.

Allergic colitis in infancy
• Dietary protein– induced proctocolitis of infancy
syndrome
• Most common cause of bloody stools in the first year
of life
• An early expression of protein-induced enteropathy
or protein-induced enterocolitis syndrome.
immunology. 2004;113(1):11-28.

Etiology
• A non- IgE–associated disease
• Some studies point to a T lymphocyte– mediated
process.
• Exact immunologic mechanisms responsible for this
condition have not been identified.
immunology. 2004;113(1):11-28.

• Bimodal age distribution
:Infantile
:Early adolescent and Adulthood
immunology. 2004;113(1):11-28.

• Diarrhea
• Abdominal pain
• Weight loss
• Anorexia
immunology. 2004;113(1):11-28.

Differential diagnosis of EC
Okpara N, Aswad B, Baffy G. Eosinophilic colitis. World journal of gastroenterology : WJG. 2009;15(24):2975-9.

Diagnostic evaluation
• No single test is the “gold standard” for diagnosis
• Peripheral blood eosinophilia or eosinophils in the
stool suggests eosinophilic colitis.
immunology. 2004;113(1):11-28.

immunology. 2004;113(1):11-28.
• Patchy erythema
• Loss of vascularity,
• Lymphonodular
hyperplasia
mostly localized to the
rectum but might
extend to the entire
colon
Gastroenterol Res Pract. 2011

Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). The Journal of allergy and clinical immunology.
2004;113(1):11-28.
• Patchy erythema
• Loss of vascularity,
• Lymphonodular
hyperplasia
mostly localized to the
rectum but might
extend to the entire
colon

Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). The Journal of allergy and clinical immunology.
2004;113(1):11-28.
• Overall architecture of
the mucosa is well
preserved
• Focal aggregates of
eosinophils in the lamina
propria, crypt epithelium,
and muscularis mucosa,
• Multinucleated giant cells
are occasionally present
in the submucosa.

Gastroenterol Res Pract. 2011
immunology. 2004;113(1):11-28.
• Overall architecture of
the mucosa is well
preserved
• Focal aggregates of
eosinophils in the lamina
propria, crypt epithelium,
and muscularis mucos.,
• Multinucleated giant cells
are occasionally present
in the submucosa.

Treatment
• Eosinophilic colitis of infancy
:Benign disease
:Withdrawal of the offending protein trigger from the
diet
-->the gross blood in the stools usually resolves
within 72 hours
--> occult blood loss may persist longer

Treatment
• Eosinophilic colitis of older
:Usually requires medical management because IgE
associated triggers are rarely identified.

Treatment
• Eosinophilic colitis of older
: Cromoglycate ,Montelukast,Histamine receptor
antagonists : generally unsuccessful
:Aminosalicylates and systemic or topical
glucocorticoids :typically used and appear to be
efficacious
:Azathioprine or 6-mercaptopurine: in severe cases

immunology. 2004;113(1):11-28.

immunology. 2004;113(1):11-28.
EGID are
generally tissue-
specific problems
HES tends to
involve the heart,
lungs, and skin

immunology. 2004;113(1):11-28.
Eosinophilic esophagitis
(EoE), a disease
mechanistically linked with
eosinophilic airway
inflammation (asthma).

immunology. 2004;113(1):11-28.
Eosinophilic
gastroenteritis,
specific regions of
the GI tract may be
selectively involved

Eosinophilic gastrointestinal disorders (part II)

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Eosinophilic gastrointestinal disorders (part II)

Editor's Notes