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 subtypesEosinophilic 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


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 IgElevels

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 eosinophilicgastrointestinal 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 IgG1and IgE, Th2-type (IL-4 and IL-5) cytokine production•Eosinophil accumulation in the blood and small intestine

Genetic absenceof eotaxin mice

(se (sensitized mice)


•Eosinophil recruitment into small intestine was ablated •Enhanced eosinophilaccumulation in the blood compared with wild-type mice.

Genetic absenceof IL-5 mice

(sensitized mice)


• Partial eosinophilaccumulation 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 eosinophilicgastrointestinal 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 IgG1and 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 eosinophilaccumulation in the blood compared with wild-type mice.


• Partial eosinophilaccumulation small intestine

•Decline in circulating eosinophil levels

These results establish that the accumulation ofgastrointestinal eosinophils is antigen induced, can occur independent of IL-5.

Genetic absenceof eotaxin mice

(se (sensitized mice)

Genetic absenceof IL-5 mice

(sensitized mice)

EotaxinCC Chemokine Original name Chemokine

receptorMajor function

CCL 11 Eotaxin CCR3 Eosinophil,Basophil,TH2recruitment

CCL 24 Eotaxin-2 CCR3 Eosinophil,Basophil,TH2recruitment

CCL 26 Eotaxin-3 CCR3 Eosinophil,Basophil,TH2recruitment

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 chemokineeotaxin-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 eosinophilicgastroenteritis 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


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



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 propriaand 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 Peyerpatches or intraepithelial locations.

• Eosinophils are frequently infiltrate in Peyerpatches regions in EGID.

Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J ClinInvest 1999;103: 1719-27

Rothenberg ME, Mishra A, Collins MH, et al. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy ClinImmunol 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

Pathologyoutlines.com


Normal Colon histologyPathologyoutlines.com


Normal Colon histology

Embryology.med.unsw.ed



Dense eosinophilicinfiltrates 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 eosinophillevels>30 eo/HPF differrentiate eosinophilicgastritis from normal adult control



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 gradualintroduction 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 (inosinemonophosphate dehydrogenase inhibitor)

• Alternative Chinese medicines


Treatment

• Cromoglycate

• Montelukast

• Ketotifen


• Mycophenolate mofetil (inosinemonophosphate 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 suplatasthas been described in 2 single patient case reports.


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 budesonidetablets. 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.



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.



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.


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 eosinophilcount :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 weredecreased at both the midstudy (63%) and end of study (70%) time points (P < .005 for both)

Anti–IL-5


Reslizumab

• an open-label clinical trial of reslizumab (SCH55700) was undertaken in 4 subjectswith EGE.• Reslizumab suppressed blood eosinophilia in a significant manner. • tissue eosinophilia was only modestly suppressed •EGE symptoms were minimally affected.

Eosinophilic Colitis

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 subtypesEosinophilic disorders • Hypereosinophilic syndrome Noneosinophilic disorders • Celiac disease • Connective tissue disease

(scleroderma) • Iatrogenic • Infection • Inflammatory bowel disease • Vasculitis (Churg-Strauss

syndrome)


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


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 enteropathyor protein-induced enterocolitis syndrome.


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.



• Bimodal age distribution

:Infantile

:Early adolescent and Adulthood



• Diarrhea

• Abdominal pain

• Weight loss

• Anorexia


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.




• Patchy erythema

• Loss of vascularity,

• Lymphonodularhyperplasia

mostly localized to the rectum but might extend to the entire colon

Gastroenterol Res Pract. 2011




• Patchy erythema

• Loss of vascularity,

• Lymphonodularhyperplasia

mostly localized to the rectum but might extend to the entire colon


Normal Colon histology


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


• 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 IgEassociated 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





EGID are generally tissue-

specific problems

HES tends to involve the heart,

lungs, and skin


Eosinophilic esophagitis(EoE), a disease

mechanistically linked with eosinophilic airway

inflammation (asthma).


Eosinophilicgastroenteritis,

specific regions of the GI tract may be selectively involved






Thank You

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Health & Medicine

Eosinophilic gastrointestinal disorders (part II)