Eosinophilic gastrointestinal disorder (EGID)

Author: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology
Reviewer: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

A 3-year old Caucasian boy with h/o severe anemia (hemoglobin 6 mg/dL) and hemoccult positive stools was admitted to the hospital. He was previously admitted 6 months ago with hemoglobin (Hb) 1.9 mg/dL, transfused, and a GI endoscopy showed a colonic polyp. The patient was started on iron therapy and the Hb improved but was never normal. According to the mother, he had no symptoms of bleeding. The patient’s stool has been black since he was started on iron.

Medications

Iron syrup.

Family and social history

Non contributory.

Birth History: he was born at 40 week gestation without any problems. Immunizations are up-to-date. Diet: Table food. Eats everything. The patient is developmentally appropriate for age.

Physical examination

Vital signs: Temp. 98.1, HR 112 bpm, RR 6, BP 92/58 mm Hg.
Wt 13.8 Kg.
HEENT: External ears normal. Canals clear. TM's normal. Nares normal. Septum midline. Oropharynx clear. Neck: supple, no adenopathy.
CVS: RRR, normal S1/S2, no m/r/g.
Chest: CTA (B).
Abdomen: Soft, Non tender BS +ive.
Extremities: no c/c/e.
Skin: color, texture, turgor normal. No rashes or lesions.

What laboratory tests would you suggest at this point?

CBCD
CMP
ESR
Stool O & P
Stool occult blood
TSH
UA
Blood cultures

Laboratory results

CBCD
WBC – 10.8
Hb – 7.3
Hct – 26.1
MCV- 68
Platelets- 194
Neutrophils - 30%
Lymphocytes - 49%
Monocytes – 4.3%
Eosinophils – 15.9% (1730)
Basophils - 1.6% (170)

CMP
Na - 138
K - 4.2
HCO3 24
BUN 26
Cr 1.1
Bilirubin Normal
AST 22
ALT 18
Ca Normal
Glucose 114
Total Protein 4.5 (low)
Albumin 2.1 (Low)

UA
Specific gravity – 1.020
pH - 5
Protein - None
Glucose - None
Ketone - None
Bilirubin - None
Blood - None
Nitrite - Negative
Leukocyte - Negative
Urobilinogen - None

TSH – 3.6
Stool occult blood - positive
Blood cultures negative
Ova & Parasites - negative
Stool Ova & Parasite
ESR – Within normal limits

The treatment team performed additional tests listed below:

Sweat Chloride test - negative
HIV: ELISA - negative, Western Blot - negative, PCR - no RNA copies identified.
Flow cytometry – Within normal limits

Radiology tests:

CXR - Within normal limits
CT Chest - Within normal limits.
CT abdomen - Within normal limits except for 1.7 cm intraluminal defect seen in the proximal jejunum without bowl dilatation.

Diagnostic procedures performed:

Sputum cytology - Within normal limits.
Pulmonary function testing - Within normal limits.
Upper Endoscopy – Showed signs of inflammation in esophagus, stomach and proximal deudenum. Biopsies were taken which showed an abundance of eosinophils (more than 50 per hpf) in the submucosa.
Colonoscopy - Showed patchy inflammation in the colon. Biopsies showed an infiltration of eosinophils in the submucosa.

Serological testing:

ANA – Negative
RA - Negative

RAST to food allergens:

Chicken - Class 0/1
Egg Class - 2
Fish Class - 0
Milk Class - 2
Soybean Class - 0
Wheat Class - 2

Thyroid antibodies
Anti thyroglobulin Ab – Negative
Anti peroxidase Ab – Negative
Anti microsomal Ab - Negative

Immunoglobulins

Total IgG - Within normal limits
IgG Subclasses (IgG1-4) – Within normal limits
Total IgA - Within normal limits
Total IgM – Within normal limits
Total IgE - 73

Food allergen skin testing - negative to Almond, Apple, Banana, Beef, Celery, Coconut, Corn, Cottonseed, Egg, Fish, Lobster, Milk, Pecan, Pea nut, Soybean, Shrimp, Walnut, Wheat.

DTH
Tetanus – Normal Response
PPD - Normal Response
Trichophyton - Normal Response
Candida - Normal Response

Delayed-type hypersensitivity (DTH) response

The standardized DTH test includes Candida, tetanus, mumps, and TB. Trichophyton is also commonly used. However, the only FDA-approved reagents for DTH are PPD, Candida and mumps.

Final Diagnosis

Eosinophilic gastrointestinal disorder (EGID).

What happened next?

The patient was advised to avoid wheat, eggs and cow's milk. He was started on Prevacid 30 mg po daily, prednisone syrup 1mg/ml, 5ml po daily for 4 weeks and advised to continue the iron syrup.

At follow-up, the patient's CBC showed Hb 12.3 mg/dL, Hct 38.9, eosinophils 2% (186). Steroids were tapered off and oral fluticasone was started. A follow-up EGD was scheduled in 6 months.

Summary

Primary eosinophilic gastrointestinal disorders are defined as disorders that selectively affect the gastrointestinal tract with eosinophil-rich inflammation in the absence of known causes for eosinophilia (eg, drug reactions, parasitic infections, and malignancy).

These disorders include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic enteritis, and eosinophilic colitis and are occurring with increasing frequency.

References

Eosinophilic gastrointestinal disorders (EGID). Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID).

Eosinophilic Gastroenteritis. eMedicine Specialties > Gastroenterology > Intestine. eMedicine, 2009.

Published: 12/07/2009

Updated: 09/07/2010

Eosinophilic Esophagitis

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Information for Patients 

Eosinophilic Esophagitis (EoE)
Allergy Testing
Food Allergy (AAAAI)
Food allergy handouts by the Food Allergy & Anaphylaxis Network (FAAN)
Food Allergy: An Overview for Patients (PDF)



Eosinophilic Esophagitis (click here to enlarge the image).

A guide to successfully managing Eosinophilic Esophagitis in Q&A format from APFED http://goo.gl/0l9PX:





8 foods cause 90% of food allergies (TEMPS WFS) (click to enlarge the image). The likelihood of a negative oral food challenge is shown in relation to the respective values of skin prick test (SPT) and serum IgE (sIgE).



Allergic (atopic) march (click here to enlarge the image).

Information for Doctors

Right Lower Quadrant Pain due to Eosinophilc Eosophagitis
Eosinophilic gastrointestinal disorder (EGID)
A Teen Who Can't Swallow: A Case of Eosinophilic Esophagitis. Medscape, 2011.
Eosinophilic Esophagitis. Ronald S. Siegel, M.D. UCLA, Department of Medicine, 2007.
Eosinophilic Gastroenteritis. Daniel Cole, M.D., M.P.H. UCLA, Department of Medicine, 2007.
Laryngopharyngeal Reflux Disease: A Case Presentation. Baylor College of Medicine.



Related reading

Eosinophilic Esophagitis: Brief Review
Mind Maps: Eosinophilic Esophagitis
Eosinophilic esophagitis. Allergy, Asthma & Clinical Immunology 2011, 7(Suppl 1):S8.
Proposed algorithm for the diagnosis and management of EoE. Allergy, Asthma & Clinical Immunology 2011 7(Suppl 1):S8.
Mnemonics: Eosinophilic Esophagitis
Eosinophilic Esophagitis videocast from The DAVE Project - Gastroenterology, 2005.
NEJM Images: Adult-Onset Eosinophilic Esophagitis. Clinical Cases and Images - Blog.
Answers from EoE Experts - YouTube Q&A from Apfed
Blog articles from AllergyNotes

Image source: Eosinophilic esophagitis, Wikipedia, GNU Free Documentation License.

Published: 09/15/2007
Updated: 09/17/2013

Right Lower Quadrant Pain due to Eosinophilc Eosophagitis

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

An 8-year-old boy is seen by his pediatrician for follow-up of abdominal pain. He had already visited the ER last week for RLQ abdominal pain and acute appendicitis had been ruled out. He complained of abdominal pain radiating to RLQ, nausea, vomiting, lack of appetite and weight loss for 6 months.

Past medical history (PMH)

Allergic rhinitis and conjunctivitis for 3 years, skin prick testing positive for house dust mite (2 years ago)

Fast medical history (FMH)

Mother with allergic rhinitis.

Medications

Prevacid (lansoprazole) daily.

Pets

Outdoor hunting dogs.

Physical examination

Diffuse abdominal tenderness, no rebound, normal BS, otherwise normal.

What would you do?

The patient was referred to a gastroenterologist who performed an EGD which showed 19 eosinophils per HPF.


"Multi-ring esophagus" in eosinophilic esophagitis (left), infiltration of eosinophils (right). Source: Wikipedia.

What is the most likely diagnosis?

Eosinophilic esophagitis.

How would you treat this patient?

Fluticasone (Flovent) PO was started with rapid resolution of symptoms within 2-3 weeks. The patient's appetite improved greatly and he gained 10 pounds during a 6-month period.

Pulmicort (budesonide) Respules, 0.5/2 mL PO bid may work better than fluticasone spray since the patients actually drinks the viscous liquid rather than using a spray.

What is the correct way to use fluticasone PO in eosinophilic esophagitis?

Fluticasone is used twice daily -- after breakfast and after dinner. After the puff, the patient should attempt to swallow. The same is repeated with the second puff. The mouth is rinsed with water and the water is swallowed. No food should be eaten for 2 hours.

The sequence is:
Spray, swallow.
Spray, swallow.
Rinse the mouth, swallow.

Does he need a biopsy in the future?

Yes, a repeat biopsy should be done to verify the effect of the treatment.

What else would you do for this patient?

He was prescribed Prevacid (lansoprazole) SoluTab 30 mg po qpm. PPI augments the therapeutic effect of inhaled fluticasone and a combination therapy (ICS plus PPI) should be used in all patients.

Veramyst (fluticasone) nasal spry daily and Pataday (olopatadine) eye drops daily were prescribed.

What are the typical symptoms of eosinophilic esophagitis in different age groups?

Infants present with vomiting.
Children present with abdominal pain and vomiting.
Older children present with the feeling that the "food is stuck."

What is the prognosis for resolution of eosinophilic esophagitis?

Uncertain.

85% of children with atopic dermatitis eventually become asymptomatic.
85% of children with asthma eventually become asymptomatic.
50% of children with allergic rhinitis eventually become asymptomatic.

There is a paucity of data to predict outcomes in eosinophilic esophagitis.

Final diagnosis

Eosinophilic esophagitis.

How to make budesonide viscous solution?

Pulmicort (budesonide) Respules, 0.5/2 mL PO bid may work better than fluticasone spray since the patients actually drinks the liquid rather than using a spray.

Mix Pulmicort Respules® (or generic budesonide) with sucralose. Each milligram of budesonide is mixed with 10 sucralose packets (Splenda®). In one pediatric study, if children's height was under 5 feet, they received 1 mg; if they were over five feet, they received 2 mg.

Summary

Eosinophilic Esophagitis, mind map diagram (click to enlarge the image).

Two inhaled corticosteroids have been used to treat eosinophilic esophagitis - fluticasone and budesonide.

The usual starting dose of budesonide in an adult is a 1 mg ampule mixed with a slurry of artificial sweetener (usually sucralose) using 10 packets, dependent upon taste, and swallowed b.i.d. In a child, 0.5 mg can be used in the same way, mixed with 5 packets.

Fluticasone is typically started at a dose of 440 mcg b.i.d. This can be lowered to 220 mcg b.i.d. subsequently.

References

Eosinophilic Esophagitis. NEJM, 2007.
Eosinophilic Esophagitis: Brief Review. V. Dimov, 2008.
Esophagus - Eosinophilic Esophagitis. The DAVE Project - Gastroenterology.
Eosinophilic microabscess in eosinophilic esophagitis. JACI, Volume 119, Issue 6, Page A6 (June 2007)
Eosinophilic disorders. Current reviews of allergy and clinical immunology/Series. JACI, Volume 119, Issue 6, Pages 1291-1300 (June 2007).

Dohil R, Newbury R, Fox L, Basian J, Aceves S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139:418-429.
Eosinophilic esophagitis, from Wikipedia, the free encyclopedia. Images under the terms of the GNU Free Documentation License.

Related reading

Proton-Pump Inhibitors (PPIs) Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use http://goo.gl/zANv

Comments from Twitter

@DrSilge: Dr. Aceves says that they use 0.5 mg budesonide respules in 5 packets, not the 1 mg. If need higher dose, use 10 packets. She states that want the volume for surface area, moreso than the higher concentration of medication.

Published: 07/16/2008
Updated: 10/19/2011

Eosinophilic Esophagitis: Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist, Fort Lauderdale, Florida

Eosinophilic esophagitis (EoE) is an eosinophilic inflammation of the esophagus which was first reported in 1978.

IL-5 is the predominant mediators in the EoE inflammation. Both IL-5 and IL-13 cause release of eotaxin which attracts eosinophils.

The receptors for IL-3, IL-5, and GM-CSF share a common β chain. All 3 cytokines stimulate the development of eosinophils.



Eosinophilic Esophagitis (click here to enlarge the image).

Clinical Manifestations

EoE is a common cause of dysphagia in children. Adult patients are usually men (3:1 M:F) in their 30s or 40s.

Presenting symptoms:
- dysphagia 93%
- food impaction 62%
- heartburn 24%

50-80% of the patients have a history of allergies. A family history of atopic disease is present in 74%.

Peripheral blood eosinophilia

31% have peripheral blood eosinophilia. Blood eosinophilia is not diagnostic and the correlation with disease activity is not established.

Total Immunoglobulin E (IgE)

Serum IgE levels are increased in 55% of patients but total IgE cannot serve as a marker for disease progression or resolution.

Natural History

EoE is a chronic disease with persistent or relapsing symptoms. Esophageal metaplasia (Barrett's esophagus or cardia-type metaplasia) has not been described in EE (different from GERD).

Diagnosis

How to diagnose EoE?

EoE is diagnosed by a biopsy of the esophagus which shows more than 15 eosinophils per HPF. Biopsy specimens should be obtained regardless of the gross appearance of the mucosa.

A peak count of at least 15 intraepithelial eosinophils per HPF is an absolute minimum number to make the diagnosis of EoE. At least 1 HPF must contain at least 15 intraepithelial eosinophils.

Patients with GERD-related esophagitis have fewer than 10 eosinophils per HPF. Any eosinophil number larger than 0 in esophagus is abnormal.

Eosinophils ascend in number as one descends in the GI tract:

0 eosinophils in esophagus
2 eosinophils in stomach
5 eosinophils in small bowel
15-50 eosinophils in large bowel

This eosonophils distribution may have evolved in the evolution to protect the body against parasitic infections ("sitting there waiting for parasites").

Endoscopic findings (abnormal in 91% of patients):

- mucosal fragility 59%
- rings or corrugated lining 49%
- strictures 40%

A corrugated esophagus characterized by fine concentric mucosal rings is a hallmark of EE. One hypothesis explains this by acetylcholine release which contracts muscle fibers in the muscularis mucosae resulting in the formation of concentric esophageal rings.

The rings or corrugated lining make the esophagus look like trachea during EGD. Some authors have called eosinophilic esophagitis "asthma of the esophagus." The changes in esophageal mucosa are reminiscent of airway remodelling in asthma.

Allergic Evaluation

Patients with EoE have a higher incidence (50-80%) of allergic rhinitis, asthma, and atopic dermatitis. Some authors have called eosinophilic esophagitis "asthma of the esophagus." An evaluation by an allergist for other atopic diseases is recommended. Skin prick testing for foods and environmental allergens (aeroallergen) should be considered in all patients.

- Food allergy: multiple food sensitizations are found in 80% of patients
- Aeroallergens: multiple environmental sensitizations are found in 90% of patients

The presence of allergic rhinitis, sensitization to aeroallergens, or both ranges from 42% to 93% in children with eosinophilic esophagitis. In addition, dietary therapy has a role in EoE treatment. According to the most recent consensus document, children with eosinophilic esophagitis should be evaluated for food and aeroallergen sensitization (Liacouras CC, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011 (July); 128(1):3-20).

Peripheral Cytokines

Eotaxin-3 expression is a promising marker for distinguishing EoE from other causes of esophagitis. Both IL-5 and IL-13 cause release of eotaxin which attracts eosinophils.

Treatment

Currently, there is no FDA-approved treatment for eosinophilic esophagitis. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation (Allergy, 2012).

Some treatment to eosinophilic esophagitis can be summarized by the following mnemonic: SADD

Steroids (local, PO)
Acid suppression with PPI
Diet (6- or 8-food elimination diet)
Dilatation of esophagus (if strictures)

Some experts advise to choose one course of therapy: medical OR diet.

Corticosteroids

Both systemic and topical corticosteroids are effective for therapy of EoE but pathological findings and symptoms reccur when discontinued.

When to use systemic corticosteroids in EoE?

In emergent cases such as dysphagia requiring hospitalization, dehydration because of swallowing difficulties, and weight loss.

Topical corticosteroids

Topical corticosteroids are often helpful when used in the setting of EoE, 87% of children respond to topical budesonide.

Two inhaled corticosteroids have been used to treat eosinophilic esophagitis - fluticasone and budesonide.

The usual starting dose of budesonide in an adult is a 1 mg ampule mixed with a slurry of artificial sweetener (usually sucralose) using 10 packets, dependent upon taste, and swallowed b.i.d. In a child, 0.5 mg can be used in the same way, mixed with 5 packets.

Fluticasone is typically started at a dose of 440 mcg b.i.d. This can be lowered to 220 mcg b.i.d. subsequently.

Starting dose is 440-880 micrograms per day for children and 880-1760 micrograms per day for adolescents/adults. This regimen is continued for at least 6-8 weeks, depending on the response. Several studies have shown that the eosiniphilic infiltration returns when the swallowed steroids are stopped.

Leukotriene receptor antagonists (Singulair) and cromolyn are not useful for treatment of EE.

How to use steroids for topical treatment of EoE?

Patients should be instructed to use a metered dose inhaler (MDI) without a spacer. MDI is inserted in the mouth and sprayed with lips sealed around the device. The powder is swallowed and not rinsed (just the opposite of using MDI in asthma). Patients should not eat or drink for at least 30 minutes.

Acid Suppression

In patients with EoE, symptoms are unresponsive or only partially responsive to acid blockade with PPIs. PPI therapy is not a primary treatment for EE but rather a co-therapy. Children with eosinophilic esophagitis (EoE) treated with PPIs show an improvement in symptoms despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE (Annals of Allergy&Immunology, 2012).

Dietary Treatment

- Elimination diet (6-food elimination diet: peanut, milk, egg, soy, seafood, wheat)
- Elemental diet

Dietary therapy (specific antigens removal or elemental formula) can be useful in children with EoE. Skin prick testing for foods and environmental allergens (aeroallergen) should be considered in all patients.

Elemental diet "cures" 95% of EoE but is difficult to implement.

Esophageal Dilatation

Esophageal dilatation is useful for patients with fixed esophageal strictures causing food impaction. Medical therapy should be attempted first.

Monitoring of therapy in EoE

One approach is to perform repeated EGDs with biopsy every 4-6 months until esophageal eosinophilia is resolved.

What is the most potent chemokine (chemoattractant) for eosinophils?

(A) IL-5

(B) IL-8

(C) LTB4

(D) eotaxin

(E) IL-4

(F) IL-13

Answer: D.

Eotaxin is the most potent chemoattractant for eosinophils but IL-5 is the most specific stimulant of their production.

References

Eosinophilic Esophagitis. NEJM Images.
Potential pathogenesis and effects of tissue remodeling in patients with EoE. JACI Images, Nov 2011.
Eosinophilic esophagitis: the newest esophageal inflammatory disease. Atkins, D. et al. Nat. Rev. Gastroenterol. Hepatol. 6, 267–278 (2009) (PDF).
Eosinophilic Esophagitis. Harrison's Online.
Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. National Guideline Clearinghouse.
Eosinophilic disorders. JACI, Volume 119, Issue 6, Pages 1291-1300 (June 2007).
Eosinophilic oesophagitis. Alyson Kakakios and Ralf G Heine. MJA 2006; 185 (7): 401.
Eosinophilic Oesophagitis: A Common Cause of Dysphagia in Young Adults? Medscape, 11/2008.

Eosinophilic esophagitis after specific oral tolerance induction for egg protein http://goo.gl/fzmip

Video

Eosinophilic Esophagitis. The DAVE Project - Gastroenterology.

Related reading

Proton-Pump Inhibitors (PPIs) Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use http://goo.gl/zANv
Repeating allergy testing in children with eosinophilic esophagitis whose original tests were negative. Ask the Expert, AAAAI, 2011.
Reslizumab (anti-IL5) led to improvements in histology, but not in symptoms in eosinophilic esophagitis. Medscape, 2012.
Eosinophilic Esophagitis treatment strategy relies on 3 D's: drugs, diets, dilation (free full text review), 2012.

Comments from Twitter

@DrSilge: Dr. Aceves says that they use 0.5 mg budesonide respules in 5 packets, not the 1 mg. If need higher dose, use 10 packets. She states that want the volume for surface area, moreso than the higher concentration of medication.

Dr John Weiner @AllergyNet: Not just hot topic, but burning, summarized superbly by @Allergy


Published: 08/09/2008
Updated: 05/21/2012