Eosinophilic Esophagitis: An Allergy Perspective

Daniel DeMerell, MD

Eosinophilic Esophagitis: An Allergy Perspective

• Disclosure- none

Eosinophilic Esophagitis (EoE): An Overview

• Definition of EoE• Epidemiology of EoE• Etiology of EoE• Role of allergies in EoE• Diagnosis of EoE• Treatment of EoE• Prognosis of EoE

Eosinophilic Esophagitis (EoE)

• First described as distinct entity related to foods in 1995 in 10 children with esophageal eosinophilia, refractory to acid suppression who then responded to elemental diet (Kelley et al.)

• 2007 expert panel released consensus recommendations for EoE in children and adults (Furuta GT et al.).– Presence of clinical symptoms related to esophageal dysfunction– Isolated esophageal eosinophilia

• >15 eos/hpf

– Absence of other causes of esophageal eosinophilia (especially GERD)

• Normal pH monitoring study of distal esophagus • Lack of response to high-dose PPI

Eosinophilic Esophagitis:2011 Updated Definition

• In 2011, expert panel updated consensus recommendation for children and adults

• “Eosinophilic esophagitis represents a chronic, immune/antigen mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation”

• Infiltration of eosinophils not affecting other areas of GI tract

Liacouras CA et al. J Allergy Clin Immunol 2011

Eosinophilic Esophagitis

• Definition is limited because mechanism(s) of EoE still not fully understood

• Challenging to design and compare studies • Diagnosis and treatment is evolving as we

learn about the mechanisms

Epidemiology of EoE

• Prevalence and incidence of EoE increasing – Prevalence of EoE ranges from 6-60 cases per 100,000 (Dohil R

et al., Prasad GA et al.- Olmstead County, MN)

– Therefore prevalence of EoE likely comparable to that of IBD, but less than that of celiac disease (Rothenberg et al 2009 )

– Not clear how much is also related to increase in endoscopy• Males: females 3:1 (genetic variant of the TSLP receptor

on the X-chromosome in males?)• Seen in all ages• More commonly diagnosed in urban and suburban areas

than rural (Spergel JM et al 2011)

Epidemiology of EoE

• Veerappan et al- found EoE in 6.5% of adults undergoing endoscopy in outpatient US military hospital (included large percentage of black patients)

• Genetics (gene locus identified on chromosome 5q22- Rothenberg M et al. 2010)

• Commonly seen in atopic individuals (approximately 75%)

• Timing of diagnosis (and exacerbations)- increased in pollen season in some patients

Symptoms of EoE

• Dysphagia and feeding dysfunction • Food impaction• GERD like symptoms • Chest pain• Abdominal pain• Vomiting• Anorexia/early satiety

Liacouras CA et al. J Allergy Clin Immunol 2011

Kapel et al. Gastroenterology 2008;134:1316

Findings Associated With EoE

Endoscopic/Radiologic• Esophageal rings• Stricture• Linear furrows• Longitudinal narrowing• Longitudinal shearing

(crepe paper esophagus)• White exudates

Histologic• Mucosal eosinophilia• Eosinophil micro abscess• Superficial layering of eos• Extracellular eos granules• Epithelial desquamation• Basal zone hyperplasia• Dilated intercellular spaces• Sub epithelial fibrosis/sclerosis• Mastocytosis and MC

degranulation• CD 8 lymphocytes and B cells

Liacouras CA et al. J Allergy Clin Immunol 2011

Differential Diagnosis of EoE

• GERD• Eosinophilic gastrointestinal diseases• Celiac disease• Crohn’s disease• Infection• Hypereosinophilic syndrome• Achalasia• Drug hypersensitivity• Vasculitis• Pemphigus vegetans• Connective tissue disease• Graft-versus-host disease

Liacouras CA et al. J Allergy Clin Immunol 2011

Differentiating EoE From GERD

• Difficult to separate into two distinct diseases • Possible relationships:

1. GERD causes esophageal injury with eosinophilia2. EoE and GERD coexist but are unrelated3. EoE causes or contributes to secondary GERD4. GERD causes or contributes to EoE

• A trial of PPIs, even when diagnosis of EoE is established, is recommended

Spechler et al. Am J Gastroenterol 2007

Why The Increase In Allergic Diseases (Atopy)?

• Genetics• Environment- allergen, pollution, chemical, pesticide,

fertilizer exposure, environmental warming?• Hygiene hypothesis - Th1 vs. Th2 lymphocytes• Increased use of GERD medications-

– Less acidic environment in gut leads to exposure to more intact proteins (altered mucosal absorption) which may affect processing of food antigens

• Food antigen processing (i.e. cooking methods of peanuts can alter allergenicity)

Hygiene Hypothesis:Why The Increase In Atopy

• Th2 cytokines- IL-4, IL-5, IL-13

• Th1 cytokines- IFN-γ, IL-2, TNF-α

www.fooddrugallergy.ucla.edu

Why The Increase In Allergic Diseases (Atopy)?

• Different routes of sensitization – Application of creams containing peanut oil to inflamed skin

can sensitize to peanut (Lack G et al.)

• Epicutaneous allergen sensitization potently primes for respiratory allergen-induced experimental EoE (Akei HS et al. Gastroenterology 2005)

– Interesting in light of high percentage of EoE patients with atopic dermatitis

• Connection between development of eosinophilic infiltration in respiratory tract and esophagus in response to external allergic triggers, but also to intrinsic Th2 cytokines (Rothenberg et al. Gastroenterology 2009)

Why Are We Seeing An Increase In EoE?

• Increased recognition• Chronic nature of EoE• Increasing atopic disease in general• Other as yet unknown factors

Seasonal Distribution in Newly Diagnosed Cases of EoE in Adults

• Retrospective review of newly diagnosed EoE patients 8/06-7/07 at Mayo Clinic

• EoE more frequently diagnosed in spring (44%) and summer (24%) than fall (17%) and winter (15%) (in light of constant number of endoscopies done year round)

• Also described in children (Wang FY et al.)

• Implicates aeroallergens (and more specifically pollens) as potential etiologic factors in EoE

• Patients with EoE have seasonal variations in symptoms (Onbasi K et al.)

Almansa C et al.

Eosinophilic esophagitis

Atopic dermatitis (eczema)

Eosinophilic gastritis

Eosinophilic gastroenteritis

Food Allergy: Immunologic Spectrum

Anaphylaxis Urticaria Angioedema Oral Allergy

Syndrome

Celiac (IgA driven) Food Protein Induced

Proctitis Food Protein Induced

Enterocolitis Food Protein Induced

enteropathy

Sampson H. et al.

IgE Mediated Non-IgE MediatedMixed

Mechanisms of EoE

• EoE etiology- appears to be multifactorial – Immediate hypersensitivity (IgE against food/pollen

proteins)(Gell and Coombs type I reaction)– Delayed type hypersensitivity (cellular- especially

lymphocyte driven)(Gell and Coombs type IV reaction)

– Mast cells have also been shown to play role• We don’t yet fully understand the complete

mechanisms of EoE

IgE Mediated Allergic Reactions: Require Sensitization and Re-exposure

Food Allergies:The Facts On IgE Reactions

• 6-7 million in U.S. suffer from food allergies • Food allergy is #1 cause of anaphylaxis in ED (over

50,000 cases anaphylaxis per year)• Estimated 180 deaths per year (majority to

peanuts/tree nuts)• Almost a 20% increase in prevalence of food

allergies from 1997-2007• Peanut allergy affects >1% school aged children

Oral Allergy Syndrome(Also Driven By IgE)

• Oral pruritus with fresh raw fruits and vegetables (< 4% become systemic)

• Occurs in subset of pollen allergic individuals– Birch- apple, apricots, peaches, carrots, cherries,

kiwi, plums, hazelnuts– Ragweed- bananas, melons, cucumbers– Grasses- cherries, tomatoes, avocado, potatoes– Mugwort- melon, apple, peach, cherry

• Very labile proteins- heating and gastric acid denature

• Segment of EoE population has OAS (may be group with more relevant aeroallergen contribution, seasonal assoc.)

EoE Mechanisms:Delayed Type Hypersensitivity (DTH)

• Primarily lymphocyte driven (rather than antibody)

• Atopy Patch Testing (APT) is used to identify delayed reactions to foods

• Other examples of DTH include PPD used to test for TB, allergic contact dermatitis (nickel or poison oak reactions)

EoE Mechanism:Delayed Type Hypersensitivity

Mechanisms of EoE: Mast Cells

• Esophageal mastocytosis and degranulation in EoE– Lead to dysmotility in children and adults associated with

dysphagia– Produce cytokines that activate eosinophils and promote

tissue remodeling• Mast cell-associated transcriptome may distinguish EoE patients

from controls (future marker?)• Increased TGF-β1 associated with esophageal remodeling and

fibrosis as well as dysmotility– Potential therapeutic target

Aceves S et al. J Allergy Clin Immunol 2010 Abonia JP et al. J Allergy Clin Immunol 2010

Esophageal Cytokine Profile in EoE• Thus far, no reliable, noninvasive biomarkers for EoE, however: 1. Eotaxin-3 – mRNA expression increased in EoE patients vs. controls (89%

sensitivity with single biopsy)– Signals migration of eosinophils from vascular space into tissue – strongly correlated with tissue eosinophilia and mastocytosis

2. IL-13 – Tissue and serum expression levels of IL-13 correlate with tissue eosinophilia

in EoE (and disease activity)– One of the most promising potential biomarkers for the disease– Induces eotaxin-3 production

3. IL-5 – Produced by mast cells, promote maturation and activation of eosinophils– Absence leads to deficiency of eosinophil number and function

Blanchard C et al. Bhardwaj et al.

Sherill JD et al.

The molecular pathogenesis of EoE. An allergic insult by either food antigens or aeroallergens initiates the transition of the esophagus from a normal (NL) to an EoE phenotype through the production of TSLP by the esophageal epithelium. TSLP-activated dendritic cells induce a robust TH2 response and enhanced IL-13, which in turn mediates marked dysregulation of gene expression (the EoE transcriptome). Enhanced eotaxin-3 (CCL26) secretion by the esophageal epithelium promotes eosinophil migration from the blood into the tissue. Eosinophil- and mast cell–derived TGF-β along with IL-13 and IL-5 act on fibroblasts and mast cells and stimulate the fibrotic response. Loss of FLG expression, partially because of IL-13 overproduction, genetic variants, or both, might further enhance or even predispose patients with EoE to antigen exposure and exacerbate TH2 inflammation (and promote food allergen uptake)

Esophageal Remodeling In EoE

• Esophageal biopsies show increased TH2 cytokines (IL-5, IL-4, IL-13) and TH1 cytokines (IFN-γ)

• Also increased eosinophil chemo attractants– eotaxin-1, eotaxin-3, and TNF-α

• Esophageal remodeling in EoE is similar to allergen induced airway remodeling in patients with asthma

• EoE patients- increased fibrosis and vascularity vs. controls and patients with GERD

• TGF-β (expressed by eosinophils) promotes fibrosis and remodeling in sub epithelia in EoE

Aceves S et al. J Allergy Clin Immunol 2007

Diagnosis of Food Allergy

• Detailed history and PE– possible causal foods, quantity ingested, time course,

other contributing factors (exercise, ASA, EtOH), possible cross contamination

• Food specific IgE testing– Skin testing– Serum specific testing– Basophil activation/release assays

• Atopy patch testing (eosinophilic GI diseases, AD)• Oral Challenge (DBPCOC, Single blinded, or open)

Diagnosis Food Allergy (IgE Mediated): Skin Prick Testing

• Small amount of the allergen is placed on top of the skin – Skin is “scratched” to introduce allergen percutaneously– Wheal and flare is measured using positive and negative

controls with results in 20 minutes• Skin prick tests (SPT) generally have better sensitivity

and predictability than serum specific testing and are the preferred initial diagnostic approach (Bernstein IL et al.)– For IgE food allergy- NPV>95%, PPV 50%– For EoE- NPV 58-95%, PPV 33-95%

Skin Testing

Delayed Reactions To Foods:Patch Testing (APT):

• Measures delayed type hypersensitivity (allergic contact dermatitis)

• Food slurry is prepared and placed in shallow aluminum wells (Finn Chambers) and taped on back touching the skin for.

• The patches are removed at 48 hours (preliminary read) and measured at 72 hours (final read) using standard patch test protocols.

Turjanmaa K et al. Spergal JM et al. Ann Allergy, Asthma, Immunol 2005

Patch Testing (APT)

Allergy Testing For EoE

• Skin testing (combination of SPT and APT to foods and SPT to aeroallergens best)

• General screen includes- cow’s milk, hen’s egg, soy, wheat, rice, corn, oat, barley, potato, beef, chicken, pork, turkey, peanut, peas, green beans, squash, carrots, peach, apple (+/- fish, shellfish, tree nuts, and other foods that are common part of individual's diet)

Spergel JM et al. J Allergy Clin Immunol 2007;119:509-11Bernstein IL et al. Ann Allergy Asthma Immunol 2008;100:s1-148

Food Allergy Tests That Are Unproven or Disproved

• Food specific IgG or IgG4 (IgG “RAST”)– May actually be more representative of foods

the gut has recently seen or tolerates• Provocation/neutralization• Cytotoxic tests/ hair analysis• Applied kinesiology (muscle response

testing)• Electro-dermal testing

Bernstein IL et al.

Treatment Of EoE

• What are goals of treatment?– clinical improvement– histological normalcy– reversal of fibrosis (remodeling)– prevention of disease progression

• Drugs, diet, and dilation

Treatment of EoE- Medications

• Medications– Corticosteroids– Proton pump inhibitors– Anti-IL-5 mAb- (reslizumab and mepolizumab) decreased

esophageal eosinophilia but limited clinical response (studies ongoing)

• Also suggests that eosinophilia may not be the key pathologic effector (?part of a larger Th2 response)

• Medications not recommended – Cromolyn sodium- mast cell stabilizer– Leukotriene receptor antagonists (monteleukast, zafirlukast)– Immunosuppressants (azothiaprine, 6-MP)- risks outweigh benefits

Spergel JM et al. J Allergy Clin Immunol 2012Assa’ad et al. Gastroenterology 2011Straumann et al. Gut 2010

Treatment of EoE

• Food elimination (elemental diet vs. targeted food diet)

• Esophageal dilation- can provide immediate and long-lasting relief of dysphagia in patients with stricture (doesn’t address esophageal inflammation)- more data needed

Treatment of EoE: Corticosteroids

1. Systemic corticosteroids- for severe dysphagia, hospitalization, inability to eat, weight loss– Significant long term risks- infection (esp fungal), HTN,

osteopenia/osteoporosis, glucose intolerance, cataracts, adrenal suppression

2. Localized corticosteroids– Swallowed fluticasone 220 mcg- 1-2 puffs bid or viscous

budesonide 1 mg bid– Disease recurs with drug cessation – Patients with more significant atopy may be less responsive– Steroid resistance in minority of patients (as seen with other

atopic diseases like asthma)

Treatment of EoE: Proton Pump Inhibitors

• Cohort of unselected adults referred for endoscopy due to upper GI symptoms with proximal esophageal eosinophilic infiltrate– Baseline endoscopy followed by Rabeprazole 20 mg bid for 2 months,

then endoscopy repeated– 75% achieved clinicopathological remission with PPIs– 50% of patients with EoE phenotype responded to PPIs

• Interestingly, pH monitoring was poorly predictive of PPI response.• Potential mechanisms of PPI response

– Placebo effect– Treat concurrent GERD– Acid hypersensitivity– Anti-inflammatory effect of PPIs

Molina-Infante J et al.

Treatment of EoE:Dietary Intervention

1. Elemental Diet- restricted to amino-acid based formula (Elecare, Neocate, or Eo28 Splash)

2. Targeted elimination diet– Based on allergy testing (SPT/patch testing (APT))

3. Empiric elimination diet– Also called 6 Food Elimination Diet (SFED)– Avoidance of most common food allergens

• milk, egg, wheat, soy, nuts (peanuts/tree nuts), and seafood (fish and shellfish)

Treatment of EoE: Dietary Intervention

• Remember to stop topical corticosteroids before starting diet to allow recurrence of symptoms in order to document clinical effectiveness of diet

• Complete removal of the food(s) for 8-12 weeks• If possible, repeat endoscopy at end of elimination

trial (consideration of cost, coverage, risk)• If clinicopathologic improvement, then add foods back

one at a time• Clinical trials often repeat endoscopy after each food

reintroduced, but not always practical

Treatment of EoE: Elemental Diet

Advantages• Very effective

• > 95% demonstrate clinical and histologic improvement

• Allows systematic re-introduction of foods

• Removes the need for medications

Disadvantages• Expensive• Unpalatable• Need for feeding tube• Quality of life issues

Chehade M et al. Castellano M et al. Penfield JD et al.

Targeted Food Elimination (Based On SPT/APT)

• Retrospective series in 146 children treated with an elimination diet guided by the results of skin prick and patch testing

• Resolution of esophageal eosinophilia was observed in 77 percent • Egg, milk, and soy were identified most frequently with skin prick

testing, while corn, soy, and wheat were identified most frequently with atopy patch testing

• On average, 4 causative foods were identified per patient• Disease reoccurred after foods reintroduced (clinically and

histologically)• Combination of SPT/APT lead to better specificity than either test

alone

Liacouras CA et al. Clin Gastroenterol Hepatol 2005Spergel JM et al. Ann Allergy Asthma Immunol 2005

Identification of Causative FoodsIn EoE Treated With Elimination Diet

• Retrospective review in cohort of >700 patients with EoE • Definitive foods identified in 319 patients

– the rest were on elemental diet or responded to elimination diet but failed to f/u, added back multiple foods at a time, or didn’t want to add foods back in once they responded clinically

• 75% of patients were atopic, similar to other studies• SPT predictive values for EoE not as good as in patients with IgE

mediated food allergies• 70% of EoE patients allergic to 1-3 foods• Milk, egg, wheat, and soy most common allergens

– Other foods usually fell into 2 general categories- grains and meats

Spergel JM et al. J Allergy Clin Immunol 2012

Treatment Of EoE: Elimination Diet: Allergy Testing vs. SFED

• Compared removing foods based on allergy testing vs. SFED– Both had histologic response of 53% (vs. 95% with elemental diets) – NPV using SPT and APT was 80-100% for all foods (including egg,

wheat, soy) except milk (44%)• Authors Proposed 2 subsets of EoE

1. Those allergic to select major allergens 2. The other (almost 20%) group were allergic to more diverse group of

foods (many suggestive of OAS to fruits/vegetables)• Concluded that SFED or allergy testing based methods had equal success,

but one advantage of allergy testing was that fewer foods were removed.

Spergel JM et al. J Allergy Clin Immunol 2012

Targeted Diet Therapy

Spergel JM et al. J Allergy Clin Immunol 2012

Comparative Dietary Therapy Effectiveness In Remission of EoE

• Retrospective observational study in cohort from Cincinnati (CCED)• Compared effectiveness and remission rates of 3 diets- elemental

(n=49), SFED (n=26), skin test directed (n=23) • Dietary therapy is highly effective in EoE (both allergy testing and

SFED groups) – No statistical difference in remission between the 2 groups– Of note, not all of the allergy tested patients had patch testing done

• Both of the directed diets are inferior to elemental diet • Skin testing alone may not be superior to SFED, but usually involves

less foods being eliminated.– Adherence inversely related to the number of foods eliminated

• More studies needed to help determine optimal elimination diets, testing, and sensitivities/specificities/NPV/PPV Henderson CJ et al.

Comparative Dietary Therapy Effectiveness In Remission of Pediatric Eosinophilic Esophagitis

Henderson CJ et al.

Targeted Food Elimination in Adults

• 6 adults with active EoE- SPT + to grass pollen, wheat, and rye

• Elimination of wheat and rye failed to reduce disease activity and challenge with these same foods didn’t provoke EoE flare– Allergy to only wheat (or wheat and rye alone) not seen in

other studies– No APT done– Patients who are grass pollen allergic often test positive to

wheat (and other grains) due to cross-reactivity on testing without clinical significance

Simon D et al.

Empiric Elimination Diet:Six Food Elimination Diet (SFED)

• Prospective, uncontrolled study in 50 adults with EoE on SFED for 6 weeks • History of bid PPI or normal pH study• 78% had greater than 50% reduction in peak eosinophils in esophagus

(64% had < 5 eos/hpf)• Decrease in dysphagia scores by 94%• Most common food allergies- wheat and milk, followed by soy, nuts, and

egg• Reintroduction of foods led to return of previous pathology and symptoms

confirming food allergies• SPT predicted only 13% of foods associated with EoE • Authors concluded SPT may not be as helpful in adults as in kids, but APT

not done, and aero-allergens were not treated/addressed

Gonsalvez et al. Gastroenterology 2012

Empiric Elimination DietSix Food Elimination Diet (SFED)

• Observational study of 2 cohorts of Children • 35 put on SFED for 6 weeks

– Histologic improvement in 74% and symptomatic improvement in 97%

• Second cohort of 27 children (similar population) treated with elemental diet– Histologic improvement in 88%– Cost $900-$1500/month for a 20 Kg child(2006)

Kagalwalla AF et al. Clin Gastroenterol Hepatol 2006

Important Considerations of Dietary Treatment

• Registered dietician- provide ongoing dietary counseling, watch for cross-contamination, adequate caloric intake, vitamins, etc.

• Selection of diet- should be based upon severity of disease, patient’s lifestyle and quality of life, as well as family resources

• Importance of being realistic and upfront with the patient from the start– Many patients hope for a quick and easy fix and it usually is not– Patients need to be ready to commit to diet (or encouraged to

wait/treat with meds until they are)• If the offending food is found and improvement is attained with

elimination, the elimination appears life-long at this time (tolerance to the food(s) doesn’t occur)

Other Dietary Tips In Treatment Of EoE

• Caution with:• Highly textured foods (meats)• Bulky foods (certain breads, potatoes)

• Cut food into small pieces• Chew extensively • Eat slowly• Wash foods down with liquids

Prognosis of EoE• EoE cohort had decreased quality of life and persistent

symptoms 15 years after presentation • EoE leads to persistent dysphagia, food impaction and

structural esophageal alterations (including stricture)• Patients with increased esophageal eosinophil counts and

food allergy (as well as atopy in general) have increased risk for food impaction and persistent symptoms and therefore should be treated and monitored more aggressively

• No malignant potential has been associated with this disease

DeBrosse C et al. Straumann A et al. Rothenberg M. 2009

Future of EoE• Critical to better understand mechanisms to help guide diagnosis and therapy

– Need to continue to evolve EoE definition• In spite of clear food allergy role, need to determine utility of food testing,

especially in adults (and role of aeroallergens)• Need to clearly define optimal treatment endpoints (histologically and

clinically)– Define what histological “normalcy” is (i.e. <5 eos/hpf)

• Need for relevant biomarkers (eotaxin-3 and IL-13 may be the most promising Bhardwaj et al.)

• Guidelines for evaluation and management of the asymptomatic patient with esophageal eosinophilia

• Determine optimal frequency of endoscopy in follow-up (as well as guidelines on number and locations of esophageal biopsies)

• Validated measurements of symptoms, endoscopic findings, histology, and quality of life

Summary of EoE

• EoE has shown increasing incidence and prevalence (paralleling that of atopy in general)

• Most EoE patients are also atopic (and control of these diseases may play role in EoE control)

• Mechanism of EoE still not definitive, but is at least in part antigen driven (especially food antigen)

• Diagnosis remains clinicopathologic– Allergy evaluation and testing is currently recommended but further

studies needed to clarify utility and best approach, especially in adults • Treatment options include use of medications

– Trial of PPI is recommended as some EoE patients respond– Swallowed corticosteroids are effective but carry risk of adverse

effects

Summary of EoE

• Dietary interventions eliminating food antigens are effective– Elemental diet is most effective dietary intervention(but also

extremely prohibitive)– Targeted elimination of diet based on allergy testing and SFED are

both effective– Relevance of aero-allergens should be assessed, especially in

hard to treat patients • Long term therapy must be individualized for each patient• Prognosis consistent with chronic process requiring ongoing

treatment • Coordination of gastroenterology, allergy/immunology,

pathology, and certified nutritionists

Eat Dirt!

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