Eosinophilic Esophagitis in children LMEF Pediatric Conference 06/20/2017 Emily C. Hon, M.D.

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Objectives Define eosinophilic esophagitis (EoE) Describe clinical presentation of EoE patients Learn how EoE is diagnosed Understand treatment options for EoE

Eosinophils White blood cells responsible for fighting parasites Increased in allergic disorders Do not exist in the esophagus under normal conditions

What is Eosinophilic Esophagitis (EoE)? 2nd most common cause of chronic esophagitis (after GERD) Leading cause of dysphagia and food impaction in children Chronic, antigen-mediated (food) TH-2 pathway, non IgE mediated First defined in early 1990s Evolving definition EoE is thought to be a chronic, antigen (primarily food-derived) mediated disease. As this is a relatively new entity, the definition has been evolving. It currently requires both clinical and histological findings 1. Esopahgeal dysfunction characterized by dysphagia, vomiting, feeding difficulties, abd pain 2. Histological findings: an eosinophil- predominant inflammation isolated to the esophagus. -where current controversy exists is how we exclude other causes of esophageal eosinophilia such as GERD and PPI-responsive esophageal eosinophilia.

What is EoE? Requires both of the following: Clinical Histological Esophageal dysfunction Dysphagia, vomiting, feeding difficulties, abdominal pain Histological Eosinophil-predominant inflammation (>15 eosinophils per field) isolated to the esophagus Need to exclude other causes of esophageal eosinophilia Persists after a high dose Proton Pump Inhibitor (PPI) trial Clinical AND Histological. Path should not be used to dx EoE in isolation.

Eosinophils and acid in the esophagus Winter- Eos in the esophagus are related to GERD. Eos/hpf were usually <10, and concentrated in the distal esophagus Attwood: Described 12 patients with high esophageal eosinoiphilia, dysphagia, 11/12 had normal pH probes, and normal endoscopy. Several papers to follow described more patients with this distinct entity, response to elemental diet, topical steroid. Steiner: Denser infiltrates of eos does not correlate with increased GERD. The finding of >20eos/hpf is likely associated with normal reflux indesx and a nonacid-related cause of esophagitis If eos/hpf >20, these patients were just as likely as completely normal EGDs to have abnormal JD scores. This study helped “confirm the minimal role that acid reflux has in eosinophilic esophagitis) The EoE consensus statement in 2007 clear stated that the esophageal abnormalities do not respond to treatment with high-dose proton pump inhibitor therapy. Then in 2011 consensus we have developed a new term called PPI-responsive esophageal eosinophilia… could be GERD, could be EoE  So now our definition of EoE or perhaps classic EoE depends on whether a pt. responds to HDPPI.

Current controversy- 2017 European Guidelines “…PPI-REE and EoE are virtually indistinguishable from one another, even at the genetic level, and very different from GERD... Therefore, the main novelty in these guidelines is the retraction of the term PPI-REE and the consideration of PPI therapy not as a diagnostic criterion for EoE, but rather as a therapeutic agent.”

Other Causes of Esophageal Eosinophilia GERD Achalasia PPI-responsive esophageal eosinophilia Drug hypersensitivity Vasculitis Eosinophilic gastrointestinal diseases Connective tissue disease Graft-versus-host disease Celiac Disease Crohn disease Infectious esophagitis Hypereosinophilic syndrome Pemphigoid vegetans is an extremely rare variant of bullous pemphigoid by vegetative and purulent lesions in the groin, axillae, thighs, hands, eyelids, and perioral lesions. Skin lesions with path c/w eosinophilic spongiosis as well as pemphigoid. Only few cases reported.

Epidemiology Prevalence in US: 56.7/100,000 (Dellon, 2014) Risk factors: Male predominance (2-3x) Personal or family history of atopy More common in non-Hispanic whites, but occurs in all racial / ethnic groups Dellon prevalence study looked at 35M pts from database of commercially insured population 2008-2011 using ICD9 code 530.13. This would have been before PPIREE definition.

Clinical Presentation Age-dependent Infants / toddlers: Persistent reflux symptoms Vomiting Feeding difficulties Refusal to eat School-age: Abdominal pain www.webmd.com

Clinical Presentation Adolescents and adults: Dysphagia (solids) Food impactions Chest pain Globus sensation Throat-clearing www.medscape.com

ENT symptoms?

True or False? All patients with dysphagia have EoE. FALSE All patients with EoE have dysphagia.

Compensating Behaviors Adaptations to esophageal dysfunction: Drinking plenty of liquids with all meals Prolonged chewing Avoiding bulky foods, meats, breads Slow or picky eaters Parents cut food into very small pieces High index of suspicion needed! May diagnose other family members However, many children have adapted to the esophageal dysfunction with the following compensating behaviors. So they don’t vomit or think they have trouble swallowing but…

Physical Exam Non-diagnostic for EoE Growth parameters can be low, normal, or high Find co-morbid allergic diseases Allergic shiners Rhinorrhea with pale boggy turbinates Eczema, urticaria Wheezing, prolonged expiration Non-diagnostic- They can be FTT, obese, epigastric tenderness?

Diagnosis How do we diagnose EoE?

Upper Endoscopy and Biopsies Only reliable diagnostic test Abnormal findings: Pallor Longitudinal furrowing White exudates Crepe paper mucosa Rings Felinization (transient) Trachealization (permanent) Strictures None are pathognomonic for EoE Once we have the clinical findings of esophageal dysfunction, we move on to EGD and biopsies. A normal esophagus has a smooth, pale pink mucosa, and visible vessels. In EoE, most commonly see pallor with poor visualization of the vessels. This photo also shows longitudinal furrowing. White exudates or specks can be seen representing eosinophilic microabscesses. This can look similar to candidal esophagitis so a fungal brushing may be sent., crepe paper mucosa, is rare but is seen when we are coming out of the EGD It’s a sign of longitudinal shearing. Last is ringing of the esophagus (transient ringing is felinization and permanent ringing is trachealization), strictures Liacouras, 2011

Histology ≥15 eosinophils per field in esophageal biopsy specimen after a PPI trial Isolated to the esophagus Other findings: Eosinophilic microabscesses Surface layering of eosinophils Eosinophil degranulation Basal cell hyperplasia Lamina propria fibrosis Other causes ruled out. With few exception,, 15 eos/hpf (peak value) is considered a minimum threshold for a diagnosis of EoE if other associated findings are seen. Eosinophilia should be isolated to the esophagus, otherwise we need to think of other etiologies such as EGE, EC, Crohn’s disease, etc. A shows a normal esophageal epithelial layer. In B, you can see the many eosinophils which is much >15 eos/hpf. In C the arrow is pointing nicely to just layers of eosinophils on the surface of the mucosa. D points to an eosinophilic microabscess. Basal cell hyperplasia refers to expansion of this basal cell layer Liacouras, 2011

PPI-Responsive Esophageal Eosinophilia GERD Usually <10 eos/hpf in distal esophagus pH Probe, PPI trial PPI-responsive esophageal eosinophilia Considered distinct from EoE, but not necessarily a manifestation of GERD Resolution of esophageal eosinophilia with high dose PPI. PPI 1mg/kg dose BID x 2 months prior to EGD Anti-inflammatory mechanism?

Treatment

Therapies Goals: Food elimination diets: Topical steroids Reduced symptoms and improved histology Prevent feeding dysfunction Prevent fibrosis and stricture formation Food elimination diets: Elemental Empiric elimination Allergy testing-based Topical steroids Prednisone for rapid improvement in symptoms Esophageal dilation We don’t know who will continue to have ongoing esophageal injury, so hard to determine how/who to treat and monitor. Defining endpoints also difficult.

Elemental Diet Disadvantages: Amino-acid based formula1 Up to 96% histologic remission rate2 Disadvantages: Poor tasting, expensive formula Development of solid food aversion NGT or GT Long food reintroduction process, many endoscopies Kelly, 1995 Henderson, 2012

Six-Food Elimination Diet (SFED) Wheat Ignore Nuts/peanuts Soy Fish/seafood Eggs Dairy When working with these diets, it’s important for families to work with a nutritionist to ensure they are still getting good nutrition while restricting these groups. Kagalwalla, 2006- 85% clinical and histological remission Variety of table foods, less cost Still socially difficult for children Requires endoscopy with each food introductions, separated by at least 6 weeks. Dietician Prevent contamination Prevent iatrogenic malnutrition Kagalwalla, 2006

4-Food Elimination Diet Milk Wheat Egg Soy Milk Elimination diet: 65% clinical and histological remission (95% CI 42-88%) Milk Elimination Diet (65%) Kagalwalla, 2012

Empiric Elimination + Meat Beef Chicken Pork Turkey

Allergy Testing Based Elimination Results similar to empiric food elimination Disadvantages: Requires painful testing Skin prick testing (IgE) Atopy patch testing (non-IgE, high variability) ADT similar to empiric food elimination: Spergel et al, 2012: SPT/APT directed + milk elimination  77% Spergel, 2012

Allergy Dietician Prevent iatrogenic malnutrition Prevent contamination

Topical Steroids Not FDA-approved for EoE 50-80% histologic remission, common recurrence Swallowed fluticasone: Metered dose inhaler without spacer Oral viscous budesonide: 10 packets of Splenda per 2 respule (0.5 mg/2 ml) Neocate Nutra ½ tsp per 2 respules Small amount applesauce No drinking or eating for 30 minutes, then drink water Can swish and spit with water Possible adrenal insufficiency Update on adrenal insufficiency concerns- look at Roma’s paper.

Esophageal Dilations Mostly in adolescents and adults Treats strictures, but not underlying inflammation 3% risk for significant adverse effect same as non-EoE (Menard-Katcher, 2017) 15% chest pain. Menard-Katcher- retrospective study of all children undergoing esophageal dilation at academic children’s hospital: “significant’= requiring some medical attention/intervnetion more than reassurance. No association with # eosinophils. www.olympus.nl

Epinephrine injection and allergy shots are NOT part of EoE treatment.

Figure 1. PPI- nonresponsive EoE diagnosis confirmed Dietary And Pharmacologic Treatments Discussed Pharmacotherapy chosen FP OVB Diet Elimination chosen Empiric, allergy testing not needed Empiric Milk Empiric Four-food Empiric Four-food + Meat (beef, chicken, pork, and turkey) Empiric Six-food Allergy Skin Test Guided + Milk Elimination (work with Allergists) Figure 1.

Questions?