1. Eosinophilic Esophagitis: Esophageal and Extraesophageal Manifestations
Philip E Putnam, MD, FAAP
Professor of Pediatrics
University of Cincinnati
CCHMC
Division of Gastroenterology, Hepatology, and Nutrition
Medical Director, Cincinnati Center for Eosinophilic Disorders

2. Normal Esophagus Stratified squamous, non-keratinized epithelium
Surrounded by
lamina propria
muscularis mucosa
submucosa
muscularis propria

3. Normal esophagus

4. Suprabasal layer Basal cell layer Rete peg
Normal Esophageal Histology Stratified squamous, non-keratinized, epithelium
Lumen
Suprabasal layer
Basal cell layer
Rete peg
Lamina propria

5. Normal Esophagus
Esophagitis

6. Esophagus: Inflammatory Disorders
Esophagitis
Acute
Infectious (e.g., Herpes, Candida)
Pill-induced (e.g., tetracyclines, oral contraceptives)
Caustic ingestion
Chronic
GERD—reflux esophagitis
Eosinophil-predominant inflammation
Other inflammatory bowel disease (e.g., Crohn’s, celiac)

7. Esophagitis Symptoms are non-specific Pain Dysphagia Odynophagia
Chest pain
Epigastric pain
Referred pain to the back (interscapular)
Dysphagia

8. Esophageal Inflammatory Disorders—Factors to Consider
Age at onset
Duration of symptoms
Esophageal Symptoms
Non-esophageal GI complaints
Diarrhea, for example
Non-GI complaints
Evidence for systemic disease
Medication use
History of immune or atopic conditions
Asthma, Atopic dermatitis
Physical exam
Diagnostic Studies
Contrast exam
Endoscopy with biopsy
Manometry
MII-pH

9. Focus: Eosinophilic Esophagitis (EoE)

10. 2011—Revised Consensus Definition of EoE
Chronic, immune-mediated disorder
Clinical features
Esophageal dysfunction
Pathologic features
Eosinophil-predominant mucosal inflammation (15eos/hpf)
Not due to acid-induced injury
Not responsive to PPI
Isolated to the esophagus
Liacouras C, et al. JACI 2011

11. What it really is: Disorder of epithelial homeostasis
Genetically susceptible individuals
Impaired barrier function: cell-cell adhesion
Dysregulation of the immune response toward Th2 mediated hypersensitivity
Initiation and perpetuation of inflammation by dietary antigen exposure
esophageal dysfunction (motor and sensory)
mural remodeling with loss of compliance
lumenal narrowing (focally or diffusely)
Disease with eosinophils, not a disease of eosinophils

12. Rothenberg, Gastro 2015

13. EoE Prevalence: 10 per 10,000 children in Hamilton County
Estimated: 55 per 100,000 overall prevalence in US
Spergel et al., 2011 JPGN
Dellon et al., Clin Gastro Hepatol 2014

14. Eosinophilic Esophagitis
Male predominant (~75% )
Familial clustering
2/3 are otherwise atopic:
Food allergies (IgE-mediated immediate hypersensitivity)
Environmental allergies
Asthma
Eczema
Chronic rhinitis
Food antigen-induced eosinophilia
95% respond to antigen removal
Recurrent disease upon reintroduction of provocative antigens

15. EoE the Disease: Clinical, Endoscopic, Histologic

16. EoE Symptoms Non-specific: Dysphagia Feeding problems Vomiting Pain
Usually chronic
Acute presentation with food impaction
Acute presentation with esophageal foreign body
Rarely, dysphagia for liquids
Laryngeal cleft, Chiari malformation, foreign body obstruction
Feeding problems
Vomiting
Pain

17. Esophageal Symptoms Feeding disorder Vomiting Pain
Infants and toddlers
Aversion, refusal, gagging, choking, vomiting
Vomiting
Chronic, intermittent, or
Consistently associated with particular foods, or
Cyclical (not attributed to food)
Pain
Chest pain
Epigastric pain
Odynophagia is NOT common

18. Eosinophilic Esophagitis: Primary presenting complaint, by age
Noel, et al, 2004 NEJM

19. Dysphagia—What kids say
Food “sticking”
Food goes down slow
Food gets ”stuck”
Eventually goes down
Retched back up
Endoscopically retrieved
ASK ABOUT COMPENSATORY MANEUVERS
Eat slowly
Chew excessively
Drink excessively to ‘wash it down’
Take small bites
Avoid specific food textures
Bread, meat, pasta, rice

20. Common Complaints in Children who have EoE
Sore throat or ‘throat tightening’
Globus sensation
Throat clearing
Cough with eating

21. “Aerodigestive” Evaluation
Forty patients with recurrent croup or cough
53% had airway abnormalities
38% had esophagitis
4 (27%) of which met criteria for eosinophilic esophagitis
There was no significant difference in the presence of gastrointestinal complaints, abdominal pain and/or FTT (p>0.05) with or without esophagitis
 Greifer M, et al. Pediatric patients with chronic cough and recurrent croup: the case for a multidisciplinary approach. Int J Pediatr Otorhinolaryngol May;79(5):749-52 

22. EoE in an Aerodigestive program
Between 2003 and 2012, 376 children with persistent symptoms undergoing triple scope
14 (3.7%) were eventually diagnosed as having EoE
The children with EoE who presented with airway symptoms
cough (n = 6; 42.9%).
Inflammatory subglottic stenosis due to EoE was identified in 1 patient.
Subsequent treatment including food allergy challenge and elimination diet resulted in a clinical improvement in half of the cases identified.
Hill CA, et al. Prevalence of eosinophilic esophagitis in children with refractory aerodigestive symptoms. JAMA Otolaryngol Head Neck Surg Sep;139(9):903-6.

23. EoE in the ENT population
92 children were diagnosed with EoE (3.8% of total children biopsied).
73% were boys and 27% girls.
presenting symptom
Cough(46%)
hoarseness, throat clearing, burping/vomiting, and abdominal pain.
43% with asthma
17% with a history of GERD.
Otteson TD(1), Mantle BA, Casselbrant ML, Goyal A. The otolaryngologic manifestations in children with eosinophilic esophagitis.  Int J Pediatr Otorhinolaryngol Jan;76(1):116-9.

24. “Aerodigestive” Complaints in EoE
Non-specific
Referred from esophagus, or
Associated with comorbid conditions
GERD
Chronic rhinitis with post nasal drainage
Infection (e.g., candida)
Cough
Reactive airways
Infection, etc. etc. etc…
Referral bias!

25. Retained Esophageal Foreign Objects
Duration of symptoms
Prolonged symptoms and/or unwitnessed ingestion
Should it have passed?
Pre-existing dysphagia or feeding problems?
Infants and Toddlers
Pre-existing anatomic abnormality (e.g. stricture)

26. Esophageal foreign bodies and food impactions
Approach to all foreign bodies presenting for endoscopic retrieval
Careful history
Examine the rest of the esophagus!
Biopsy the esophagus away from the point of impaction
Children with food impactions have EoE til proven otherwise!
Meat: 100% with EoE
Inanimate objects: 45% with EoE
Williams P, al. Esophageal foreign bodies and eosinophilic esophagitis--the need for esophageal mucosal biopsy: a 12-year survey across pediatric subspecialties. Surg Endosc Jun;27(6):

27. Esophageal foreign body, characteristics in EoE
food impaction (89%)
older age (average 12.2 years)
male sex (78%),
atopic disease (61%)
previous esophageal foreign body or frequent dysphagia (83%)
endoscopic abnormalities (100%).
Hudson S, et al. Foreign body impaction as presentation of eosinophilic esophagitis. Otolaryngol Head Neck Surg Nov;149(5):679-81

28. Endoscopy in EoE

29. Rings
Furrows

30. Mucosal rings

31. Endoscopic photograph of distal esophagus with thickening and furrowing

32. Exudate

33. Endoscopic photograph showing typical exudate (‘white specks’)

34. Patchy furrowing with exudate, distal esophagus

35. EREFS—Scoring the endoscopic findings
Edema
Rings
Exudate
Furrows
Stricture
Hirano I et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. . Gut Apr;62(4):

36. EoE, GERD, or both?

37. Normal Esophagus
Esophagitis

38. Eosinophilic Esophagitis: Not just eosinophils
Reactive Changes
Expansion of the basal cell layer (proliferation)
Extension of the rete pegs toward surface
Dilated intercellular spaces
Inflammatory cell infiltrate
Lymphocytes
Eosinophils, microabscess
Mast cells
Remodeling
Lamina propria fibrosis

39. Esophageal histology overlap
GERD
Basal zone hyperplasia
Rete peg elongation
Dilated intercellular spaces
Inflammatory cell infiltrate
Neutrophils
Lymphocytes (squiggle cells)
Eosinophils
Surface ulceration
EoE
Basal zone hyperplasia
Rete peg elongation
Dilated intercellular spaces
Inflammatory cell infiltrate
Eosinophils
Lymphocytes
Mast cells
Eosinophilic microabscesses
Surface layering of eos

40. Symptoms vs. histology Symptoms correlate poorly with histology
Many patients with active inflammation have no symptoms
Some patients with no inflammation still complain of pain or dysphagia
The absence of symptoms does not imply the absence of inflammation
Pentiuk S, et al JPGN

41. EoE Diagnosis

42. EoE Diagnosis Ultimately, the final clinical diagnosis requires
EoE has characteristic symptoms, endoscopic findings, and histology
BUT, they are all nonspecific, individually and collectively.
Ultimately, the final clinical diagnosis requires
Comprehensive evaluation of the child
Comorbidity determination
Distribution of eosinophilia in the gut
Histologic response to therapeutic intervention
8 week trial of PPI 1mg/kg/dose bid 30 minutes before b/d

43. Eosinophilic esophagitis (EoE) vs. esophageal eosinophilia
There is a differential diagnosis when eosinophils are present in the esophagus
Eosinophils are not specific for any particular condition
Pathologists don’t diagnose EoE
They describe esophageal eosinophilia
Clinician correlates histology with relevant data
The number of eosinophils/hpf DOES NOT discriminate EoE from other conditions
Histologic eosinophil-predominant esophagitis is not sufficient to diagnose clinical EoE

44. Negative result Positive result Confirms the absence of reflux
If reflux is the most common confounding diagnosis, why not just do MII-pH in all?
Negative result
Confirms the absence of reflux
But, doesn’t account for “PPI-responsive esophageal eosinophilia”
PPI trial is still required for diagnosis
Positive result
Confirms presence of reflux events, but not the pathogenesis, and
Can’t identify those who have coincident EoE plus GERD

45. EoE Diagnosis Hx, PE, Clinical assessment Endoscopy with biopsy
PPI trial
Non-invasive testing and clinical symptoms alone cannot make the diagnosis
No blood tests (CBC, AEC, IgE, etc.)
No x-rays
No allergy test(s)

46. Treatment of Children who have EoE

47. EoE Management Principles
Chronic disease
requires chronic, consistent, effective therapy
Goals:
Symptom improvement
Mucosal healing
Prevent Complications
Liacouras, et al., JACI, 2011

48. EoE Management Options
Dietary Antigen Elimination
Steroids
Systemic
Topical
Combination therapy with dietary antigen elimination and topical steroids
Immunomodulators?
Biologics?
Anti-IL5, Anti-IgE, Anti-TNF (ineffective!)
Anti-IL13
Dilatation of the esophagus
Anti TGF-beta?

49. Initial Antigen Elimination Diet
The starting diet upon confirmation of the diagnosis (after PPI trial)
Simultaneous elimination of single or multiple antigens to induce remission
MUST NOT be done before, or with, initial PPI trial or steroids

50. Dietary Management Principles
The final diet achieved is the one that is
Least restrictive without provoking EoE
Meets all the child’s nutritional needs

51. Reintroduction of selected antigens followed by Endoscopy*
“Starting” Diet
Remission
Reintroduction of selected antigens followed by
Endoscopy*
“Final” Diet
* Disparity between starting diet and final diet determines the number of cycles of reintroduction/endoscopy

52. Concept In a perfect world, the Starting Diet would be the Final Diet
“Testing” would precisely identify all provocative antigens
Positives would be true positives and always cause esophagitis
Negatives would be true negatives and never cause esophagitis

53. Dietary Management Principles: THE PROBLEM
EoE is a non-IgE mediated disorder, so IgE-based tests are of little value
Skin Prick Testing
50% false positives
Serum specific IgE
Atopy patch testing is not standardized and remains at best controversial
We no longer recommend allergy testing to drive decision-making regarding dietary management of EoE.

54. Henderson et al
JACI, 2012

55. Topical Steroids for EoE
Fluticasone
440mcg bid- 880mcg bid
‘Hold your breath, squirt and swallow’
NPO for 30 minutes post dose
Budesonide
250mcg-1mg bid
Mix contents of vial with 3-5 packets of Splenda
NPO for 30 minutes post dose

56. Response to swallowed fluticasone: distal esophagus
Konikoff, M. et al. Gastroenterology 2006

57. Which therapy? Which form of therapy is feasible for child and family?
Educate, negotiate, understand the family dynamic
Don’t prescribe—let the family choose
Support
Nurse, dietician, psychologist, social work
Modify the plan for clinical failures, recurrent/persistent esophagitis, social failures

58. The Implications of Biopsies
Biopsy results reflect the response to what is being eaten
Normal biopsies confirm that provocative antigens must be in the group being avoided
Abnormal biopsies only confirm that provocative antigens are still being ingested
Nothing can be assumed regarding the avoided foods
Nothing goes back in the diet til the biopsies are normal

59. Biopsies in EoE
Because of the poor correlation between symptoms and histology, esophageal biopsies are required to assess the response to any change in therapy

60. Desirable Esophageal Monitoring
Non-invasive
Nothing inserted into the nose/mouth/esophagus
No need for anesthesia, x-ray
No need for tissue
Accurate
Equal to biopsies in detecting early EoE recurrence with food challenge or drug change
Able to discriminate among all causes of esophagitis
Recognizes EoE and EoE plus GERD and PPI-REE
Reasonable cost covered by insurance

61. Esophageal monitoring after diagnosis—Repeat Endoscopy
The only method available to assess the esophageal lining for esophagitis that is sensitive enough to detect EoE.
Biomarkers?
Blood test?
Saliva?
Stools?
Impedance?
String test?

62. Esophageal impedance
“Impedance” is a measurement of the resistance to electrical current flow between two points
Catheters with the ability to measure Impedance
Detect and quantitate retrograde bolus flow attributed to GERD in the esophageal lumen (MII-pH studies)
Observe esophageal emptying during esophageal manometry testing
Direct measurement of mucosal impedance
Katzka DA et al. Endoscopic Mucosal Impedance Measurements Correlate With Eosinophilia and Dilation of Intercellular Spaces in Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol Jul;13(7): e1

63. Natural History? Adult EoE Chronic disorder
Requires constant, consistent, effective therapy
Adult EoE
Dysphagia is the predominant complaint
Persistent esophagitis with recurrent symptoms requiring dilatation
“Remodeling” of the esophagus
Strauman, A , Gastrointest Clin N Am

64. EoE: Remodeling Chronic dysphagia
Small caliber esophagus
Esophageal stricture
REVERSIBLE early on with either diet or pharmacotherapy