1. Eosinophilic Esophagitis, Food Allergies, and Pediatric Dysphagia.
Greg Black, MD
SC SOM Associate Professor of Pediatrics
Carolina Allergy and Asthma Consultants, Columbia, SC
SCSHA 2018 Conference
February 16th, 2018

2. Disclosures
No financial disclosures.
No conflicts to declare.

4. Greg Black, MD Clemson University 2001 MUSC 2005
Medicine and Pediatrics at University of AL at Birmingham 2009
Northland District Health Board, Whangarei 2010
Tulane University Allergy and Immunology 2012
Private Practice
Clinical Experience:
Allergic Rhinitis
Asthma
Eczema
Food Allergies
Anaphylaxis
Immune Deficiency
Chronic Urticaria
Drug Allergy
Resident Education

5. Road Map Dysphagia Food Allergy (FA)
Gastroesophageal Reflux Disease (GERD)
Eosinophilic Esophagitis (EoE)
Q&A

6. Dysphagia
Disruption in the swallow sequence that results in compromise of the safety, efficiency of adequacy of nutritional intake.
One percent of pediatric population estimated to experience swallowing difficulties (Bhattacharyya Laryngoscope 2015).
Children with dysphagia often present with multiple forms of impairment in swallowing that also differ from adult presentations.
Children with multisystem disorders/diagnoses with dysphagia at great risk of pneumonia.

7. Dysphagia Disorders Affecting Infants and Children
Prematurity
Respiratory and Cardiac
Neurological
Maternal and Perinatal Issues
Congenital Syndromes
Iatrogenic Complications
Caustic Injuries
Gastrointestinal Disorders: Food Allergies, GERD, and Eosinophilic Esophagitis.

8. Food Allergies
National Institute of Allergy and Infectious Disease defines Food Allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”
Thus specific allergic symptoms are not required for Food Allergy to be diagnosed in general.
Sensitivity vs Allergy.

9. Food Allergies: The Scope of the Problem
CDC estimates 8% of children and 4% of adults in US have a FA diagnosis.
CDC estimates 50% increase in pediatric FA
Gupta et al in 2012 reports economic burden of FA is $25 billion USD.
FA results in 300,000 ambulatory care visits a year, and 200,000 ED visits per year (half of ED visits are diagnosed as food allergen induced anaphylaxis).
FA is the leading cause of anaphylaxis outside of the hospital setting.
Co-diagnosis of asthma is a risk factor for fatal food allergy.

10. FA Diagnoses Urticaria and Angioedema or Anaphylaxis
Food Protein Induced Enterocolitis (acute and chronic FPIES)
Allergic Proctocolitis
Food Dependent Exercise Induced Anaphylaxis
Red meat allergy (alpha-gal sensitivity)
Oral Pollen Syndrome
Celiac Disease
Atopic Dermatitis
Auriculotemporal Syndrome
Eosinophilic Esophagitis and Gastrointestinal Disease (EGID)
Latex Fruit Syndrome
Pork Cat Syndrome

12. Making the Diagnosis of FA
Ninety percent of immediate hypersensitivity to foods in US due to milk, soy, egg, wheat, peanut, tree nut, fish, and shellfish.
Peanut, tree nut, fish, and shellfish FA typically long lived.
Self reporting of food allergies by patients consistently is higher than true immediate hypersensitivity as documented by Oral Food Challenge (OFC) .
12% self report vs 3-4% on OFC confirmation.
Food allergy more common in children, and high co- occurrence of other atopic conditions.
Children with moderate to severe persistent atopic dermatitis at 35% increased risk to develop immediate hypersensitivity.

13. Fatal FA
AAAAI Statistics Page: 38.7% of FA children have a history of severe reaction.
Xu et al in 2014 reported on 92 cases of fatal anaphylaxis from the Ontario, Canada Coroner’s office.
Forty (43%) due to food allergens.
Sixteen (17%) due to peanut.
RF for FA fatalities: asthma, peanut allergy, teenagers, delayed epinephrine administration.
Umasunthar et al reported on 10 studies in 2013 in a meta- analysis concerning reported on 240 cases of fatal food allergy at per million person years, assuming a FA prevalence of 3.9%.
Incidence of fatal FA less than that of fatal accidents in Europe.

15. FA Risk Factors Family History Sex Ethnicity Genes
7 fold increase in risk of Peanut allergy if primary relative is peanut allergic
Sex
M:F for peanut allergy in childhood 5:1.
Ratio changes to 1:1 with adulthood.
Ethnicity
Lieu et al documents risk of FA in non hispanic blacks increased over whites OR 3.06 (95% CI ). NHANES
Genes
STAT6
IL10
CD14
TSLP

16. Theories on increase of FA Diagnoses
Hygiene Hypothesis
Lack of early infectious exposure leads to increased allergic sensitization
C-sections involved?
Early Probiotic administration may protect against eczema onset, but not allergic sensitization.
Dietary guidelines
Former AAP guidelines concerning families at risk (atopic history) was to delay introduction of typical allergenic foods, until recently.
No major role for dietary restrictions in pregnancy or lactation that would affect development of FA.

17. Dual Allergen Hypothesis

18. Making the Diagnosis of FA
History of Ingestion?
Time to symptoms
Foods ingested
Means of preparation
Location where food consumed
Symptoms?
Urticaria
Angioedema
Nausea, Vomiting
Stridor
Change in sensorium
Resolved/Recurring?
Time to resolution
Factors involved in resolution
Has patient returned to eating the food?
Confounders?
NSAIDS, Antibiotics
Venom
Exercise
Latex
Sexual activity

19. Methods of FA Screening
Skin prick testing
Inexpensive
Outpatient setting
Immediate results ( minutes)
May use extract or “prick to prick” method with fresh allergen.
Intradermal testing to food allergens prone to false positivity and anaphylaxis.

21. Skin Prick Testing (SPT) for FA
Skin prick testing for FA has a sensitivity of 85% and a specificity of 74% (Sampson H et al JACI 1984).
Judicious and limited skin prick testing should be done within the context of a given anaphylactic or allergic event.
Proves sensitization, not clinical allergy.
Based on wheal diameter of positive prick tests, threshold values to determine if OFC’s are necessary have been set:
Milk 8 mm
Egg 7 mm
Peanut 8 mm
Sesame 8 mm

22. Sensitization itself is not FA.
Sensitization is a clinical term for the formation of an allergic antibody (IgE) to a given allergen.
Summary Statement 23 from Joint Task Force Practice Parameter on FA: “The clinician should use specific IgE tests (skin prick tests, serum tests, or both) to foods as diagnostic tools; how ever, testing should be focused on foods suspected of provoking the reaction, and test results alone should not be considered diagnostic of food allergy.”
The patient’s history, physical exam findings, and tests must align to confirm a diagnosis of FA.

23. Serology (sIgE) Testing for FA
Fluoroscence-labeled antibody assays to detect the presence of circulating IgE to a suspected food allergen.
Also only proves sensitizations, not clinical allergy.
Non specific testing to multiple allergens should be avoided.
Can be useful if history is suggestive of anaphylaxis and spt is negative or if patient cannot do without antihistamine, severe skin disease, dermatographism, etc.
Published cutoff values associated with anaphylaxis:
Egg 7 kUA/L
Peanut 14 kUA/L
Milk 15 kUA/L
Sesame 7 kUA/L

24. Limitations Skin Prick Test: Immunocap (sIgE):
PPV based on population and food
NPV relatively high but negative result does not rule out allergy
Food allergy extract not standardized
Wheal size to establish OFC reactivity not determined for most allergens
Cannot skin test patients with active dermatitis
Immunocap (sIgE):
Often leads to unnecessary elimination diet
Total IgE level and non- specific cross reactive binding
Fleischer et al in 2011 shows large majority of pediatric patients successfully reintroduced foods avoided based on sIgE values only.

25. FA Diagnosis: Food Challenge
Gold standard of FA diagnosis is Double Blind Placebo Controlled Food Challenge (DBPCFC).
Cumbersome, lengthy, and usually only performed in academic centers.
OFC simple and easier to administer in outpatient setting.
Lieberman et al in 2011 evaluated 701 OFC’s for 521 patients.
18.8% elicited reaction, 1.7% required epinephrine.
OFC’s should start with 0.1% - 1 % of total challenge food.
OFC’s goal challenge dose should be 8-10 gm dry food, gm meat or fish, 100 ml wet food; dosing interval should be every 15 minutes.

26. Prevention of FA? LEAP Trial (NEJM ) 2015 EAT Study (NEJM) 2016
Risk of Allergy with C-Section Delivery
Breastfeeing vs partial/extensive hydrosylate formula
Dog Exposure
Link Between Atopic Dermatitis and FA
Early Antibiotic Usage

27. NIAID Addendum Guidelines for Prevention of Peanut Allergy in the United States
Infant Criteria
Recommendations
Earliest Age of Introduction 1
Severe Eczema, Egg allergy, or both
Check sIgE to peanut or skin test to peanut and perform OFC if necessary. Consider peanut introduction based on results.
4 to 6 months 2
Mild to moderate eczema
Introduce Peanut containing foods
Around 6 months 3
No eczema or food allergy
Age appropriate and in accordance with family/cultural preferences

29. Unproven Diagnostic Methods
Serum IgG level to potential food allergens
Applied Kinesiology
Hair analysis
Cytotoxicity
Electrodermal testing
Rescue dogs

30. Management of FA Re-assessment of immunologic reactivity.
Avoidance!
There is no cure.
Education of patient, family, friends, school, social contacts etc.
Training of patient and caregivers on correct Epi Pen or Auvi Q technique.
Anaphylaxis Action Plan
Early Epinephrine administration saves lives.
Re-assessment of immunologic reactivity.
Tolerated an accidental ingestion after years of consisted avoidance?
Twenty percent likelihood of outgrowing peanut allergy.

32. Egg, Milk, and Peanut FA Milk Allergy Egg Allergy Peanut Allergy
“Mixed cellular effect.”
Baked milk ingestion tolerance can be determined by blood test.
Baked milk ingestion can promote uncooked milk tolerance.
Egg Allergy
Baked egg tolerance can be determined by blood test.
Baked egg ingestion can promote raw or partially cooked egg tolerance.
Peanut Allergy
20% of patients outgrow allergy.
Boiled vs Roasted peanuts.
Tree Nut Allergy
9% of patients outgrow allergy.
Cross reactive pattern on skin and blood testing does not necessarily translate to clinical allergy.
Fish and Shellfish Allergy
No evidence that either can be outgrown.

33. Immunotherapy (IT) for FA
Need is clear as prevalence of FA worldwide is growing.
Avoidance is a imperfect management.
Accidental ingestion is common (20%).
Gupta et al in 2011 reports 38.7% of children diagnosed with FA have experienced anaphylaxis that includes hypotension and/or dyspnea.
Terms for defining goals of Immunotherapy FA Trials.
Desensitization: tolerating escalating doses of food allergen during a trial.
Sustained unresponsiveness: tolerated a controlled food challenge 2-6 weeks after desensitization was halted and food allergen was avoided.
Immunological Tolerance: “Growing Out of It.”

34. Forms of IT for FA OIT: Oral Immuno- therapy
SLIT: Sublingual immunotherapy
Recombinant Protein Therapy
Epicutaneous Immunotherapy
OIT trials are most numerous and better characterized compared to other forms.
More patients reach active desensitization but with a higher rate of adverse events.

35. OIT Schema Initial Dose Escalation Build-up phase Maintenance Phase
Avoidance Phase
Assessment of response by food challenge

36. Novel Approaches Co-administer Peanut OIT with probiotic
OIT for multiple foods (Stanford Program)
Xolair (monoclonal antibody directed against IgE) usage for rush oral desensitization
DARPins
Epicutaneous patch therapy
Rectal delivered peanut vaccine of Ara h 1/2/3 with E.coli as adjuvant

37. Personal Burden of FA Anxiety/Depression Bullying in schools
Cost of medical visits, recurrent epinephrine injector renewals
Workplace accommodation
Risk of accidental ingestion and misuse of epinephrine injector
Food aversion

38. FA: Take Home Points
History and skin testing play most important roles in accurate diagnosis.
Do not rely on blood tests alone.
Avoidance, education of family/caretakers, and appropriate treatment of accidental ingestions are the keys to FA management.
Action plans, early epinephrine administration, etc.
Regular follow up with your allergist allows you opportunity for monitoring, epinephrine injector refills, and updates on FA research advancements.

39. GERD in a Pediatric Patient

40. GERD
Gastroesophageal reflux results with immaturity or inappropriate relaxation of the lower esophageal sphincter, thus resulting in retrograde flow of stomach contents into the esophagus. Symptoms in children include:
Crying and irritability
Wheezing
Vomiting
Low heart rate
Failure to thrive/poor weight gain
Chronic cough and hoarseness
Chest and abdominal pain
POST PRANDIAL PRESENTATION OF SYMPTOMS

41. GERD Physiologic vs Pathologic
Most common reason for Pediatric GI referral
80 % of GER symptoms resolve by 18 months of age, though evidence of GER may still be present. True prevalence of GERD in older children difficult to ascertain.
Not related to food allergy.

42. Risk Factors for GERD Medication use Smoking Alcohol ingestion Obesity
Diazepam
Theophylline
Smoking
Alcohol ingestion
Obesity
Motility disorder
Poor Dietary Habits
Greasy, acidic foods
Supine Position
Developmental Disorders
Cerebral Palsy
Trisomy 21
Pervasive Developmental Delay
Traumatic Brain Injury
Inborn error of metabolism
Craniofacial abnormality
Premature Delivery

43. GERD Presentation and Considerations
No true classic physical exam finding of GERD.
History of symptoms
Secondary complications of FTT, Pneumonitis
In older children may look for dental caries, halitosis, chronic cough, post nasal drip
Prior to making a diagnosis of GERD you must consider:
Anatomic Abnormalities
Antral web
TEF
Pyloric Stenosis
Peptic Ulcers
Motility Disorder
IBS
Food Allergy

48. GERD Evaluation Manometry EGD with biopsy pH monitoring
Can assess sphincter function
EGD with biopsy
Direct visualization
Most useful in one who does not respond to medication
pH monitoring
Upper GI imaging series
Not a sensitive test, but can be used to look at emptying time
Gastric Scintiscan
Most useful for assessing pulmonary aspiration
Impedance studies
Can detect acid vs non acid reflux

49. GERD Treatment Uncomplicated Complicated Happy Spitter Infants
Parental reassurance
Diet modification
Should symptoms worsen or persist after 2 years of age:
H2 Antagonist vs PPI
Upper GI imaging
Consider GI referral
Complicated
Failure to Thrive
Stricture management
Pneumonia, chronic respiratory symptoms, apnea, dysphagia
Early GI referral with pH monitoring, Endoscopy, and Medication rx.
Nasogastric Tube Feeding and Fundoplication rarely necessary.

50. GERD: Take Home Points
History of symptoms can lead to successful empiric treatment.
Imaging and endoscopy are necessary for structural abnormalities.

51. Eosinophilic Esophagitis

52. Eosinophilic Esophagitis (EoE)
Chronic, immune mediated, esophageal disease characterized by symptoms related to esophageal dysfunction and histologically by eosinophil predominant inflammation.
USA Prevalence estimated at 50-60/100,000 patients.
Prevalence varies by country (China 0.4%, Denmark 1.7%).
First described in one case in 1977, a group of 10 difficult to treat GERD patients in 1995 were demonstrated to have high numbers of eosinophils infiltrated into the esophageal mucosa.
Published researched on EoE explodes after 2000 (>75% all papers)

53. What Causes EoE?

54. EoE: Clinical Features
Highly variable and can have multiple presentations.
Classic EoE patient: young male with dysphagia and a history of food impactions, that have resolved with dilation and/or topical steroid treatment.
Classic EoE patient: highly atopic toddler with vomiting and feeding dysfunction, whose GI symptoms improve on an elemental diet.
As clinical research advances, more EoE phenotypes are being defined.
Atypical presentations such as isolated food impactions are not uncommon.

55. EoE Pathology Slides

56. Eosinophils in the GI tract
Eosinophil Cells per high powered field, by section:
Esophagus: 0
Stomach: 2-20
Small Intestine: 2-20
Colon: 10-50

57. Eosinophils: Form and Function
A type of White Blood Cell, produced by the Bone Marrow, that is detected by a red stain called Eosin in laboratory examinations.
Important for allergic inflammation and defense against parasites, and certain bacteria that can replicate inside mammalian cells.
Eosinophils contain, produce and release:
Major Basic Protein
Eosinophilic Cationic Protein
Eosinophil derived neurotoxin
Eosinophil peroxidase

58. Whitish Exudates

59. Longitudinal Furrowing

60. Furrows vs Rings

61. Crepe-Paper Esophagus with a Laceration from Dilation

62. EoE Esophagram

63. EoE Dysmotility Ineffective peristalsis Aperistalsis
High amplitude contractions
Non peristaltic contractions
Reduced esophageal distensibility

64. Diagnosis of EoE
Consider a diagnosis of EoE in a patient with upper GI symptoms that is not responding to PPI therapy.
Minimum threshold is 15 eosinophils or more per hpf.
Disease should be confined to the esophagus.
Two to four biopsy specimens are recommended in the proximal and distal esophagus.
Gonsalves et al discovered in 2006 that one biopsy alone in the diagnosis of EoE had a sensitivity of 55%. Increasing the number of biopsies to five raised the diagnostic sensitivity of biopsy to 100%.

65. EoE vs GERD
There are no pathognomonic findings that distinguish GERD from EoE.
Patients with esophageal eosinophilia may respond to 8 to 12 weeks of acid suppression therapy (omeprazole).
EoE patients tend to be unresponsive to PPI’s alone, younger, have a history of dysphagia and/or food allergies, distinct endoscopic findings, higher mucosal eosinophil counts, and markers of eosinophil degranulation.

66. EoE Forms of Treatment Acid Suppression (Proton Pump Inhibitor)
Topical Steroids (ingested fluticasone spray or budesonide slurry)
Allergy Testing
Empiric Food Elimination
Four and Six Food Elimination, Elemental Diet
Systemic Corticosteroids
Experimental Therapies
Endoscopic Dilation

67. Topical Steroids for EoE
Ingested Fluticasone inhaler mcg vs Budesonide 1 mg per day
Side effects
Thrush
Growth Retardation
Osteopenia
Cataracts
Systemic Corticosteroids for weight loss, small caliber esophagus, hospitalization.

68. Allergy Testing Milk is the number one most common EoE trigger food.
Avoiding milk and dairy improves patient’s symptoms, even when skin test is negative.
Testing to common food allergens to customize patient’s diet has had mixed results therapeutically.
Spergel et al JACI 2012
74% patients tested are atopic.
33% of patients tested had no positive skin tests to food allergens.
No clear evidence that allergic antibodies influence disease process.
Mouse models
Omalizumab trials in human patients with EoE.

69. Dietary Triggers in EoE Patients

70. Dietary Modification Elemental Formula Four Food Elimination Diet
High rate of remission and very successful in children
High cost of elemental dietary formula
Risk of solid food aversion development
Slow, protracted evaluation with systematic food re- introduction
Four Food Elimination Diet
Milk, Egg, Soy, Wheat
64% remission rate in study.
Six Food Elimination Diet
Milk, Egg, Soy, Wheat, Peanut/tree nuts, Seafood.
74% remission rate in study.

71. Monoclonal Antibodies
Mepolizumab
Targets IL 5, that is an attractant and a survival factor for eosinophils.
Tezepelumab
Targets TSLP, and is being evaluated for asthma, BUT could there be a role for EoE managment?

72. Esophageal Dilation
Provides rapid relief and clinical improvement but is not anti- inflammatory in nature.
Schoepfer et al in 2010 examined the outcomes of esophageal dilation in 404 EoE patients that underwent 839 procedures; the procedural rates of chest pain and esophageal perforation were 5% and 0.8%, respectively.
“Through-the-Scope” Balloon Dilation offers exclusively applied radial force and immediate assessment of esophageal injury.
Mucosal tears and perforations are the most serious complications.

73. Esophageal Dilation Risk Factors for Dilation Complications:
Younger age
Repeat dilation
Narrowing in upper third of the esophagus
Inability to traverse narrowing of the scope prior to dilation

74. EoE: Take Home Points
EoE is chronic, rare, complicated to diagnose and requires multidisciplinary management.
Reflux associated mucosal eosinophilia MUST be ruled out prior to making an EoE diagnosis.
Not every EoE patient responds to the same treatment.
Regular follow up with GI and Allergy MD required for appropriate management and updates on new forms of treatment.

75. Thanks!!!
Questions?

76. References
Sicherer et al. Advances in diagnosing peanut allergy. JACI In Practice. 2013: 1 (1); 1-13.
O’Keefe et al. Diagnosis and management of food allergies: new and emerging options: a systematic review. Journal of Asthma and Allergy. 2014: 7;
Lack, G. Update on risk factors for food allergy. JACI. 2012: 129 (5);
Kattan, JD et al. Allergen component testing for food allergy: ready for prime time? Curr Allergy asthma Rep. 2013: 13;
Chhiba, KD et al. New development in immunotherapies for food allergy. Immunotherapy. 2015: 7(8);
Fleischer et al. Consensus communication on early peanut introduction and the prevention of peanut allergy in high risk infants. Pediatrics. 2015: 136;
Bartnikas, LM et al. Epicutaneous sensitization result in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis. JACI. 2013; 131 (2);
Noti et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis. JACI. 2014: 133 (5);
Du Toit, G et al. Randomized Trial of Peanut Consumption in Infants arisk for peanut allergy. NEJM. 2015: 372 (9);
Valenta, R et al. Food allergies: the basics. Gastroenterology. 2015: 148;

77. References
Asarnoj, A et al. Peanut component Ara h 8 sensitization and tolerance to peanut. JACI. 2012; 130(2):
Nicolaou, N et al. Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component resolved diagnostics. JACI. 2010; 125(1);
Caubet, J et al. Significance of ovomucoid and ovalumin specific IgE/IgG4 ratios in egg allergy. JACI. 2012; 129(3):
Umasunthar, T et al. Incidence of fatal food anaphylaxis in people with food allergy. Clin Exp Allergy. 2013; 43:
Xu et al. Anaphylaxis related deaths in Ontario: a retrospective review of cases from Allergy, Asthma, and Clin Imm. 2014; 10(38): 1-8.
Leonard, SA et al. Dietary baked egg accelerates resolution of egg allergy in children. JACI. 2012; 130(2):
Lemon-Mule, H et al. Immunologic changes in children with egg allergy ingesting extensively heated egg. JACI ; 122 (5):
D’Urbano LE et al. Performance of component based micro-array in the diagnosis of cow’s milk and hen’s egg allergy. Clin Exp Allergy. 2010; 40:
Escudero C et al. Early Sustained Unresponsiveness after short course egg OIT: a RCT study in egg allergic children. Clin Exp Allergy. Ahead of publication.
Alessandri C et al. Ovomucoid specific IgE detected by microarray predicted tolerability to boiled hen’s egg and an increased risk to progress to multiple environmental allergen sensitisation. Clin Exp Allergy. 2011; 42:

78. References
Nowak-Wegrzyn, A et al. Tolerance to extensively heated milk in children with cow’s milk allergy. JACI. 2008; 122 (2):
Anagnostou, K et al. Study of induction of tolerance to oral peanut: STOP II TRIAL. Efficacy and Mechanism Evaluation. 2014; 1(4).
Ott, H et al. Clinical usefulness of micro-array based IgE detection in children with suspected food allergy. Allergy. 2008; 63:
Brough, HA et al. Peanut protein in household dust is related to household peanut consumption and is biologically active. JACI (3):
Johannsen, H et al. Skin prick testing and specific IgE can predict peanut challenge outcomes in preschool children with peanut sensitization. Clin Exp Allergy. 2011; 41 (7):
Kim JS et al. Dietary baked milk accelerates of cow’s milk allergy in children. JACI. 2011; 128(1):