Practitioner Case Study – November 2019

INTRODUCTION

About Eosinophilic Esophagitis:

Eosinophilic esophagitis (EE) was first characterized in 1993 as an allergic inflammatory condition that is biased toward type-2 helper T cells (T_h2). It presents most commonly with heartburn, epigastric pain, dysphagia, and nausea and vomiting. Eosinophilia and elevated total IgE are common laboratory findings. More than 50 percent of those suffering from EE also have a history of atopic and allergic disease, particularly food allergies; however, airborne allergens have also been identified as triggers for EE.

EE does not generally respond to antireflux therapy. Diagnosis is difficult, but key signs and symptoms are a lack of a favorable response to acid-blocking therapy and a history of allergic disease. Diagnosis can be confirmed with an esophageal biopsy, identifying eosinophil infiltration. Interventions include the use of steroids and avoidance of trigger foods. A high degree of relapse exists with the condition because of poor dietary compliance.^1-3

The treatment approach commonly used for EE is the suppression of inflammation with steroid therapy with short-term removal of offending foods. However, an attempt to reduce allergic bias and inflammation and treat intestinal permeability is not a part of the standard approach and may explain the high rate of relapse with the condition.

EE patients often present with polysensitization, including allergies not only to multiple foods but also to environmental allergies. Furthermore, an increased incidence of EE onset occurs during allergy season.⁴ In 2013, van Rhijn et al, showed that food sensitizations in EE patients are mainly caused by cross-reactivity to food allergens after primary birch-pollen sensitization, which appeared to be the case with the patient in the current case study.⁵ Studies have been mixed, however, with regard to outcomes with regard to birch desensitization reducing apple cross-reactivity.^6,7

Eosinophilic gastroenteritis (EG) is considered relatively rare and often is misdiagnosed, although it is rising in incidence. The most common complaint of patients is nonspecific abdominal pain. Diagnosis involves a positive identification of eosinophil infiltration of mucosa—which is most common—or of the muscle tissue or serosa of the stomach and/or intestinal tract, with eosinophilia and elevated IgE on laboratory evaluation. EG is also strongly associated with atopic and allergic disease, particularly food allergies.

The treatment approach commonly used for EE or EG is suppression of inflammation with steroid therapy with short-term removal of offending foods. An attempt to reduce allergic bias and inflammation and treat intestinal permeability is not a part of the standard approach and may explain the high rate of relapse with the condition. In theory, if a treatment restores the intestinal mucosa, certain foods can at some point be reintroduced and tolerated. It makes mechanistic sense that successful desensitization to environmental allergens using immunotherapy would also reduce food cross-reactions. Therefore, treatment should take this into account with the goal being to remove offending foods, reduce general inflammation and reduce T_h2 bias.

PATIENT INFO:

• Angie, 16-year-old female
• Chief Complaint: Abdominal pain in the lower right quadrant, ranging in intensity from 2 to 10 on a visual analog scale. The pain was not associated with reflux, a fever, or blood in her stools.
• Previous Diagnosis and Interventions: Eosinophilic esophagitis (EE) had been previously diagnosed, but treatment with diet and a proton pump inhibitor was not successful.

VISIT 1

Angie was 16 years old when she presented to the author’s clinic with constant pain in the right lower quadrant of her abdomen, which ranged from 2 to 10 on a visual analog scale (VAS) for pain, where 0=no pain and 10=worst possible pain. She had had 3 previous episodes, with pain ranging from 8-10 out of 10; none of those episodes were associated with reflux, a fever, or blood in her stools. Angie was unable to attend school because of the pain and was feeling depressed and anxious given the lack of successful treatment.

History:

The first of the episodes had taken place 6 weeks before her first visit to the author’s clinic, had followed a large meal, which was associated with vomiting and diarrhea. The pain woke her from sleep and was 10/10. She was taken to her local hospital’s emergency department, where an abdominal CT scan showed no radiographic evidence of appendicitis but did show some gastric thickening. Laboratory studies showed an elevated white-blood-cell count (18.0) and increased sedimentation. Ibuprofen offered some pain relief, and she was referred to a gastroenterologist. He performed an endoscopy and colonoscopy, diagnosed eosinophilic esophagitis, and prescribed a proton pump inhibitor (PPI). The PPI provided no relief.

Angie also noted that menstrual cramping precipitated a pain attack; however, a gynecological examination was unremarkable, and the gynecologist felt that the pain was likely to be of gastrointestinal (GI) origin.

Angie’s medical history was significant for allergies to fruit; trees, including birch; weeds; and pollen. Two to 3 years prior to her visit to the clinic, she had experienced an anaphylactic reaction while eating a raw apple, but she did not have the same reaction to cooked apples. She then developed a similar reaction to most fruit, including bananas and melons but not berries and grapes. As for other food sensitivities, she reported that wheat and tomato were the primary foods that triggered symptoms, and both of those foods have been associated with EE.⁷ Angie’s family members also suffered from severe allergies and atopic disease.

Review of Systems:

In a review of her systems, Angie reported ongoing constipation and flatulence. Her medications included Zyrtec, ibuprofen, and an Epi-pen. She had no history of excessive antibiotic or steroid use.

Angie was a picky eater, drank an occasional soda, loved pizza, and primarily ate a standard American diet (SAD). She did not drink coffee.

Physical Exam:

Angie experienced pain when the right lower quadrant of her abdomen was palpated, although she had no rebound tenderness or guarding. She also experienced pain during a straight leg raise (SLR) exam for her right leg. She had keratosis pilaris on the posterior aspect of her upper arms, and she had mild macroglossia.

DIAGNOSTIC FOCUS AND ASSESSMENT

Laboratory Tests:

The initial laboratory evaluations focused on GI and immune function, including deficiencies commonly associated with immune dysfunction, such as deficiencies in vitamin D, zinc, and magnesium. The following tests were ordered (results indicated in parentheses):

• Complete blood count (CBC), with a manual differential [5.6 (4.0-10.0)]
• Celiac profile (IgA total, antigliadin antibody, and tissue transglutaminase) [negative]
• Sedimentation rate (ESR) [normal]
• C-reactive protein (CRP) [normal]
• urinary analysis (UA) [normal]
• Complete metabolic panel (CMP) [normal]
• Vitamin D
• RBC essential elements
• Ferritin
• Gastrointestinal microbiota and function stool test (GIfX)
• Food allergy and sensitivity panels for immunoglobulin E (IgE) [positive for wheat, rye, corn, rice, tomato, oat, orange, strawberry, apple, peach, grape, melon]
• Immunoglobulin G4 food panel (IgG4).

The patient did not complete all of the lab work, including IgG4 food sensitivities panel, vitamin D, ferritin, RBC essential elements, and the stool test.

VISIT 2 (6 weeks later)

Diagnoses:

Based on the prior history, examination and testing, the author diagnosed: (1) eosinophilic esophagitis, (2) constipation, (3) atopic disease, (4) food and environmental allergies, (5) premenstrual syndrome, (6) intestinal permeability, and (7) possibly eosinophilic gastroenteritis.

Impressions:

The approach in Angie’s case was straightforward. She needed: (1) to eliminate foods associated with her IgE food allergies, which are known triggers and mediators of eosinophilic esophagitis/gastroenteritis, and (2) to reduce her T_h2 allergic bias and inflammatory response by treating her intestinal permeability and balancing her gastrointestinal microbiota using probiotics, vitamin D, glutamine, zinc carnosine, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and an elimination diet.^9-13

Recommendations:

The author suggested the following regimen for the patient:

1. An elimination diet based on the laboratory results for IgE and known allergens
2. One-half tsp per day of a probiotic powder at 200-billion colony forming units (CFUs), mixed in juice or water
3. A nutraceutical supplement containing glutamine, zinc carnosine, slippery elm, and DGL, as directed, with the ability to mix it with juice or water
4. 2 capsules once per day of EPA/DHA 360/250
5. 2 drops daily of vitamin D, at 2000 IU per drop

VISIT 3 (2 months)

At Angie’s two-month follow-up, she had returned to school; seen improvement in her symptoms when she avoided antigenic foods, especially wheat and tomatoes in pizza; found probiotics to be helpful with pain and constipation; and had no severe pain episodes. She continued, however, to experience sporadic pain, admitting that she was not perfect in following her diet.

Case Discussion

In the current case study, the patient was diagnosed with EE, although she did not present with heartburn, which is the main symptom associated with the condition. Her chief complaint was a pain in the right lower quadrant of her abdomen. Endoscopy demonstrated eosinophilic infiltration of the esophagus but apparently not of the stomach or small intestine. The patient’s abdominal CAT scan identified the gastric thickening that has been associated with eosinophilic gastritis. The patient also had peripheral eosinophilia and a number of IgE food allergies, the identification of which was based on an enzyme-linked immunosorbent assay (ELISA). Although the author did not request a second endoscopy, her suspicion was that the patient may have had eosinophilic infiltration of both the esophagus and stomach. The latter diagnosis is difficult to make, given the patchy distribution of eosinophils in the stomach. EE and EG can present together.¹⁴

The patient had a strong personal and family history of atopic and allergic diseases, including recent-onset anaphylaxis to a number of fruits, including raw apples. She also had significant environmental allergies, including to birch pollen, weeds, and grasses. Thus, her heightened state of allergic inflammation increased her risk for the development of EE or EG. Her fruit allergy and apple anaphylaxis specifically suggested cross-reactivity to an environmental allergen. Up to 70% of those individuals with a birch allergy have a cross-reaction to fruits, most commonly apples and other stone fruits; ie, fruits with a large, hard seed.^7,15,16

The patient had experienced anaphylaxis to raw apples but could tolerate them when they were cooked. That fact shows that an antigenic peptide was no longer a problem for her when it was altered by cooking. Termed conformational epitopes, reaction to heat-labile peptides can be outgrown. Insufficient stomach acid, as is encountered with acid-blocking therapy, can contribute to this type of IgE food allergy, however, and may explain why the incidence of anaphylaxis is on the rise in adults.¹⁷ Tolerance to cooked apples and other cooked, cross-reactive fruits in a birch-allergic individual also suggests that the antigenic proteins are both of the PR-10 family.¹⁸ Other protein families shown to be associated with EE include profilins and lipid transfer proteins.¹⁹

Conclusion

Probably the most important thing to remember when working with teenagers is that the plan must be straightforward, and the teen must be in agreement with the approach. While the author can think of a number of laboratory evaluations and treatment interventions that may have resulted in a fuller resolution, the patient was not willing to adhere to the entire plan. Without the patient’s cooperation, nothing can be accomplished.

In hindsight, the author could have opted for a collection of a blood-spot specimen for IgG4 food testing and dysbiosis markers for urinary organic acids, as the ease of collection may have improved compliance. Additionally, research identifying the presence of IgG4 and other food-immune complexes deposited at the site of esophageal inflammation of adult EE patients suggests a strong pathogenic role.²⁰ That said, with the laboratory data and clinical history that the author did have, a sound and largely successful treatment plan was designed.

Dr. Ruscio’s Commentary

• Great case study illustrating the power of diet, probiotics, and gut nutrient support. Thanks, Dr. Kara
• EoE is something you will likely see in practice commonly described as ‘food gets stuck in my throat’. This is how it feels, but it’s actually immune system irritation causing this feeling, nothing is usually stuck. 
• While open, I would not have issued food allergy testing in this case. You certainly can.  However, it is my opinion it best to save the patient’s money.  It has been fairly well established that standard food elimination can yield impressive results in EoE.  In the research this is known as a 4, 6 or 8 food elimination diets that can be used in a step-up (start with 4 and work up) or a top-down (start with 8 and then reintroduce) approach.     

References

1. Anton Remirez J, Escudero R, Caceres O, Fernandez-Benitez M. Eosinophilic esophagitis. Allergol Immunopathol (Madr). Mar-Apr 2006;34(2):79-81.
2. Katzka DA. Eosinophilic esophagitis. Curr Opin Gastroenterol. Jul 2006;22(4):429-432.
3. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. Aug 26, 2004;351(9):940-941.
4. Wechsler JB, Bryce PJ. Allergic mechanisms in eosinophilic esophagitis. Gastroenterology clinics of North America. Jun 2014;43(2):281-296.
5. van Rhijn BD, van Ree R, Versteeg SA, et al. Birch pollen sensitization with cross-reactivity to food allergens predominates in adults with eosinophilic esophagitis. Nov 2013;68(11):1475-1481.
6. Kinaciyan T, Jahn-Schmid B, Radakovics A, et al. Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d 1. J Allergy Clin Immunol. Apr 2007;119(4):937-943.
7. Bolhaar ST, Tiemessen MM, Zuidmeer L, et al. Efficacy of birch-pollen immunotherapy on cross-reactive food allergy confirmed by skin tests and double-blind food challenges. Clin Exp Allergy. May 2004;34(5):761-769.
8. Roy-Ghanta S, Larosa DF, Katzka DA. Atopic characteristics of adult patients with eosinophilic esophagitis. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. May 2008;6(5):531-535.
9. Perrier C, Corthesy B. Gut permeability and food allergies. Clin Exp Allergy. Jan 2011;41(1):20-28.
10. Vassallo MF, Camargo CA, Jr. Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children. J Allergy Clin Immunol. Aug 2010;126(2):217-222.
11. Wang B, Wu G, Zhou Z, et al. Glutamine and intestinal barrier function. Amino acids. Jun 26, 2014.
12. Miyata J, Arita M. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases. Allergology international: official journal of the Japanese Society of Allergology. Jan 2015;64(1):27-34.
13. Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that estabilises small bowel integrity and stimulates gut repair processes. Feb 2007;56(2):168-175.
14. GI Motility Online: Part 1: Oral Cavity, Pharynx, and Esophagus. 2006; http://www.nature.com/gimo/about/index.html. Accessed 3/10/2012, 2012.
15. Moneret-Vautrin DA, Morisset M. Adult food allergy. Curr Allergy Asthma Rep. Jan 2005;5(1):80-85.
16. Scientific T. ImmunoCAP Allergens. 2011; immunocapinvitrosight.com. Accessed 3/10/2012, 2012.
17. Untersmayr E, Bakos N, Scholl I, et al. Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients. Faseb J. Apr 2005;19(6):656-658.
18. Popescu FD. Cross-reactivity between aeroallergens and food allergens. World journal of methodology. Jun 26 2015;5(2):31-50.
19. Simon D, Straumann A, Dahinden C, Simon HU. Frequent sensitization to Candida albicans and profilins in adult eosinophilic esophagitis. Jul 2013;68(7):945-948.
20. Clayton F, Fang JC, Gleich GJ, et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology. Sep 2014;147(3):602-609.

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