Mulder, Daniel J.*; Hookey, Lawrence C.†; Hurlbut, David J.‡; Justinich, Christopher J.§
*Department of Anatomy and Cell Biology
†Department of Medicine, Gastroenterology Division
‡Department of Pathology and Molecular Medicine
§Departments of Anatomy and Cell Biology, Physiology, Pediatrics, and Medicine, Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada.
Address correspondence and reprint requests to Dr C. Justinich, Queen's University, Kingston, ON K7L 3N6, Canada (e-mail: email@example.com).
Received 4 October, 2010
Accepted 2 February, 2011
The study was supported by Physicians’ Services Incorporated Foundation Grant PAED-237-09, Kingston General Hospital, and the Queen's University Gastrointestinal Diseases Research Unit.
The authors report no conflicts of interest.
Eosinophilic esophagitis (EoE) is an emerging disease defined by symptoms, endoscopic findings, and ≥15 intraepithelial eosinophils per high-power field on esophageal biopsy (1). The cause of EoE is unknown; it is thought to be associated with the T helper lymphocyte (TH) type 2 response (2). Treatment strategies include restricting food allergens and topical corticosteroids to dampen the immune response (3). Withdrawal of therapy frequently leads to relapse of EoE, and sustained resolution of the disease is rare (4). A study of the natural history of EoE in 30 patients for an average of 7.2 years found that EoE persisted in all of the patients (5).
Crohn disease (CD), a chronic inflammatory bowel disease, is associated with a TH1 and TH17 cytokine profile (6). CD may also affect the esophagus. A combination of genetic, environmental, and immune factors influence T helper lymphocyte differentiation and their unique cytokine expression profiles (7). The interplay between TH1 and TH2 immunity in the gastrointestinal tract in humans is complex and poorly understood; no distinct boundary exists between these 2 types of inflammatory response. Coexisting TH1 and TH2 diseases have been shown to have reciprocal or additive effects (8). The following case provides insight into the disease pathophysiology by demonstrating reciprocal influences of CD (TH1) and EoE (TH2 disease).
An 11-year-old boy presented with dysphagia of 2 years’ duration. He denied symptoms of reflux disease. He had a history of asthma, allergic rhinitis, and multiple food and environmental allergies. Skin prick testing was positive for peanut, soybean, shrimp, walnut, celery, tomato, cat, ragweed, and tree pollen. The patient was avoiding all skin prick–positive foods. Asthma was managed with montelukast (5 mg daily, Singulair, Merck Frosst, Kirkland, Canada), a β2-receptor agonist, and fluticasone propionate (250 μg twice daily, Flovent, GlaxoSmithKline, Mississauga, Canada).
Esophagogastroduodenoscopy revealed gross endoscopic features of EoE (Fig. 1A). Distal and mid-esophageal biopsies had >40 intraepithelial eosinophils/high-power field, consistent with EoE. The patient had peripheral blood eosinophilia (1.2 × 109 cells/L) and elevated total immunoglobulin E (IgE) 1157 (normal 300 μg/L); IgE radioallergosorbent test (RAST) for peanut was 7.12 kU/L. Montelukast was increased to 10 mg daily.
For approximately 2 years the patient was relatively asymptomatic without any change in diet or medication. The patient then presented with a food impaction after eating roast beef. At endoscopy, diffuse esophagitis with white exudate and friability (Fig. 1B) was seen. Biopsies showed persistent EoE with up to 37 intraepithelial eosinophils/high-power field (Fig. 1C). Immunohistochemistry for mast cell tryptase (DakoCytomation, Mississauga, Canada) was performed using an automated protocol (BenchMark XT; Ventana Medical Systems, Tucson, AZ) and revealed an average of 31 intraepithelial mast cells/high-power field (over 10 HPFs, Fig. 1D). No change in therapy was recommended. The patient was not taking proton pump inhibitors.
One year after the food impaction (3 years from the initial diagnosis of EoE), the patient experienced acute abdominal pain and diarrhea, leading to an appendectomy. At that time, his symptoms of dysphagia had improved and glucocorticoid inhalers were no longer being used. The appendix revealed acute appendicitis with transmural granulomatous inflammation (Fig. 2A). He was anemic, with a high erythrocyte sedimentation rate. The patient underwent endoscopic studies. The patient was taking no medications (for CD or otherwise) at this time. Endoscopy revealed a normal esophagus, severe gastritis and duodenitis with aphthous ulcers, ileitis, and cecal disease, all with chronic inflammation and granulomas diagnostic of CD. Esophageal biopsies showed 2 eosinophils/high-power field with minimal basal cell hyperplasia (Fig. 2B). Immunostaining for mast cell tryptase demonstrated, on average, only 4 mast cells per high-power field (Fig. 2C). Treatment then began with prednisone on a 16-week tapering schedule, 5-ASA (1 g twice daily, Salofalk, Axcan Pharma, Mont-Sainte-Hillaire, Canada), and the patient was taken off montelukast. After 1 year, the patient's CD had progressed, with severe colitis of the descending and sigmoid colon. He now had no asthma symptoms, no dysphagia, and no histologic evidence of esophagitis. Absolute peripheral eosinophil count was now within normal limits (0.1 × 109 cells/L), total serum IgE was decreased to 383 (normal 0–129 IU/mL), and peanut-specific IgE RAST was decreased to 3.13 kU/L.
This report describes a pediatric patient with complete resolution of EoE, a predominantly TH2 disease, after development of CD, a predominantly TH1 disease. This suggests that skewing of the immune response toward an opposing T helper phenotype can significantly alter these disease states. We cannot rule out the possibility that EoE resolved spontaneously in this patient, although it is worth noting that EoE resolved when CD was diagnosed and the CD appeared to involve the esophagus. In addition, not only was EoE resolved but also the patient's asthma, peanut allergy, and IgE levels improved with the development of CD.
Both EoE and CD are idiopathic diseases in which a dysregulated mucosal immune response causes inflammation. Evidence from human and animal studies point to CD being a TH1-type disease with a TH17 component (9). The observed cytokine profile of EoE is compatible with that of a TH2 disease (2). Our case provides compelling evidence that development of CD coincided with resolution of both EoE and other atopic diseases. Improvement in symptoms and diagnostic markers has been sustained for more than 2 years. Seasonal variation is likely not a factor in this case because the patient was diagnosed with CD during the same calendar month as the previous endoscopy showing EoE. High-dose proton pump inhibitors may also alter EoE (10), but our patient never received proton pump inhibitor therapy.
We postulate that the TH2 environment of immune cells and cytokines in this atopic adolescent was reversed with development of a dominant TH1 disease. One published report describes a similar case of an atopic woman who had a history of severe CD (11). Three years later, she was diagnosed as having EoE, although her CD was described as mildly active. This report supports the possibility that TH2 skewing occurred, whereas CD was quiescent. The case described in this report provides evidence that the predominance of T helper lymphocyte response may influence EoE when more than 1 disease is present.
1. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology
2. Gupta SK, Fitzgerald JF, Kondratyuk T, et al. Cytokine expression in normal and inflamed esophageal mucosa: a study into the pathogenesis of allergic eosinophilic esophagitis. J Pediatr Gastroenterol Nutr
3. Bohm M, Richter JE. Treatment of eosinophilic esophagitis: overview, current limitations, and future direction. Am J Gastroenterol
4. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol
5. Straumann A, Spichtin HP, Grize L, et al. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology
6. MacDonald TT, Monteleone G. Overview of role of the immune system in the pathogenesis of inflammatory bowel disease. Adv Exp Med Biol
7. Reiner SL. Development in motion: helper T cells at work. Cell
8. Tian J, Olcott AP, Hanssen LR, et al. Infectious Th1 and Th2 autoimmunity in diabetes-prone mice. Immunol Rev
9. Brand S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut
10. Molina-Infante J, Ferrando-Lamana L, Ripoll C, et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin Gastroenterol Hepatol
11. Suttor VP, Chow C, Turner I. Eosinophilic esophagitis with Crohn's disease: a new association or overlapping immune-mediated enteropathy? Am J Gastroenterol