US Pharm. 2010;35(12):44-54.
Over the past 10 to 15 years, the presence of eosinophilia (an abnormally high number of white blood cells) in the esophagus has been noted in patients who were believed to have had gastroesophageal reflux disease (GERD). However, it is now recognized that eosinophilic esophagitis (EE), an inflammatory condition of the esophagus, is a new disease. EE is described by the presence of esophageal and/or upper gastrointestinal (GI) symptoms that are also associated with eosinophilia as defined by ³15 intraepithelial eosinophils per high-power field in one or more esophageal biopsy specimens and no signs of pathologic GERD. No sign of pathologic GERD is witnessed by a normal pH monitor study of the distal esophagus, or by no response to high-dose (up to 2 mg/kg/day) proton pump inhibitor (PPI) therapy (TABLE 1).1
GERD and EE may co-exist, which can complicate the diagnosis, since EE does not respond to acid suppression therapy. EE is seen in both children and adults. Symptoms include heartburn, chest pain, difficulties with feeding, swallowing, pain with swallowing, and food impaction, with the presentation being slightly different in children and adults (TABLE 2).1,2 Other diseases that can co-exist with EE are eosinophilic gastroenteritis, Crohn's disease, connective tissue disease, hypereosinophilic syndrome, infection, and drug hypersensitivity response.
The review and consensus recommendations published in 2007 by the First International Gastrointestinal Eosinophil Research Symposium (FIGERS) Subcommittees focused on those cases in which EE was the clear primary diagnosis. The patient ages ranged from 2 months to 89 years.1 It was reported that males are more commonly affected in both children (66%) and adults (76%).1 Although EE has been reported worldwide and in a variety of ethnic groups, it is unclear whether one group has a higher prevalence over another. It is now noted that there is a hereditary association,3 and preliminary studies have shown co-occurrence of EE in patients with celiac disease and erythema nodosum.4,5 To date, Barrett's esophagus, esophageal adenocarcinoma, and cardiac-type metaplasia have not been associated with EE, nor has EE been associated with ulceration or destruction of the mucosa. The disease does not appear to impact life expectancy. However, narrowing and strictures of the esophagus can occur, which could result in food impaction, the major complication with EE.2,6,7 EE is generally chronic, with relapsing or persistent symptoms.
Possible Etiology of EE
Allergic responses have been strongly suggested as a cause of EE. This has been evidenced with results showing that 50% to 80% of patients with EE have co-existing conditions such as atopic dermatitis, allergic rhinitis, asthma, and eczema.1,8 The patients with EE also show allergic antigen sensitization from skin testing or antigen-specific immunoglobulin E (IgE) presentation from plasma testing. Other evidence shows that EE is associated with the Th2 cytokines seen in patients with allergies. Interleukin (IL)-4, IL-5, IL-13, and mast cells are found in the esophagus of patients with EE.9-11 Seasonal differences in symptoms have been reported, and case reports have shown seasonal changes in eosinophilic levels in the proximal esophagus.12,13 The high rate of eczema and other atopic allergies requires that the patient be evaluated by an allergist who is familiar with EE. Inhaled allergens may also play a role in EE, and the patient should thus be evaluated for this as a contributing factor.1,13,14
Currently, there are no FDA-approved medications for the treatment of EE. There are, however, several clinical trials under way, which could result in FDA approvals. These medications are reslizumab, anti-IL-5, mepolizumab, and viscous budesonide.15 See TABLE 3 for medications that have been used to treat EE and those that are currently in clinical trials.1,15-17
In patients with food allergies, most individuals improve on allergen-free diets. If patients do not respond to food elimination of specific antigens, amino acid-based formula treatment is the current gold standard for evaluating whether food antigens are the culprit of EE.1 This therapy has been very effective in children, with a success rate of 92% to 98%.1,18,19 Resolution of symptoms occurred within 7 to 10 days, with histologic improvement seen within 4 to 5 weeks. Amino acid-based formulas generally have an unpleasant taste, and often the feedings are given via nasogastric or gastrostomy tubes.18,19 A slow introduction of certain foods can be started when symptoms resolve and histology improves. The six most common allergic foods are dairy, eggs, wheat, soy, peanuts, and fish or shellfish.20
Inhaled allergens may also contribute to EE. A small study (n = 8) suggests that montelukast 20 to 40 mg/day for 14 months was beneficial in controlling symptoms in 7 of the 8 patients. However, 6 of the 8 patients had a reoccurrence of symptoms within 6 weeks of discontinuation.16
Systemic corticosteroid use can resolve acute EE inflammation. Unfortunately, systemic use of corticosteroids can result in significant side effects. Systemic corticosteroids might be considered in the case of hospitalization due to dysphagia and swallowing problems that result in dehydration or weight loss.1 The disease generally recurs after the discontinuation of systemic or topical corticosteroids, and the use of topical corticosteroids for maintenance treatment has not been studied. Studies have shown a recurrence in symptoms in 3 to 18 months after discontinuation of topical corticosteroid therapy in 17 of 37 patients.1,14,21-23
The use of swallowed topical steroids given by a metered-dose inhaler (MDI) or in a viscous solution can provide the desired effect with fewer systemic side effects. The medication is administered directly to the esophageal mucosa, and the dose is significantly lower than a systemic corticosteroid dose. However, local fungal infections have been reported with the topical use of corticosteroids.1
The expert consensus group (FIGERS) recommends a starting dose of fluticasone MDI without a spacer, to be given two to four times per day for a total daily dose of 440 to 880 mcg/day in children and 880 to 1,760 mcg/day for adolescents and adults.1 The patient should be counseled to insert the MDI into the mouth, spray with the lips sealed around the MDI, then swallow the powder without rinsing. The patient should not eat or drink for 30 minutes. The recommended continuation of the regimen is for 6 to 8 weeks.1 FIGERS also recommends that the patient be followed with regular clinic visits to improve long-term recognition of complications due to EE, since data are currently lacking in this arena.1
An alternative regimen that may be used in children is oral viscous budesonide (OVB). The dose has been 1 mg/day OVB for children under 10 years of age and 2 mg/day OVB for children greater than 10 years of age. Each 0.5 mg Pulmicort Respule (0.5 mg budesonide/2 mL) was mixed with 5 g (5 packets) of sucralose (Splenda) for a volume of 8 to 12 mL.17 Patients were not allowed to ingest solid or liquid food for 30 minutes after the dose was given. Results were reported in terms of symptoms and histologic improvement, which did not necessarily correlate on a per-patient basis.
PPIs are not effective in treating EE; however, they may be used in patients with co-existing GERD and can be useful in the diagnostic process. There is also some thought that patients with EE may have greater sensitivity to acid, and thus PPI co-treatment may in part diminish some symptoms.1
Esophageal dilation may be needed in patients with food impactions caused by fixed strictures as a result of esophageal narrowing. Esophageal dilation may be done to treat the stricture in cases of dysphagia or esophageal impaction. It is recommended that, if possible, an endoscopy with biopsy be done prior to an esophageal dilation, followed by medical or dietary treatment.1 Complications from dilation can result in esophageal tears or lacerations. Currently, there are no data to predict which patients will be at increased risk for complications. However, patients who have already developed esophageal rings, strictures, or narrowing are considered to be at increased risk for complications.1
EE is a chronic disorder, recognized as a new disease in the past 10 to 15 years. Previously, it may have been misdiagnosed as GERD. Though GERD can co-exist with EE and both have similar symptoms, EE does not respond to high dose (2 mg/kg/day) PPI therapy.1 The disease is described as a clinicopathologic disorder showing significant eosinophils in the esophagus along with clinical symptoms (TABLES 1 and 2).1,2 Allergic responses have been strongly suggested as a cause of EE, and many patients respond to an allergen-free diet. Other non-FDA approved treatments include short-term use of systemic and topical corticosteroids. Montelukast has been used in a small number of EE patients with inhaled allergens.16 Reslizumab, anti-IL-5, mepolizumab, and viscous budesonide are currently in clinical trials for the treatment of EE.15 Finally, esophageal dilation may be required in patients who develop a food impaction as a result of esophageal narrowing.2,6,7
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6. 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. 2003;125:1660-1669.
7. Vasilopoulos S, Murphy P, Auerbach A, et al. The small-caliber esophagus: an unappreciated cause of dysphagia for solids in patients with eosinophilic esophagitis. Gastrointest Endosc. 2002;55:99-106.
8. Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005;3:1198-1206.
9. Straumann A, Kristl J, Conus S, et al. Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract. Inflamm Bowel Dis. 2005;11:720-726.
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18. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109:1503-1512.
19. Markowitz JE, Spergel JM, Ruchelli E, et al. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003;98:777-782.
20. Kagalwalla AF, Sentongo TA, Ritz S, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2006;4:1097-1102.
21. Remedios M, Campbell C, Jones DM, et al. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc. 2006;63:3-12.
22. Arora AS, Perrault J, Smyrk TC. Topical corticosteroid treatment of dysphagia due to eosinophilic esophagitis in adults. Mayo Clin Proc. 2003;78:830-835.
23. Teitelbaum J, Fox V, Twarog F, et al. Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate. Gastroenterology. 2002;122:1216-1225.
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