A Trial of Montelukast for Maintenance Therapy of Eosinophilic Esophagitis in Children

Eosinophilic esophagitis (EE) is a disease diagnosed using both clinical and pathologic results. Presentation varies among age groups with younger children suffering from vomiting, failure to thrive, or food refusal and adolescents suffering from dysphagia, odynophagia, or food impaction. It is more prevalent in males. EE is suggested when an upper endoscopy yields eosinophils greater than 15 per high power field (hpf) in both the middle and distal esophagus. Therapy for EE depends upon age and ability to be compliant. Three main categories of treatment are options for families, including the use of medicines, removal of the most allergenic foods, and the use of an elemental diet (formula) (1-2). Treatment can be different within the two main phases of therapy for EE, initial and maintenance therapy. Initial therapy occurs when the patient is first diagnosed and has eosinophils over 15 per hpf and can last for years if the patient does not respond to treatment. Maintenance therapy only occurs after the patient has responded to treatment with a reduction of his/her eosinophil counts below 5 per hpf. Typically, medicinal therapy with steroids (either oral prednisone or swallowed fluticasone) improves eosinophil counts but has a large side effect profile suggesting that steroids are not ideal for maintenance therapy. Dietary therapies are effective in both treatment phases but many patients find it difficult to remain compliant with food restriction for a prolonged length of time. Unfortunately, EE recurs upon withdrawal of oral therapy (3-7).

EE is believed to be an imbalance of the TH1/TH2 immune system and is more prevalent in patients with asthma and allergies (8-9). Some EE centers have started treating patients with targeted elimination diets and elemental diets and are having good success. Unfortunately, most families and in particular teenagers, are noncompliant with the dietary therapies. Formula for the elemental diet is not covered by most insurance and is very costly as well. Therefore, finding a drug that would keep a patient with EE in maintenance therapy and reduce both the long term consequences of steroids and potential for esophageal strictures would be ideal.

Many adults with EE present with dysphagia or food impactions and subsequently are found to have an esophageal stricture requiring multiple esophageal dilatations for treatment. Esophageal subepithelial fibrosis has been found in the adult literature in patients with EE. Chehade et al evaluated distal esophageal biopsy specimens in children with EE, eosinophilic gastroenteritis, gastroesophageal reflux disease, and controls for the presence of increased collagen deposition indicative of fibrosis. They found that fibrosis was present in 57% of patients with EE, of which 42% had symptoms of dysphagia and 80% had food impactions. The degree of fibrosis was not associated with eosinophil count but was associated with eosinophilic degranulation (10). Upon degranulation, eosinophils release major basic protein (MBP) and transforming growth factor (TGF-β). MBP changes smooth muscle contractility by blocking M2 muscarinic receptors therefore changing the motility of the esophagus. TGF-β is believed to cause an increase in the production of the extracellular matrix and smooth muscle hypertrophy and hyperplasia leading to esophageal thickening and fibrosis. TGF-β is a key growth factor that increases fibroblasts and subsequent fibrosis in the lung as well. Corticosteroids have been shown to reverse esophageal remodeling, but no large clinical trials have evaluated the treatment of esophageal fibrosis related to EE. To quote Aceves and Ackerman: "[f]ibrosis likely contributes to multiple clinical aspects of EE, including dysphagia symptoms, disease chronicity, and stricture formation." Fibrosis is measured in esophageal tissue by evaluating the amount of collagen that is deposited. Trichrome stains specifically for collagen (11).

Patients with EE have an abundance of inappropriate cells within the esophagus, including eosinophils and mast cells. A normal esophagus is devoid of eosinophils. Mast cells likely have an active role in the development of eosinophilic esophagitis; unfortunately the precise mechanism is unknown. Mast cells are found in the majority of vascularized tissues and are abundant in the gastrointestinal tract. They are located in the submucosa and lamina propria. Within the esophagus specifically, they are found in the mucosa and submucosa with rare expansion into muscularis layer. With severe eosinophilic inflammation, mast cells can be seen in the muscularis layer. Biopsies from patients with EE have demonstrated marked increase in mast cells in the mucosal layer of the esophagus. There has been correlation of mast cell number with degree of eosinophilia. Mast cells within the GI tract contain tryptase as well as other preformed mediators and can synthesize mediators that promote inflammation. Tryptase may activate eosinophils and therefore induce eosinophilic degranulation and cytokine secretion. Mast cells release chemokines and leukotrienes specific to eosinophil recruitment. Ultimately mast cell mediators worsen edema, create more inflammation, induce smooth muscle contractility and potentially affect tissue fibrosis. Therefore, active mast cells are proinflammatory, modify esophageal function, and encourage the development of strictures (12). Mast cells may be a key component in the propagation of the inflammatory state as well as of significant importance in the development of fibrosis. Evaluating tryptase levels could lead to a better understanding of the inflammatory process and ultimate problem of fibrosis.

Eosinophils and mast cells contain leukotrienes in abundance. Cysteinyl leukotrienes are inflammatory mediators derived from arachidonic acid. They are important in eosinophil attraction and migration, smooth muscle bronchoconstriction, vascular permeability, and mucus hypersecretion (13). Montelukast is a leukotriene receptor antagonist and blocks specifically the leukotriene D4 (LTD4) receptor. Attwood et al treated 8 patients with EE with Montelukast for which 6 reported complete subjective improvement and 5 remained asymptomatic on a maintenance regimen. Treatment with Montelukast did not change the density of eosinophils present in the esophagus however (14). Montelukast has been used in mouse models to decrease fibrosis occurring in both the liver and the lung. El-Swefy and Hassanen performed a randomized study in which they subjected mice to one of 4 groups, no bile duct ligation plus saline, no bile duct ligation plus montelukast, bile duct ligation plus montelukast and bile duct ligation plus saline. Bile duct ligation induced inflammation leading to cirrhosis and fibrosis. They found that bile duct ligation increased the amount of TGF-β, which correlated with the amount of fibrosis found. Of more import is that montelukast significantly reduced the amount of fibrosis as well as decreased the amount of TGF-β (15). Izumo, Kondo, and Nagai evaluated the use of montelukast in the prevention of pulmonary fibrosis after exposure to bleomycin. They found that mice given montelukast had significantly lower levels of TGF-β and fibrosis of the lung (16).