Pediatr Drugs DOI 10.1007/s40272-015-0126-4

REVIEW ARTICLE

Eosinophilic Esophagitis in Children Prerna Trivedy1 • Jonathan E. Teitelbaum2

Ó Springer International Publishing Switzerland 2015

Abstract Eosinophilic esophagitis (EoE) is a relatively common chronic immune-mediated disease of the esophagus characterized clinically by symptoms of esophageal dysfunction that vary by age. Histologically, EoE results in marked esophageal eosinophilia despite treatment with high-dose proton pump inhibition. The cornerstone of treatment is dietary restriction and/or pharmacologic therapy, mainly with topical steroids. This review briefly describes dietary therapy, but focuses on the various medical options in the treatment of EoE, with an emphasis on steroid-based therapy. Numerous landmark studies are reviewed describing the symptomatic and histologic endpoints as well as safety data. The literature strongly supports the use of topical steroid therapy as a means of significantly decreasing eosinophilic mucosal disease. Specifically, high-dose fluticasone propionate appears to be very effective, and has been shown to result in the resolution of mucosal eosinophilia in a large percentage of treated patients. Long-term studies over many years will need to determine whether mucosal healing will change the natural history of this stricture-causing disease. In addition to topical therapy, various other drug-based therapies are reported, including newer immune-based monoclonal antibodies.

& Jonathan E. Teitelbaum [email protected] 1

The Unterberg Children’s Hospital at Monmouth Medical Center, Long Branch, NJ, USA

2

Pediatric Gastroenterology, Department of Pediatrics, The Unterberg Children’s Hospital at Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, USA

Key Points Dietary management of eosinophilic esophagitis (EoE) is successful, but has a significant impact on quality of life, particularly if multiple food allergies are identified, thus prompting the use of pharmacologic therapy as sole treatment or in combination with dietary limitation. Topical steroid therapy in the form of swallowed fluticasone or budesonide is highly effective at decreasing tissue eosinophilia; however, long-term safety and efficacy data are lacking. Multiple immune-modulating drugs have been studied in EoE with variable success, mostly in small series, and thus require further study.

1 Introduction Eosinophilic esophagitis (EoE) is an increasingly recognized chronic immune-mediated inflammatory disorder. Clinically, it is associated with esophageal dysfunction and, historically, it is characterized by eosinophil-predominant infiltration [1–4]. Without treatment, it can result in significant morbidity, including esophageal stenosis and fibrosis, and can severely affect quality of life. The prevalence is approximately 52 per 100,000 individuals [5]. It is more commonly seen in males and in patients with atopic diseases [6]. Clinical manifestations of EoE in children are nonspecific and vary by age; hence, diagnosis based on symptoms alone is not feasible. Infants and toddlers often

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present with feeding difficulties, which can result in failure to thrive, whereas school-aged children are more likely to present with vomiting or abdominal pain. Gastroesophageal reflux disease (GERD)-like symptoms, including chest pain and food impaction, are common presentations for adolescents [3, 7]. The most recent definition of the disease according to published guidelines includes the histological presence of C15 eosinophils per high power field (eos/hpf) in at least one endoscopic esophageal mucosal biopsy (peak value) taken at upper gastrointestinal endoscopy, and/or the presence of other microscopic features of eosinophilic inflammation such as eosinophilic micro-abscesses, superficial layering, or extracellular eosinophil granules. These findings must be present in an individual in whom other causes of mucosal eosinophilia, such as GERD, have been excluded [1, 3]. To maximize diagnostic sensitivity, it is recommended that at least two to four biopsies should be taken from both the proximal and distal esophagus, regardless of the endoscopic appearance of the esophagus [3]. Genomic research has led to the identification of single nucleotide polymorphisms in the gene encoding thymic stromal lymphopoietin (TSLP), and subsequently in the gene encoding its receptor, as disease susceptibility markers in some patients with EoE [8]. EoE is considered a chronic disease, and many patients experience periods of remission and exacerbation. These patients require therapy for an indefinite period of time.

The goal of the treatment should ideally be both the resolution of symptoms and the normalization of the macroscopic and microscopic abnormalities. However, patient-reported outcome measures are difficult to assess in children, particularly in infants and young or learningdisabled children. Hence, at present, histology with absolute eosinophil counts remains the best objective measure of the disease activity [1]. Various treatment modalities are presently available for EoE, including dietary therapy, pharmaceutical therapy, and endoscopic dilatation (Table 1). Each of these approaches has limitations and side effects. Despite a temporary resolution of symptoms, most patients relapse upon discontinuation of treatment. Acutely symptomatic patients with severe esophageal narrowing who fail to respond to medical management may benefit from esophageal dilatation. However, it should be noted that, in the absence of severe esophageal stenosis, it is mandatory to try medical or dietary therapy before performing esophageal dilatation. To accomplish this review, the authors have focused on English-language, peer-reviewed literature for the pharmacologic treatment of EoE. Published guidelines were used to form a framework for the paper. Various other manuscripts were identified based on the author’s personal knowledge/prior review of the literature, and well as by searching in PubMed for specific pharmacologic treatments.

Table 1 Treatment modalities for eosinophilic esophagitis Dietary therapy Amino acid-based formula Empirical elimination diet: six-fooda or four-foodb elimination diet Targeted elimination diet Pharmacological treatment Corticosteroids: mainstay of treatment. Either used alone or in combination with dietary management Topical steroid Swallowed FP: puffed and swallowed through MDI. Dose: 88–440 lg 2–4 times/day OVB: dose for age \10 years 1 mg daily, dose for age [10 years 2 mg daily Systemic corticosteroids: used for emergency cases in pts requiring rapid improvement in symptoms (severe dysphagia/hospitalization/ weight loss). Prednisone 1–2 mg/kg Ciclesonide: nonhalogenated parent compound of des-CIC. Further studies needed Nasal corticosteroid: may be useful in children with seasonal exacerbation of EoE Other treatment modalities Cromolyn sodium, montelukast, immunosuppressive agents (azathioprine, 6-MP) are not recommended for treatment of EoE Monoclonal antibodies (mepolizumab, reslizumab, omalizumab), anti-IL-13, anti-TNFa, anti-eotaxin, CRTH2 antagonist. Further studies are needed to evaluate safety and efficacy Esophageal dilatation: for acutely symptomatic patients with severe esophageal narrowing who do not respond to dietary/medical therapy CHRH2 chemo-attractant receptor-homologous molecule on Th2 cells, des-CIC desisobutyryl-ciclesonide, EoE eosinophilic esophagitis, FP fluticasone propionate, IL interleukin, MDI metered-dose inhaler, OVB oral viscous budesonide, TNF tumor necrosis factor, 6-MP 6-mercaptopurine a b

Dairy, soy, eggs, wheat, peanuts, fish/shellfish Dairy, wheat, eggs, legumes

Eosinophilic Esophagitis in Children

2 Proton Pump Inhibitor (PPI)-Responsive Eosinophilic Esophagitis (EoE) Proton pump inhibitor (PPI)-responsive EoE (PPI-REE) is the term used to describe patients with esophageal eosinophilia on biopsy who respond symptomatically and histologically to a course of PPI therapy. It was first observed in a series of pediatric patients. It is currently unclear whether PPI-REE is a subtype of GERD, an EoE phenotype, or an independent condition. In a prospective study, Dellon et al. [9] enrolled adult patients undergoing outpatient upper endoscopy. If they had C15 eos/hpf, they were treated with twice-daily PPIs for 8 weeks, and endoscopy was repeated. Those who had \15 eos/hpf on repeat endoscopy were diagnosed as PPI-REE. Of the patients with dysphagia, 38 % had esophageal eosinophilia. After the PPI trial, 23 % were confirmed to have EoE, whereas 14 % had PPI-REE [9]. While this entity may be related to EoE, it is included only for completeness. A broader discussion of this entity falls outside the focus of this review.

3 Dietary Management of EoE Dietary therapy was one of the earliest treatment modalities in children with EoE [6, 10]. Reports have shown that up to 90 % of children with EoE may have food or environmental allergy [2, 3]. Because food antigens trigger eosinophilic inflammation, the dietary approach of identification and exclusion of causative food antigens helps to induce and maintain both clinical and histologic remission [11]. Food antigens triggering the disease vary from patient to patient. Therefore, the optimal dietary intervention needs to be individualized and requires dietetic support to ensure nutritional adequacy, whereas ongoing difficulties in adhering to a complex exclusion diet may require additional psychosocial support [12]. The available initial dietary approaches include the following. 3.1 Amino Acid-Based Formula The amino acid-based formula approach involves complete removal of food allergens from the diet and exclusive enteral nutrition with an age-appropriate amino acid-based formula [11, 13]. It was the first dietary intervention assessed for efficacy of reducing esophageal eosinophilia and improving symptoms [11]. It is better accepted and tolerated in infants than in older children. In older patients, its use is limited by several disadvantages, including poor palatability of such a severe food restriction, frequent need for nasogastric tube or gastrostomy placement, and high cost. This approach is used

mostly in children with multiple food allergies, failure to thrive, and severe disease in which a strict diet with multiple eliminations is ineffective or impossible. 3.2 Empirical Elimination Diet The elimination of six common food group antigens from the diet (dairy, soy, eggs, wheat, peanuts, and fish/shellfish) for at least 6 weeks was reported in an observational study to achieve clinical and histological remission in 49 of the 67 treated adults (73.1 %) with EoE [14]. Another study by Molina-Infante et al. [15] looked at the efficacy of a fourfood elimination diet in achieving remission in EoE. Of the 52 adult patients, 28 (54 %) achieved clinicopathological remission on the four-food elimination diet. 3.3 Targeted Elimination Diet In the targeted elimination diet, food is eliminated based on the suggestive history of food triggers and results of allergy testing such as serum immunoglobulin E (IgE) antibody, positive skin prick test or atopy patch test [10]. Elimination diets based only on radioallergosorbent test results (i.e., RAST IgE test) or skin prick test results have failed to show clinical and histologic remission in children [16]. The failure of a targeted elimination diet to induce remission of EoE reported in some studies has been attributed to the inability of allergy tests to accurately detect causal food antigens. A cow’s milk-elimination diet based on a combination of skin prick test and atopy patch test was reported to achieve resolution of both symptoms and histological abnormalities in 77 % of children with EoE [6]. Following remission, food can gradually be reintroduced as tolerated in a stepwise manner, with care taken to introduce the most allergenic food (like peanut, egg, milk) last. Lucendo et al. [17], in a prospective study, demonstrated that after successful six-food elimination diet, 88 % of the patients in the study (aged 17–56 years) achieved and maintained remission on cow’s milk-based extensively hydrolyzed formula. The efficacy of the three dietary approaches was addressed in a recent systematic review and meta-analysis. The authors concluded that elemental diets and six-food elimination diets were the most effective, achieving \15 eos/hpf in 90.8 and 72.1 % of patients, respectively [18]. Dietary treatment for 4–12 weeks to induce remission is a therapeutic option in all children with confirmed diagnosis of EoE. However, exclusion of important food elements from a growing child’s diet over their lifetime to maintain remission can have nutritional consequences, including impaired growth, rickets, and vitamin deficiencies. Counseling by a dietitian experienced in pediatric nutrition is highly recommended. After histologic remission is

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documented by endoscopy, one can maintain the diet if it is not too restrictive (e.g., if only a few items were eliminated). If the initial diet elimination included numerous antigens, as in the six-food elimination diet or amino acid-based formula diet, foods can then be gradually reintroduced into the diet. Foods that result in return of symptoms will likely need to be permanently eliminated from the diet, particularly if there was corresponding return of esophageal eosinophilia. Most experts agree that repeat examination of the esophagus is warranted after two to three foods are successfully introduced, to ensure maintenance of histologic remission since correlations between the absence of symptoms and normal histology are unreliable. Repeat endoscopy after introducing a limited number of new foods allows easier identification of those food antigens that are responsible for tissue eosinophilia. It is common for affected patients to have multiple food allergies. If the resulting diet is too restrictive, a combination of diet elimination and pharmacologic therapy can be used.

4 Role of PPIs PPIs might be useful as a co-therapy in patients with diagnosed EoE, since the already inflamed esophagus may be predisposed to injury and more sensitive to physiologic acid exposure [19]. EoE and GERD are not mutually exclusive and can exacerbate each other. In symptomatic children with histological findings of esophageal eosinophilia, a trial of PPIs (1–2 mg/kg/day) is recommended by current guidelines for 8 weeks. This helps eliminate PPI-REE as well as GERD from the differential diagnosis of causes of esophageal eosinophilia. A second esophagogastroduodenoscopy (EGD) should be performed under PPI therapy in all children, even if symptoms resolve [1]. Zhang et al. [20] showed that omeprazole, a PPI, inhibits interleukin (IL)-4-stimulated eotaxin-3 expression in EoE esophageal cells and blocks STAT6 binding to the promoter [20]. Moawad et al. [21], in a randomized controlled trial of 42 adult patients with esophageal eosinophilia, randomly assigned patients to esomeprazole or aerosolized swallowed fluticasone for 8 weeks. Follow-up included upper gastrointestinal endoscopy with biopsy. In patients without GERD, no significant difference was found in the resolution of esophageal eosinophilia between fluticasone and esomeprazole (24 vs. 18 %, p = 1.00). In patients with established GERD based on positive pH probes, resolution of esophageal eosinophilia was noted in 0 % (0/4) of the fluticasone group compared with 100 % (4/4) of the esomeprazole group [21]. This study emphasizes that some patients with esophageal eosinophilia have GERD that

responds to PPIs. Interestingly, patients without GERD based on pH probe can have resolution of eosinophilia with PPI alone. This latter group of PPI-REE either has GERD or benefits from the immune-mediator properties of PPIs. However, Dohil et al. [22], in a prospective randomized controlled trial of children with EoE, demonstrated that lansoprazole alone was unsuccessful in achieving histological response or symptom improvement. This discrepancy can be attributed to a number of factors, including differences in children versus adults, esomeprazole versus lansoprazole, or the patient populations, such that the Dohil et al. [22] group contained only EoE patients and no PPIREE patients. PPIs at present are used only as an adjunct to steroid treatment and dietary modification in EoE. Whether or not to discontinue the PPI once a diagnosis of EoE is made remains a relevant but poorly studied question.

5 Pharmacologic Management Most pharmacologic treatment modalities focus on symptom resolution and healing of esophageal mucosa. The exact endpoint of treatment (e.g., symptom relief, mucosal improvement, or complete healing) has not been clearly defined. In the pediatric population, maintenance of growth and development is an integral part of successful treatment. 5.1 Corticosteroids Corticosteroids have been shown to be effective in resolving eosinophilic inflammation in various allergic diseases like eczema and asthma. The proposed mechanism of action of corticosteroids in EoE includes induction of apoptosis, down-regulation of chemotactic factors, and inhibition of pro-inflammatory mediators [2]. In EoE, steroids have shown good efficacy in reducing eosinophilic load, reducing eosinophilic inflammation and reversing fibrosis [23]. Steroid therapy represents the cornerstone of pharmacologic treatment of EoE. However, discontinuation is frequently associated with recurrence of symptoms. Long-term systemic steroids can have debilitating effects, especially for growing children, including growth impairment, adrenal suppression, osteopenia, and cataracts. Due to the potential toxicity of systemic steroids, off-label topical preparations of corticosteroids are being used as first-line medical therapy. There are some theoretical concerns that topical therapy may only treat the mucosal layer of the esophagus and as such may not successfully prevent long-term fibrosis and stricture formation due to ongoing eosinophil damage within the submucosa. Various steroid formulations and delivery methods have been studied. Many of the defining studies are described below.

Eosinophilic Esophagitis in Children

5.1.1 Swallowed Fluticasone Propionate Fluticasone propionate (FP) is a synthetic trifluorinated glucocorticoid. It binds to the glucocorticoid receptors with 18 times greater affinity than dexamethasone and twice as great as that of budesonide. It is primarily metabolized in the liver. Due to its rapid first-pass effect and low oral bioavailability (less than 1 % of the orally administered dose), FP has significantly lower systemic side effects than systemic glucocorticoids [24]. It has been well studied as topical therapy for the esophagus. It is generally well tolerated; however, side effects have included oral or esophageal candidiasis (reported in 5–30 % of cases), though many times this was incidentally noted on follow-up endoscopy. Candidiasis is typically treatable with antifungals. In addition, dry mouth and herpetic esophagitis have been reported [25]. The degree to which topical therapy causes adrenal suppression and/or effects on height velocity is unclear. Successful use of topical fluticasone was first reported by Faubion et al. [26] in 1998 in the treatment of three children with EoE. The investigators theorized that steroid inhalers, without the use of a spacer, deposit a significant portion of inhaled steroid to the esophagus and hence can be used as an effective route for topical steroid treatment in EoE. All three patients were boys aged between 12 and 13 years, and none had previous history of allergies. They were treated with oral FP 220 lg, four puffs twice a day. Duration of treatment ranged from 6 weeks to 4 months and post-treatment biopsy was obtained in two of the three patients. All had prompt symptomatic relief, and no side effects were reported [26]. This prompted further studies in the use of topical therapy. A prospective translational research study compared the impact of diet restriction and FP on 11 pediatric patients aged between 1 and 19 years with EoE and sought to better define the pathophysiology of the disease. Immunohistochemical analysis showed a significantly greater number of mucosal cluster of differentiation (CD)-3 and CD8 lymphocytes, as well as CD1a? antigen-presenting cells compared with normal controls. CD1a? cells are primarily located at mucosal surfaces. These cells likely function as antigen-presenting cells and, in allergic conditions, participate in host sensitization. Patients were evaluated by an allergist and placed on diet restriction based on RAST/skin prick test results. After 8 weeks of diet restriction, all patients were re-evaluated. If symptoms persisted despite strict adherence to the diet, they were placed on FP (aged 2–4 years, 44 lg/puff; aged 5–10 years, 110 lg/puff; aged C11 years, 220 lg/puff) two puffs by mouth twice daily swallowed without inhaling and without use of a spacing device. Diet restriction did not induce clinical improvement in any patients, whereas all children who completed

treatment with FP had resolution of symptoms, thus supporting the efficacy of topical therapy. Furthermore, posttreatment analysis of proximal and distal esophageal mucosa showed a significant reduction in the number of eosinophils (proximal esophagus: pretreatment 22.5 ± 4.9 vs. post-treatment 2.8 ± 2.4; distal esophagus: pretreatment 23.0 ± 2.7 vs. post-treatment 2.7 ± 1.4) and in CD3 and CD8 lymphocytes compared with pretreatment sections [16]. A randomized controlled trial comparing swallowed FP (n = 40) with the previous ‘gold standard’ oral prednisolone (n = 40) showed that both were equally effective in achieving initial histological and clinical improvement at week 4, where there was 100 % resolution of symptoms seen in the prednisolone group and 97.2 % in the FP group. Histologic improvement by a grade of 1 or more was seen in 93.7 % of patients in the prednisolone group and in 94.4 % of patients treated with FP. However, discontinuation of therapy was associated in both groups with symptom relapse in 50 % of patients by week 24 [27]. Systemic adverse events were noted in 40 % of the prednisone arm and in 15 % of the FP arm. In a double-blind randomized controlled trial, 36 children were randomly assigned to swallowed FP (880 lg/day in two divided doses, n = 21) or placebo (n = 15) during a 3-month period. The primary endpoint was histologic remission, defined as a peak eosinophil count of B1 eosinophil in both the proximal and distal esophagus. Among these children, resolution of vomiting occurred in 67 % of those receiving FP and 27 % of those receiving placebo, whereas histological remission was reported in 50 and 9 %, respectively [28]. The authors noted a more pronounced effect in nonallergic and younger individuals, especially in the proximal esophagus. A recent randomized, multisite, double-blind, placebocontrolled trial evaluated the efficacy and safety of highdose swallowed FP and dose reduction in patients with EoE. Participants aged between 3 and 30 years were included in the study; 28 received 1760 lg of daily FP, and 14 received placebo. After 3 months, participants given FP who were in complete remission (i.e., had B1 eos/hpf in the proximal and distal esophagus) received 880 lg FP daily. Those participants in the FP or placebo groups who were not in complete remission were continued or started, respectively, on 1760 lg fluticasone daily for 3 additional months. After 3 months, an outstandingly high 65 % of subjects given FP were in complete remission compared with none in the placebo group (p = 0.0001). A 50 % dose reduction remained effective in 73–93 % of patients who initially responded to FP. Extending FP therapy in FP-resistant participants did not induce remission [29]. This study also examined the adrenal status of patients. Eight patients had decreased cortisol levels. Seven of those

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occurred after a participant had received high-dose FP while one of eight events occurred at screening before randomization. Of the seven events that occurred after randomization, five occurred during phase I while the participant was receiving high-dose FP, and two occurred during phase II in participants who went from placebo to high-dose FP. For the five instances of decreased cortisol occurring during phase I of the study, one resolved before the 3-month visit, three resolved during phase II after FP dose reduction, and one did not resolve after dose reduction. The decreased cortisol events in phase II did not resolve before the end of the study. Of note, all of these patients were from a single site, and most of the cortisol levels were conducted with saliva. None of the patients were reported to show clinical signs of adrenal insufficiency or glucocorticoid toxicity. The current recommendation for the use of FP is that patients are instructed to spray the metered dose inhaler in the mouth with lips sealed around the device. Following administration, patients should not eat, drink, or rinse for 30 min. The usual recommended dose is 88–440 lg/day in divided doses, typically twice daily, and can be age or weight based. Higher doses of 1760 lg/day appear to be very effective and well tolerated. 5.1.2 Oral Viscous Budesonide Oral viscous budesonide (OVB) is a thick liquid that is intended to coat the entire length of esophagus and hence treat pan esophageal EoE [30]. This may then represent an advantage over FP, which some hypothesize targets the proximal esophagus to a greater degree than the distal esophagus. The use of FP may also be problematic for younger children and those with developmental delay who are unlikely to utilize the puff and swallow technique effectively. OVB is easy to administer and usually requires once-daily dosing. Whether there is a palatability preference between the FP and OVB is unclear. Currently, the use of FP versus OVB appears to be one of personal physician preference and experience. A randomized controlled trial of adults with a mean age of 35 years compared the two methods of topical steroid delivery, nebulized and viscous, in EoE. Subjects with EoE received budesonide 1 mg twice daily for 8 weeks, either nebulized and then swallowed (NEB) or in oral viscous slurry (OVB). The mucosal medication contact time, measured by scintigraphy, was higher for the OVB group than for the NEB group (p \ 0.005) and was inversely correlated with eosinophil count (R -0.67; p = 0.001). OVB was more effective than NEB in reducing numbers of esophageal eosinophils in patients with EoE. OVB provided a significantly higher level of esophageal exposure to the therapeutic agent, which correlated with lower

eosinophil counts [31]. This study confirms the anecdotal observations of some adult clinicians that FP, particularly at a low dose, may provide better topical effects proximally, whereas OVB may better treat the distal esophagus as well as the proximal esophagus. Whether this is true in pediatric EoE, where the esophagus is shorter in length, has not been adequately studied. OVB was first used in 2005 in two patients who were unable to utilize FP therapy due to developmental reasons. It was prepared by mixing a liquid solution of budesonide and sucralose (a synthetic sugar substitute). Both children had resolution of symptoms and of histological abnormalities [32]. Budesonide can also be administered using a nebulizer, and patients are then instructed to swallow the accumulated liquid. In a retrospective open-label ‘proof-of-concept’ study of OVB in 20 children (mean age 5.5 years, median 4.1), the primary histologic endpoint (B7 eos/hpf) was achieved in 80 % of patients [30]. In a double-blind randomized controlled trial over 3 months comparing OVB with placebo in 24 children (aged 1–17 years) the histological endpoint of B6 eos/hpf was achieved in 87 % of children with EoE. Improvement in symptoms was noticed in 86.7 %. These endpoints were significant when compared with those of the placebo group, in which none were classified as responders. Children shorter than 5 feet tall received 1 mg OVB daily, and those above 5 feet received 2 mg daily [22]. Gupta et al. [33] evaluated the efficacy and safety of OVB in a double-blind, placebo-controlled PEER (Pediatric Eosinophilic Esophagitis Research) study, in which 81 children aged 2–18 years were randomized to 12 weeks of treatment with placebo or low-dose (subjects aged 2–9 years received 0.35 mg once daily, those aged 10–18 years received 0.5 mg daily), medium-dose (1.4 mg or 2 mg daily, respectively), or high-dose (1.4 mg or 2 mg twice daily, respectively) OVB. No difference was noted between low-dose OVB and placebo groups. A significant, dose-related increase in the percentage of subjects with both pan esophageal (proximal/mid/distal) histologic response (peak eosinophil B6/hpf) and remission (peak eosinophil B1/hpf) was observed in the medium- and highdose groups compared with the placebo group. Endoscopic abnormalities were significantly reduced at end of treatment in both the medium- and the high-dose groups compared with placebo. Histological remission was achieved in 11.8 % of patients in the low-dose group, 42.1 % in the medium-dose group, 76.5 % in the high-dose group, and in none of the patients in the placebo group [33]. Thus, taken together, these studies show similar efficacy to FP, particularly when given at high doses. Current dosing recommendations for OVB is typically 1–2 mg daily. Patients should not ingest any solid or liquid food for 30 min after its administration. Children under the

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age of 10 years receive OVB 1 mg daily, while those aged C10 years receive 2 mg daily. Viscous budesonide is made by mixing each 0.5 mg Pulmicort RespuleTM with 5 g (five packets) of sucralose (SplendaTM) to create a volume of 8–12 mL. A Pulmicort RespuleTM is liquid budesonide intended for nebulized administration (0.5 mg budesonide/ 2 mL) [30]. Grapefruit juice should be avoided by patients receiving budesonide, as it inhibits cytochrome P450 (CYP)-3A, which is responsible for the high first-pass budesonide metabolism. 5.1.3 Ciclesonide Ciclesonide is a nonhalogenated parent compound that is converted by epithelial esterases to form the biologically potent desisobutyryl-ciclesonide (des-CIC). This conversion facilitates a high concentration of active metabolite at the mucosal surface. des-CIC exhibits local anti-inflammatory effects that include reduction in eosinophil migration, diminished lymphocyte cytokine production, decreased fibroblast eotaxin release, and reduced smooth muscle actin expression. Further, the systemic levels of biologically active steroid components are lower in patients receiving ciclesonide compared with those receiving fluticasone or budesonide (inhaled corticosteroids) [34]. Ciclesonide has been evaluated in small case series. Schroeder et al. [35] reported treatment of EoE with ciclesonide in four patients who were refractory to topical fluticasone treatment. All four patients experienced both a clinical and a histologic benefit from the use of swallowed topical ciclesonide. Ciclesonide might have offered clinicopathologic benefit in children with EoE because of high local des-CIC concentrations. Further studies are needed before it can be recommended for patients with EoE. 5.1.4 Systemic Steroids Systemic steroids are highly effective in managing symptoms; however, use is limited due to the significant systemic side effects. As previously noted, a study comparing FP with prednisone showed both forms to be effective in achieving initial histologic and clinical improvement [27]. An initial study by Liacouras et al. [36] described his experience with prednisone. A total of 1809 patients were evaluated prospectively for symptoms of gastroesophageal reflux; 20 patients with persistent symptoms of esophageal eosinophilia despite treatment with omeprazole and cisapride were treated with oral methylprednisolone 1.5 mg/ kg per day, divided into twice-daily doses for 4 weeks. Histologic findings upon examination of specimens obtained in pretreatment esophageal biopsies from children with primary EoE indicated significantly greater

eosinophilia (34.2 ± 9.6 eos/hpf) compared with those from children with GERD who responded to medical therapy (2.26 ± 1.16 eos/hpf; p \ 0.001). After corticosteroid therapy, all but one patient with primary EoE had dramatic clinical improvement, supported by histologic examination (1.5 ± 0.9 eos/hpf, p \ 0.0001) [36]. A subsequent 10-year retrospective study of prednisone as reported by Liacouras et al. [37]. Of the 381 patients with EoE retrospectively analyzed, 39 patients (28 males), mean age 8.2 ± 2.9 years, were treated with oral methylprednisolone (1.5 mg/kg/day; maximum dose 40 mg/day). Before treatment, patients had an average of 33.5 ± 9.5 eos/hpf; after 4 weeks of treatment, the number of esophageal eosinophils was significantly reduced to 0.9 ± 0.6. At 6 months after therapy discontinuation, the number of esophageal eosinophils returned to near pretreatment levels of 28.7 ± 5.8. Clinically, 27 of 29 patients with GERD symptoms became completely asymptomatic when receiving oral steroids; the other two patients showed an improvement in symptoms during the 3rd and 4th weeks of therapy. Upon discontinuing therapy, clinical symptoms recurred or worsened in 24 of the 29 patients within 6 months. With regard to patients who had dysphagia, ten of ten patients became clinically asymptomatic with treatment. Upon removal of the medication, dysphagia recurred in all ten patients within 4 months [37]. Currently, systemic steroids are used for emergency cases only in patients who require rapid improvement in symptoms, such as severe dysphagia, hospitalization, and weight loss [27]. They can thus be used as a bridge to dietary or topical therapy. Long-term use is not recommended. The recommended dose is 1–2 mg/kg/day in divided doses. Inhaled aeroallergens have been shown to induce esophageal epithelial eosinophilia and thus trigger symptom relapse [38]. Although available data are limited, nasal corticosteroids have been shown to attenuate asthma symptoms in patients with allergic rhinitis and may be useful in some children with recognized seasonal exacerbation of their EoE [39].

6 Experimental and Other Therapies 6.1 Cromolyn Sodium Preformed mediators found in granules released by mast cells have been theorized to cause esophageal inflammation and tissue eosinophilia in patients with EoE. Cromolyn sodium is a mast cell stabilizer that prevents the release of these granules. The role of cromolyn sodium in managing symptoms of EoE has not been established. Liacouras et al. [37] described 14 patients treated with cromolyn sodium

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100 mg four times daily. The number of esophageal eosinophils remained unchanged after treatment for all the patients and none reported any improvement in symptoms. At this time, cromolyn sodium is not recommended for use in patients with EoE due to a lack of proven efficacy. 6.2 Montelukast Montelukast, a leukotriene receptor antagonist, has been observed to provide symptomatic improvement in small case series in patients with isolated EoE. This class of drugs acts by binding to cysteinyl leukotriene (CysLT) receptors and blocking their activation and the subsequent inflammatory cascade. In a retrospective series of eight patients with EoE who were receiving montelukast, three patients had a clinical response attributable to montelukast. Four others responded clinically but they had also been receiving other therapies. Histologic response could not be verified in this study [40]. In a study involving eight patients with EoE, patients were reported to have clinical improvement during treatment with montelukast for 14 months. However, in a subgroup of four patients who underwent repeat biopsy, histological improvement was observed in the distal esophagus but not the proximal esophagus. Thus, it failed to provide histological remission [41]. At present, the evidence is inadequate to recommend montelukast use in the treatment of EoE.

treatment for anti-mepolizumab antibodies and blood eosinophil counts. As assessed by immunofluorescence, a marked reduction of mean esophageal eosinophilia was seen in the mepolizumab group compared with the placebo group 4 weeks after initiation of treatment. Mepolizumab reduced tenascin C and transforming growth factor b1 expression in the esophageal epithelial layer 13 weeks after initiation of treatment. However, clinical improvement of symptoms was not significant [43]. 6.3.2 Reslizumab Reslizumab is another humanized monoclonal antibody to IL-5. It neutralizes circulating IL-5 by preventing it from binding to its receptor, IL-5 receptor a, which is expressed by several cells, including eosinophils. A controlled trial evaluated the effect of reslizumab on 226 children and adolescents aged between 5 and 18 years with EoE. Patients were randomly assigned in a 1:1:1:1 ratio to receive intravenous reslizumab 1, 2, or 3 mg/kg or placebo. Study medication was administered every 28 ± 7 days for a total of four doses. A significant reduction in peak eosinophil count compared with placebo was observed. However, all the treatment groups experienced significant reductions in symptoms, and the differences were not significantly different from placebo [44]. Further studies will be required to determine the utility of anti-IL-5 for EoE.

6.3 Monoclonal Antibodies 6.3.3 Omalizumab 6.3.1 Mepolizumab Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus [42]. IL-5 is involved in the maturation, recruitment, and activation of eosinophils. Inhibition of IL-5 has been shown to result in the reduction of circulating and tissue eosinophil counts. Mepolizumab is a fully humanized monoclonal antibody against IL-5. Straumann et al. [43] conducted a randomized, double-blind, placebo-controlled study to evaluate the ability of mepolizumab to reduce peak esophageal eosinophilia to \5 eos/hpf. They randomized 11 adults with active EoE and dysphagia to mepolizumab or placebo. Treatment was initiated with two intravenous infusions of either mepolizumab 750 mg or placebo on days 0 and 7, administered over 30 min; 4 weeks after the first infusion, patients underwent repeat EGD. Patients who had not responded and had no treatment-related safety concerns received two further infusions of either mepolizumab 1500 mg or placebo according to their original treatment allocation, given 4 weeks apart at weeks 5 and 9, respectively. All patients were assessed 21 weeks after the start of

Omalizumab is a humanized anti-IgE monoclonal antibody. It binds to IgE and hence prevents activation of mast cells and basophils. A prospective randomized, doubleblind, placebo-controlled trial of subjects (aged 12–60 years) who either relapsed or were refractory to therapy with topical corticosteroids looked at the efficacy of omalizumab in reducing the eosinophilic esophageal infiltration in EoE patients. The secondary objective was to determine efficacy in reducing EoE symptoms. Subjects were randomized to receive omalizumab or placebo at day 1 and every 4 weeks for 16 weeks. No improvement was observed in eosinophil infiltration with placebo or omalizumab treatment in EoE patients. Dysphagia scores similarly improved with both omalizumab and placebo [45]. In a case report of two children aged 9 and 18 years with EoE and multiple food allergies, subcutaneous omalizumab 300 mg was administered every 2–4 weeks. Omalizumab did not appear to change endoscopic or histological features of EoE in either of these patients [46]. At this point, efficacy data are insufficient to support the use of anti-IgE antibodies in EoE.

Eosinophilic Esophagitis in Children

6.3.4 Anti-Tumor Necrosis Factor-a Infliximab, a chimeric IgG1 monoclonal antibody, is a potent inhibitor of tumor necrosis factor (TNF)-a. In a case series of three adults with severe, corticosteroid-dependent EoE, infliximab did not induce a resolution of the eosinophilic tissue infiltration, nor did it markedly reduce the resulting symptoms [47]. Treatment of EoE with this class of drug cannot be recommended at this time. 6.3.5 Anti-Interleukin-13 A recent study evaluated QAX576, a monoclonal antibody against IL-13, in the treatment of patients with EoE. Patients (aged 18–50 years) with PPI-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months; 23 patients completed the study. The mean esophageal eosinophil count decreased by 60 % with QAX576 versus an increase of 23 % with placebo (p = 0.004), and the decrease was sustained for up to 6 months. A trend for improved symptoms was observed, particularly dysphagia. QAX576 improved the expression of EoE-relevant esophageal transcripts, including eotaxin3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment [48]. Further studies are required. 6.4 CRTH2 Antagonist Chemo-attractant receptor-homologous molecule on Th2 cells (CRTH2) is a prostaglandin D2 (PGD2) receptor expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, which mediate chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and is orally bioavailable. In a randomized, double-blind, placebocontrolled trial, 26 adult patients with active EoE, dependent on or resistant to corticosteroids, were treated with either 100 mg OC000459 tablets or placebo twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary endpoint was the reduction in esophageal eosinophil infiltration. After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly in the treatment arm, whereas no reduction was observed with placebo [49]. Further studies are required to more completely define the utility of this agent and class of pharmacologic in the treatment of EoE. 6.5 Anti-Eotaxin Eotaxin-2 is chemoattractant that selectively acts on eosinophils and has minimal effect on other leukocytes. It is

secreted in response to TNFa, IL-5 or IL-3. The effect of eotaxin is mediated by a specific eotaxin receptor that induces activation of Gi proteins, mitogen-activated protein kinase (MAPK) signaling and involves changes in intracellular calcium levels and cytoskeletal reorganization. Using a whole-genome expression analysis approach, the transcription of CCL26 (eotaxin-3), a potent eosinophil chemoattractant in humans, was revealed to be highly dysregulated in the esophageal tissue of patients with EoE. To date, we are unaware of any published therapeutic trials evaluating the efficacy of an ‘anti-eotaxin’ pharmaceutical. 6.6 Immunosuppressive Agents Azathioprine (AZA) is a prodrug that is quickly converted into 6-mercaptopurine (6-MP). After absorption, 6-thioguanine nucleotides accumulate in tissue, where they are thought to act by inhibiting purine synthesis and ultimately DNA and RNA synthesis [50]. AZA and 6-MP also inhibit the proliferation of T and B lymphocytes, which leads to a decreased production of cytotoxic T lymphocytes and plasma cells. In EoE, increased esophageal infiltrations with CD3? T cells, CD8? T cells, CD1a? dendritic cells, and mast cells have been reported. A case report of three adult steroid-dependent patients with EoE treated with AZA or 6-MP showed clinical and histological remission that was maintained during the follow-up period (range 3–8 years). The investigators postulated that AZA and 6-MP delay the recruitment and/or proliferation of lymphocytes into the esophageal epithelium, and hence lead to decreased antigen processing in the esophagus and thereby reduce inflammation. AZA was introduced at a dose of 2–2.5 mg/kg body weight. Common side effects of AZA and 6-MP include allergic reactions, pancreatitis, bone marrow suppression, nausea not related to pancreatitis, and infections. Significant adverse events requiring withdrawal from clinical trials occur in up to 10 % of patients. At the beginning of such a therapy, the complete blood count, liver enzymes, and pancreas amylases should be checked weekly during the first 8–12 weeks, and thereafter every 3–6 months [51]. To date, experience with these agents is limited to anecdotal reports, thus larger controlled trials are required to determine its efficacy in EoE, particularly as a steroid-sparing agent.

7 Open Questions for Research While treatment of EoE has progressed over the past decade, many questions still remain. The pathophysiology of the disease remains incompletely understood. While some patients have identifiable genetic polymorphisms, this is not true for the majority of affected individuals. A greater

P. Trivedy, J. E. Teitelbaum

understanding of the predisposing factors and triggers is required. This may allow better characterization of patients based on genotype and phenotype (e.g., inflammatory, dysmotility, structuring), which may allow for targeted therapy. In addition, a greater understanding of the pathophysiology may lead to the development of unique therapies. Less invasive biomarkers of active disease would be helpful in monitoring patient’s response to therapy as well as for long-term maintenance of mucosal healing. Finally, the safety and efficacy of long-term maintenance therapy needs to be investigated so as to determine whether there is any impact on decreasing the lifelong risk of esophageal stricture.

8 Conclusion At present, dietary and pharmacologic therapy are key to the successful treatment of pediatric EoE. A clinician’s choice to use dietary therapy versus pharmacologics or a combination thereof should be determined on an individual basis, taking into consideration issues related to symptomatology, quality of life, growth, and development. Steroids, typically used topically, have proven to be the mainstay of pharmacologic treatment with excellent shortterm efficacy and a good short-term safety profile. Future studies are needed to evaluate the long-term efficacy of medications in EoE, particularly with respect to structuring disease, as well as possible long-term side effects. Larger randomized placebo-controlled studies of specific immune modulators, based on our ongoing understanding of the immune basis of EoE, are required. Conflict of interest Prerna Trivedy, MD, and Jonathan E. Teitelbaum, MD, have no relevant conflicts of interest.

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Eosinophilic esophagitis in children.

Eosinophilic esophagitis (EoE) is a relatively common chronic immune-mediated disease of the esophagus characterized clinically by symptoms of esophag...
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