aCharacteristic of EE.
Endoscopy findings in EE are extremely variable (Table 5.1) and may reflect disease severity and chronicity; at one end of the spectrum the esophagus may appear normal and at the other end luminal narrowing and strictures (usually in adults with long-standing symptoms) may be evident [20]. Furuta suggests that apart from the findings of longitudinal shearing and “crepe paper” mucosa, endoscopic features described in EE are not unique to this condition [1]. Nevertheless, identification of more than one of the typical features (including exudates or micro-abscesses appearing as raised white dots or nodules, esophageal narrowing, ringed (or feline) esophagus, longitudinal furrows or longitudinal shearing and friability) in the context of consistent clinical symptoms should raise the index of suspicion for EE [1 ]. Barium studies are not routinely recommended but may be useful to define the site and extent of esophageal narrowing found at endoscopy and to exclude other diagnoses.
In accordance with the current AGA guideline [1] diagnostic criteria include:
- Clinical symptoms of esophageal disease and
- Histological abnormality: (≥15IEE in one or more HPF on a biopsy specimen) and
- Exclusion of differential diagnoses including GERD (by normal pH study or lack of response to high dose PPI) and
- Consistent endoscopic findings
Prognosis
Due to the relative rarity and recent recognition of this disorder, there are few prospective longitudinal cohort studies that provide good evidence about the long-term prognosis of EE. Three follow-up studies in adults were identified in the AGA guideline [1]. In summary, most patients had significant prior symptoms of refractory GERD, dysphagia, or impaction at study entry and up to 86% went on to develop oesophageal narrowing, strictures, or corrugation. Strictures were proximal in over half of the patients and dilation commonly caused longitudinal tears. The diagnosis of EE had frequently been missed and treatment delayed. Symptoms were chronic and in one study, symptoms worsened during the follow-up period (up to 11.5 years) in about one-quarter of patients and remained stable in about one-third but were not life-threatening [21]. In some patients there was histological evidence of increasing subepithelial fibrosis or thickening of the esophagus over time in the absence of macroscopic change at endoscopy. There is no evidence in these cohorts with relatively short-term follow-up that EE is associated with development of esophageal neoplasia.
Outcomes in children are also poorly studied. Liacouras reported on nearly 400 children with EE who had presented with refractory GERD at less than 10 years of age and were followed for up to 10 years [18]. About 6% developed esophageal narrowing but only one child required dilation. Clinical and histological response to oral steroids was almost universal and response to inhaled fluticasone was about 50%, but most children relapsed when either treatment was ceased. The majority of children subjected to dietary manipulation (with a restriction diet or elemental diet) went into disease remission, which included improvement in esophageal calibre. A recent retrospective review of 89 children with EE supports the observation that EE is both chronic and relapsing; 79% of the 66% who initially responded to treatment had relapsed within the eight-year follow-up period [22].
Management
A range of pharmacological therapies has been used to treat EE, including oral and inhaled (swallowed) corticos-teroids, sodium chromoglycate, PPIs, montelukast (a leu-kotriene inhibiter) and mepolizumab (an IL-5 monoclonal antibody). Dietary interventions include restricted or elemental diets and surgical interventions include esophageal dilation. However, there is a dearth of high-level evidence to support use of any of these interventions. Only three RCTs (two placebo-controlled trials and one comparing two current therapies) have been performed in EE [9–11]. All had methodological limitations, including small sample size, inconclusive results, and potential confounding from simultaneous use of co-therapy. Two of the RCTs were conducted in children and evaluated the role of steroids [9, 10] but used different criteria for the diagnosis of EE, for inclusion of trial participants and for determining histological response. Neither evaluated long-term maintenance therapy (Table 5.2). There is only one small RCT (n = 11) evaluating a novel therapy in adults with EE [11].
Pharmacological therapies
Corticosteroids
Steroids have been widely used in the treatment of EE and several uncontrolled studies, previously summarised [1, 8] suggest that both oral and topical steroids may improve histological abnormalities and clinical symptoms. Historically, oral steroids were reserved for patients with EE with severe dyspagia, strictures and weight loss because of concerns of adverse effects. The more recent use of topical steroids (fluticasone propionate or beclometha-sone), administered by a metered-dose inhaler and swallowed, has been documented in uncontrolled studies with variable effectiveness for the initial treatment for EE [1, 8] and few adverse effects. There is limited evidence about the long-term use of either topical or oral steroids, although available studies suggest that discontinuation of steroid therapy frequently results in relapse.
HPF: high power field (400x); PPI: proton pump inhibitor.
Since publication of the AGA guideline [1] two RCTs have been published (summarised in Table 5.2), which provide the only reliable evidence for steroid therapy for EE. The first was a well-designed and adequately powered, open-label RCT that recruited 80 children (16 years or under) with EE (defined as ≥15IEE per HPF and negative pH studies) [9]. Children were randomised to receive four weeks’ initial treatment with either oral prednisone or topical fluticasone and were weaned off treatment over the next eight weeks. A histological grading score incorporating both eosinophil count and thickness of the basal cell zone was used to assess therapeutic response. Although most of the 68 children who completed the study had symptomatic improvement and showed histological improvement within one month, there was no significant advantage for one medication over the other. Importantly, 40% of the prednisone group experienced adverse effects of treatment and three children withdrew from the trial within four weeks of commencing therapy because of severe adverse effects. Of the fluticasone group, the majority (34/36) showed histologic improvement, 35/36 improved clinically and 15% experienced esophageal can-didiasis, which was sometimes asymptomatic and responded to anti-fungal treatment.
Symptom relapse usually occurred within six weeks of stopping therapy and had occurred in 45% of all trial participants at six-month follow-up (although endoscopy and biopsy were not performed at this time) with no difference between treatment groups in the rate or timing of relapse. A potential confounder in this study is that 58% of all children tested positive for food allergies prior to commencing steroids and were asked to eliminate the relevant food. Although the proportion receiving a special diet was similar in each group it is possible that benefits of the diet resulted in an overestimation of the beneficial effect of both medications. In view of the similar effectiveness of the two steroid preparations and the potential adverse effects of oral steroids documented in this RCT, inhaled (swallowed) steroids should be used in preference to oral steroids as initial treatment for uncomplicated EE. A1c Patients should be advised to use the medication without a spacer and, after spraying the medication into their pharynx, to swallow rather than inhale. Patients should be asked not to eat or drink or wash out their mouths for half an hour after medicating. B4 In view of the high relapse rate of EE after treatment is stopped, the long-term use of fluticasone requires evaluation both for efficacy and for adverse effects. Systemic effects from long-term fluticasone use have not been evaluated in EE. It has been suggested that oral therapy should be reserved for short-term use in patients with acute or severe dysphagia or stricture requiring dilation [1], although RCT evidence in this group is lacking.
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