Javier Molina-Infante is a Senior Consultant in Gastroenterology at Hospital Universitario de Caceres.
Alfredo Lucendo is Head of the Department of Gastroenterology and Research Laboratory at Hospital General Tomelloso, Spain, and Head of the Spanish Research Group on EoE at Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid.
Eosinophilic oesophagitis (EoE) is an increasingly common immune-mediated oesophagal disease, characterized clinically by oesophagal dysfunction symptoms and histologically by eosinophil-predominant inflammation.1 First described in the early 90s, EoE is currently the most frequent cause of dysphagia and food bolus obstruction in children and adults under 50 years. Diagnostic criteria and first therapies (proton pump inhibitor treatment and elimination diets) were consolidated over the past decade and clearly outlined in the first international evidence-based guidelines, published in 2017 in the United European Journal of Gastroenterology. Since then, mounting evidence on epidemiology, natural history, and novel pharmacological treatments, including orodispersable budesonide and biologics, has rebuilt our views on this disease.
Here, we aim to discuss the frequent pitfalls we often see in clinical practice, mostly evidence-based but also in accordance with new data and our long-standing clinical experience.
© UEG 2017 Molina-Infante and Lucendo.
Cite this article as:
Molina-Infante J and Lucendo AJ. Mistakes in eosinophilic oesophagitis and how to avoid them. UEG Education 2017: 17; 6–XX.
Correspondence to:
Conflicts of interest:
The authors declare there are no conflicts of interest.
Published online:
February 23, 2017
Reviewed: March, 2024.
EoE has been historically considered a rare disease (prevalence below 50 cases/100,000 people), but this is not the case anymore. Recent systematic reviews and meta-analyses2-4 on incidence and prevalence have consistently shown sharp increases in EoE incidence (new cases) everywhere across the world, especially during more recent years. Prevalence (total number of existing cases) has increased >800% from the earliest studies (between 1976–2001) to the most current ones carried out between 2017–20223, whereas pooled figures published after 2018 have been reported to be over 60 cases/100,000 people2,3. For both children and adults, the highest prevalence has been reported in studies from Spain and the USA (>100 cases/100,000 people before 2020)2-4, which has been recently reproduced in Sweden5. Since EoE is a chronic disease and incidence is skyrocketing all around the world, rapidly growing prevalence rates are expected over the next few years.
Early papers on the natural history of the disease consistently demonstrated that the natural history of untreated EoE is a continuum from an inflammatory to a fibrostenotic disease.6-9 These findings posed the question of whether all EoE patients should undergo indefinite chronic therapy. However, two seminal papers10,11 have recently suggested the existence of different EoE endotypes based on clinical, endoscopic, histologic, molecular and genetic findings on oesophageal tissue, with remarkable heterogeneity in Th2 gene expression among active EoE patients. In fact, three different endotypes, independent of peak eosinophil count, have been described: 1) a mild endotype (mild symptoms and endoscopic findings), which is believed to represent most proton pump inhibitor (PPI) responders; 2) an intermediate endotype, with more severe inflammatory features and worse response to topical corticosteroids, including 30-40% of patients; and 3) a fibrostricturing/narrow calibre oesophagus endotype (around 10% of patients), who exhibit the highest degree of endoscopic and histological severity, including fibrosis-related features.10 While a relevant proportion of patients in the first group tend to be rarely continually symptomatic off therapy in the long run12, some others in the latter may show a quick relapse in symptoms and endoscopic fibrostricturing features upon corticosteroids or endoscopic dilation withdrawal.13,14 As such, we should strive to individualize treatment regimens according to these potential endotypes, likely with a flexible strategy for patients with a mild endotype but also with strict maintenance therapy and on-demand endoscopic dilation for severe endotypes. It remains to be elucidated when and how these different patient phenotypes may reverse or progress over time.
The EoE Endoscopic Reference Score (EREFS), first published in 2013, was developed and validated to homogenize the recognition, reporting, classification, and grading of several endoscopic features characteristically associated with EoE (oedema, rings, exudates, furrows, stricture).15 Undoubtedly, the standardized nomenclature of EREFS has improved consistency for reporting of EoE endoscopic findings among practitioners, and although still limited in Europe16, it should be used routinely in clinical practice17. These endoscopic features, nonetheless, are not included in the current diagnostic criteria for EoE1. Up to 10% of patients with active EoE may show a normal endoscopic appearance, as recently proven in a retrospective study18 conducted in North Carolina. This study18 demonstrated that implementation of the EREFS significantly decreased reports of normal-appearing oesophagi [from 21% (2002-2008) to 7% (2013-2018), p<0.01], but still, a minority of patients may exhibit a normal oesophagus, even for endoscopists familiar to the EREFS system and those who use current endoscopes and should not preclude taking oesophageal biopsies.17,18 On the other hand, histological remission after treatment correlates best with the disappearance of whitish exudates, but other inflammatory features (oedema, furrows) may persist as markers of tissue remodelling after inflammation.19 Likewise, rings and strictures, which belong to fibrostricturing endoscopic features, may not reverse after an effective anti-inflammatory therapy. As such, endoscopists should use in their routine practice the EREFS score for a common standardized report, as well as to monitor endoscopic activity, but both symptoms and eosinophilic infiltrate in biopsies remain the mainstay of diagnosis and surveillance for the disease.
EoE is defined by guidelines1 as a clinicopathologic disorder, so both symptoms and eosinophilic inflammation should be considered in combination when evaluating a response to a given therapy. However, many clinicians rank EoE activity after treatment exclusively on a symptom basis16, likely aiming at reducing the need for endoscopic procedures. This strategy, even using the validated activity index (EEsAI) for dysphagia, has been proven ineffective in predicting either histologic or endoscopic remission in adult EoE patients.20 An international multicentre cohort study21 lately determined that variation in eosinophil counts after therapy only explained 19% of the symptom variation in severity. Multiple recent placebo-controlled, randomized control trials22-25 in EoE have consistently corroborated higher histological response compared to a lower dysphagia remission. Conversely, dysphagia may improve without histologic remission, usually after a trial of PPI therapy. The biggest study26 on PPI as induction therapy so far, including over six hundred patients in the European EoE Connect Registry, showed a 48% histologic response along with a 71% symptom improvement. Dysphagia is a complex symptom that may be difficult to report and explain during childhood, whereas adults may minimize it through behavioural modifications, such as food avoidance, altering the consistency of the ingested food or the eating pace. Additionally, atypical oropharyngeal symptoms, like sore or oesophageal globus, or oesophageal hypervigilance and food-specific anxiety27 may be mistaken for dysphagia.
In summary, clinicians should not make assumptions about the biological activity of EoE exclusively upon symptoms, and endoscopic oesophageal biopsies currently continue to be necessary to accurately monitor the disease activity.
Regarding PPI monotherapy for induction therapy, current recommendations1 are to initially use a double dose (omeprazole 40 mg once daily or equivalent, preferably on a split dose) for a duration of 8 weeks. A first systematic review28 with meta-analysis on PPI therapy, published in 2016, showed histologic remission in 50.5% (95% CI 42.2– 58.7%) with symptomatic improvement in 60.8% (95%CI 48.38–72.2%) of cases. Noteworthy, a trend towards higher efficacy was noted when PPIs were administered twice daily compared to once daily. This trend has lately been confirmed in a study29 including 305 newly diagnosed EoE patients who were randomized to receive omeprazole 20 mg once daily, 40 mg once daily, 20 mg twice daily or 40 mg twice daily for ≥8 weeks. Overall, 42.3% achieved histologic response to PPI, with higher rates for twice-daily (moderate: 52.8%/high:54.3%) than once-daily (standard: 11.8%/moderate: 10%) dosing (p<0.0001). On multivariable analysis, twice-daily moderate (aOR 6.75, CI: 2.53-18.0, p=0.0008) and high (aOR 12.8, CI 4.69-34.8, p<0.0001) doses independently predicted histologic response. In the aforementioned EoE Connect Registry study26 on PPI, increased efficacy of PPI was reported on the multivariate analysis in those who prolonged treatment length from 8 to 12 weeks (OR 2.7; 95% CI, 1.3-5.3).
Accordingly, split PPI doses as induction therapy should be given (likely, omeprazole 20 mg twice daily or equivalent), whereas novel data hint at higher response rates when treatment duration is prolonged up to 12 weeks.
Since 2006, a 6-food elimination diet (milk, wheat, egg, soy, nuts, fish and seafood), with subsequent individual food reintroduction followed by repeated endoscopies, was proven to be consistently effective in 3 out of 4 paediatric and adult patients as shown by initial studies30-32 and a first meta-analysis33. Fish, seafood and nuts were found to be almost negligible as food triggers during the reintroduction process30-32, leading to the development of a 4-food elimination diet (milk, wheat, egg, soy and legumes). Remission rates between 54% (adults34) and 64% (children35) demonstrated that easier and simpler diets were also effective with numerous advantages, with over half of responders to a 4-food elimination diet with just one or two food triggers. As there was still room for diet optimization, a first big prospective multicentre study36 from Spain using a step-up approach, with an initial 2-food (dairy and wheat) elimination diet, reported remission in 43% of children and adults. Non-responders were stepped up to a 4-food elimination diet and, in case of lack of response, to a 6-food elimination diet. Interestingly, most patients responding to a 2- or 4-food elimination diet were found to have just 1 or 2 food triggers, whereas responders after scalation to a 6-food elimination diet were shown to have 3, 4 or 5 food triggers. Starting with dairy and wheat elimination (i.e., a two-food elimination diet) reduced endoscopic procedures and diagnostic process time by 20% compared to an empiric 6-food elimination diet, as well as saving multiple unnecessary dietary restrictions. In another further computer-based simulation model analysis37, a step-up approach revealed maximized efficiency in identifying food triggers while balancing the number of endoscopies required. Additional data in support of a less-restrictive diet elimination approach come from more recent clinical studies and randomized trials38,39. Milk-elimination diet has been demonstrated to achieve remission in half of paediatric patients38, whereas a first randomized trial39 comparing milk elimination and an empiric 6-food elimination diet surprisingly showed similar histologic response rates for both approaches (34% vs. 40%, p=0.58). Poor compliance may be a major explanation for such a low response to an initial 6-food elimination diet since 43% of non-responders to a milk-elimination diet were ultimately rescued with a 6-food elimination as salvage therapy (likely with better compliance after initial failure).
Overall, the optimal choice for initial dietary therapy in clinical practice has shifted from a highly restrictive 4- or 6-food elimination diet to a milk (children) or 2-food (milk and wheat, likely in adults) elimination diet, reserving stepping-up to a 4- or 6-food elimination diet for highly motivated patients, who are willing to potentially undertake maintenance therapy with avoidance of numerous food triggers.
Among swallowed topical glucocorticoids, fluticasone propionate and viscous budesonide have been best studied, with no relevant differences between them when compared in a first randomized trial40 or in a recent meta-analysis41. Albeit it seems plausible that increased viscosity may increase mucosal contact time of the drug, no head-to-head studies comparing liquid and viscous formulations of budesonide have been performed yet. Data from real-world experience in the EoE Connect Registry in Europe showed a global (both fluticasone and budesonide) clinical and histological response of 80.1%.42 At the end of 2017, the European Medicines Agency (EMA) approved a novel orodispersible formulation of budesonide specifically designed for topical delivery in the oesophagus. Striking histologic remission rates around 93% with a 6-week duration were published in Phase 2 and 3 placebo-controlled randomized trials43,44. More recently, a new paper45 from the European Registry has assessed 1456 prescriptions of swallowed topical corticosteroids used in 866 individual patients. Histological remission rates were 65.4% for fluticasone (mostly nasal drops) and 83.8% for budesonide (including several types of viscous budesonide and the oral disintegrating tablet). On the multivariate analysis, the most important predictor of histological remission was the type of topical corticosteroid, with the highest efficacy for the orodispersible tablet (OR 18.9, p < 0.001), followed by the use of high doses (OR 4.3, p = 0.03) and less severity in baseline symptom score. In line with these findings, a novel fluticasone disintegrating tablet has shown notable efficacy in a recent phase 2 randomized trial46, best with 1.5 mg twice a day (86%).
Collectively, evolving evidence points towards orodispersible tablets as the most effective administration route for swallowed topical corticosteroids, with the highest efficacy for the budesonide disintegrating tablet.
EoE patients on endoscopic and histological remission, after an effective anti-inflammatory therapy, might suffer from residual dysphagia due to irreversible structural changes related to fibrosis and reduced oesophageal distensibility. A narrow-calibre oesophagus (in the range of 12 to 15 mm), without a dominant stricture identified, is frequently overlooked when using an adult standard 9 to 10 mm diagnostic endoscope.47 A recent expert consensus conference17 on the endoscopic approach to EoE has recommended performing empiric pan-oesophageal dilation (with a final goal of a 16 mm oesophageal calibre) in patients with persistent dysphagia in a normal appearing oesophagus on endoscopic and histologic remission. Careful selection of initial dilator size and increase in size (“starting low and going slow”) is recommended in a similar fashion to standard dilation for oesophageal strictures in EoE.
According to 2018 guidelines1, elemental diet or experimental drugs were considered salvage therapies for EoE patients showing a lack of remission after PPI, diet or swallowed topical corticosteroids. This recommendation is obsolete with novel and encouraging data on biologic drugs for EoE, especially dupilumab. Dupilumab is a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13 signalling, which is currently approved for poorly controlled asthma, atopic dermatitis, nasal polyposis and, since 2023, for EoE as well. A recent phase 2, randomized, placebo-controlled trial24 with dupilumab in adult and adolescent EoE patients displayed a remarkable 60% histologic remission, defined by ≤6 eos/HPF in biopsies, along with relevant dysphagia improvement, in a cohort of patients previously refractory to multiple therapies (73%). A subsequent phase 3 trial sub-analysis48 has shown that response to dupilumab is independent of prior use, inadequate response, intolerance and/or contraindication to swallowed topical corticosteroids. In line with these findings, a recent real-world retrospective series49, including 46 patients with refractory fibrostricturing EoE (failure to PPI, diet and topical corticosteroids), has confirmed the efficacy of dupilumab in difficult-to-treat patients. Symptomatic and oesophageal calibre improvement was accompanied by high histological remission rates (80% with< 15 eos/HPF, 57% with < 6 eos/HPF) in multi-refractory patients. As such, dupilumab should be strongly considered for patients with failure, loss of response or intolerance to multiple conventional therapies for EoE.
Early findings for oesophageal dilation in EoE patients reported a high rate of complications, mainly oesophageal perforation and chest pain.38,39 These findings were not confirmed in the first systematic review and meta-analysis of the literature, comprising 525 adult EoE patients and 992 endoscopic dilations.40 Only three oesophageal perforations (0.3%) and one haemorrhage (0.1%) were reported, all at the same institution. Accordingly, the rate of major complications is consistent with that reported for endoscopic dilation in other oesophageal diseases (<1%).
Endoscopic dilation should be recommended to all EoE patients who have dysphagia/food impaction that is related to fibrostenotic abnormalities (either narrow-calibre oesophagus or strictures) and unresponsive to medical or dietary therapy.6 Endoscopic dilation is highly effective, with clinical improvement documented in 75% of patients in the aforementioned meta-analysis.40 Mucosal lacerations after dilation should not be considered complications, but rather the intended outcome of the endoscopic procedure.
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About the Authors
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Your eosoinophilic oesophagitis briefing
Week
- What is the best recipe for EoE: PPI, steroids or monochrome? Session at UEG Week 2023
- Eosinophilic esophagitis and GORD. Session at UEG Week 2022
- Dupilumab improves histological and endoscopic features of eosinophilic oesophagitis in children aged 1–11 years in the phase 3 EoE kids trial. Presentation at UEG Week 2022
Standards and Guidelines
- Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults
- Liacouras CA, et al. Eosinophilic esophagitis: updatedconsensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3–20.
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