1. What is EoE?

Eosinophilic oesophagitis (EoE) is a chronic inflammatory disease of the oesophagus. This immune-mediated disorder is characterised clinically by oesophageal dysfunction and histologically by eosinophil-predominant inflammation. Common symptoms in adults with EoE include; dysphagia (difficulty swallowing) and odynophagia (pain with swallowing), in addition to chest pain or regurgitation (both occurring during or immediately after eating) and/or food bolus obstruction, the latter of which may require extraction in an emergency department.1,2 EoE was first described as a standalone clinicopathological only entity in 1993,3 however, the first consensus guidelines for diagnosis of EoE were not published until several years later, in 2007. These guidelines have now been updated a number of times since, including most recently by the British Society of Gastroenterology, in 2022.4,5

2. What is the aetiology of EoE?

The aetiology of EoE is presumed to involve the ingestion of dietary &/or airborne substances, which in genetically susceptible individuals, are allergenic. In EoE, these allergens are presented to T helper (Th)-2 cells in the mucosa of oesophagus, eliciting the release of the cytokines; IL-4; -5 & -13, which with the chemokine, eotaxin-3, stimulate the maturation and migration of eosinophils to the oesophageal mucosa. There the eosinophils release pro-inflammatory and pro-fibrotic mediators, which, over time, lead to pathologic changes in the oesophageal mucosa, seen on biopsy (see Fig. 1). Over time, in a patient receiving no or ineffective treatment, this can lead to a fibrostenotic phenotype with a low calibre oesophagus and a high associated risk of recurrent food bolus obstructions requiring endoscopic rescue to remove the obstruction and the potential need for dilation procedures. Eventually, this leads to adverse macroscopic changes in the oesophageal wall, observed on endoscopy (see Fig. 2), associated with oesophageal dysmotility and the symptoms of oesophageal dysfunction. A history of atopic disorders, such as asthma, eczema or allergic rhinitis is common in EoE. However, it remains unclear whether atopy predisposes individuals to EoE.1,6–8 The most-relevant food allergens for EoE include animal milk and dairy products, wheat, eggs, soy, and nuts, as well as fish/shellfish and legumes.9 Aeroallergens and oral/sublingual immunotherapies have also been postulated as potential triggers of EoE.11,14

 

Adverse cellular and macroscope changes in EoE

Fig. 1. Histological signs of EoE. Eosinophil-rich inflammatory infiltrate (left panel), eosinophil-rich microabscess (right panel); © Prof. Dr. Thomas Günther, Pathologie Lademannbogen, Hamburg, Germany.

Furrows and oedema

Rings and oedema

Rings (trachealisation), exudate, oedema

Exudate

Strictures (severe)

Fig. 2. Examples of the typical features of EoE. © Prof. Dr. Stephan Miehlke, Gastroenterology Center at the Facharztzentrum Eppendorf, Hamburg, Germany.

 

Aetiology

There are a range of risk factors associated with EoE.8

Aeroallergens May cause EoE or increase disease activity; can cross react with food allergens; may explain seasonal variation in diagnosis
Food allergens Directly trigger EoE; elimination can lead to disease remission
Helicobacter pylori Inversely associated with EoE; decrease in H. pylori prevalence has accompanied increase in EoE prevalence over the last 20 years; aetiology unclear
Infections (herpes simplex virus; mycoplasma) Associated with EoE; aetiology unclear
Oral or sublingual immunotherapy Causes or induces EoE in certain patients; baseline EoE status for reported cases usually not know prior to immunotherapy
Proton pump inhibitors Reported to induce IgE antibodies to certain foods
Cold or arid climates Increased risk of EoE in these climate zones, but not in temperate or tropical zones
Population density Risk of EoE increase as population density decreases
Early life factors Antibiotic use, Cesarean section, and preterm delivery increase the odds of pediatric EoE
Connective tissue disorders Ehlers-Danlos, Marfan Syndrome, and Loeys- Dietz syndrome have been associated with EoE
Coeliac disease Associated with EoE; EoE is more common in patients with coeliac disease than would be expected
Autoimmune conditions Inflammatory bowel disease, rheumatoid arthritis, IgA deficiency, multiple sclerosis, and Hashimoto’s thyroiditis associated with EoE

 

Table 1. Adapted from Dellon ES and Hirano I. 2018.15 Risk factors for EoE and disorders associated with EoE.

Fig. 3: Common food-allergen triggers of EoE (animal milk and dairy products, soy/legumes, nuts, wheat, egg, fish/shellfish)

 

EoE is the manifestation of a TH2 immune response involving activated eosinophils, mast cells and the cytokines eotaxin-3, interleukin-5, and interleukin-13. Genetic susceptibility factors (TSLP, CAPN14) have also been reported.12

3. What is the epidemiology of EoE?

EoE is the most most frequent eosinophilic gastrointestinal disorder as well as the second most common cause of dysphagia and chronic oesophagitis after gastro-oesophageal reflux disease (GORD).13 Based on a recent systemic review of population-based studies, conducted principally in Europe and North America, the prevalence of EoE in adults was approximately 42 per 100,000, which is consistent with EoE being classified as a rare or ‘orphan’ disease (i.e. less than 50 per 100,000 or less 1 in 2000). However,  there has been a steady increase in both the incidence and prevalence of EoE documented over the last several years. This might be related to greater awareness of the disease, in addition to the establishment of specific diagnostic guidance, although the actual augmentation in the epidemiology of this disease cannot be discounted.14,15

Eosinophilic oesophagitis can develop at any age, however, onset is principally during late adolescence and between the ages of 30 and 50, with males disproportionally afflicted.13,16,17 EoE is a common cause of food bolus obstruction (FBO), however, is it possible that EoE is not diagnosed in many patients presenting with a FBO due to endoscopies not being performed, or if they are, oesophageal biopsies are not collected.18,19

 

 

Fig. 4: Summary estimates and 95% CIs of population‐based prevalence from studies dealing with the epidemiology of eosinophilic oesophagitis in adult patients. Summary estimates are expressed as the number of EoE patients/100 000 inhabitants.14
4. What are the symptoms of EoE?

EoE is characterised clinically by symptoms of oesophageal dysfunction and histologically by eosinophilic infiltration of the oesophageal mucosa. Left untreated, the disorder is associated with the risk of inflammation and progressive fibrosis and development of a small-calibre oesophagus. The primary symptom of EoE is dysphagia: patients experience difficulty swallowing solid foods such as bread or meat and are at risk of food bolus impaction, in some cases requiring extraction by endoscopy in an emergency department. About half of all patients also report retrosternal pain. For some patients, the dysphagia becomes severe and may require dilation with an endoscopy to effectively manage these symptoms. Other symptoms include heartburn and regurgitation (during or immediately after eating). 

Clinical manifestation of EoE
  • ADULTS

  • Dysphagia (difficulty swallowing)
  • Odynophagia (pain with swallowing)
  • Bolus obstruction
  • Chest pain (during or immediately after eating)
  • Heartburn
  • Regurgitation (during or immediately after eating)
Table 2: Clinical manifestation of EoE. Adapted from Miehlke et al., 2015.20 Lorem Ipsum is simply dummy text of the printing and typesetting industry. Lorem Ipsum has been the industry's standard dummy text ever since the 1500s, when an unknown printer took a galley of type and scrambled it to make a type specimen book.
Many patients develop adaptive strategies to prevent symptoms during eating, such as chewing slowly, cutting food into small pieces, drinking copious amounts of liquids and/or adding liberal amounts of sauce to act as a lubricant. They may also avoid certain foods with textures which are hard to chew, such raw fruits and vegetables, crusty bread or certain meats (see Fig. 3). Notably, patients with EoE are at risk of social isolation due to a fear of embarrassment or distress following a choking episode and may avoid all gatherings involving food. For some, this may be associated with anxiety or depression.21 This may be accentuated by the constant need for close vigilance of every piece of food they eat and by the fear of a food bolus obstruction which they are unable to self-clear and thus are required to attend an emergency department for extraction.

Therefore, investigation of the patient’s medical history should specifically focus on difficulty swallowing and use adaptive behaviours taken to counteract these difficulties when eating solid foods. A discussion around mental health would also be an important consideration. This allows adequate assessment of the severity of symptoms and the associated disease burden on the patient. Furthermore, this provides a baseline to reference when evaluating the impact of a therapeutic intervention in the patient, including whether any of these adaptive behaviours have changed with this treatment. The latter could be particularly relevant if the patient still has some symptoms of oesophageal dysfunction after the initiation of the treatment, however, they are no longer avoiding certain foods or needing to drink a lot of liquids while eating, and/or eating slowly, etc.

Fig. 5: Typical foods that provoke swallowing difficulties include rice, meat, raw produce (e.g., carrots, apples) or French fries (hot chips). The swallowing difficulties arise because these foods have a hard texture, creating a higher risk for choking, not because they may trigger an allergic reaction per se.22    
5. What is the clinical course of EoE?

Eosinophilic oesophagitis (EoE) is a chronic, progressive inflammatory disease. Left untreated, the risk of oesophageal remodelling, leading to primary fibrostenotic phenotype with one of more strictures (e.g. small calibre oesophagus) increases over time; see Fig. 6 & 7). This is associated with worsening symptoms and the risk for the requirement for endoscopic rescue for small dilation and/or food bolus obstruction.23,24 The progressive nature of the disease is also demonstrated by manometry studies that reveal progressive loss of oesophageal motility over the duration of the disease.25

Fig. 6: Time-dependent endoscopic progression of EoE without treatment24

Fig. 7: The Risk of Stricture Development over Time in Cohort of Untreated EoE Patients24

 

6. References
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  • Kim HP and Dellon ES. An Evolving Approach to the Diagnosis of Eosinophilic Esophagitis. Gastroenterol Hepatol (N Y). 2018; 14 (6):358–366.
  • Dhar A, Haboubi HN, Attwood SE et al. British Society of Gastroenterology (BSG) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) joint consensus guidelines on the diagnosis and management of eosinophilic oesophagitis in children and adults. Gut. 2022; 71(8):1459–1487.
  • González-Cervera J, Arias Á, Redondo-González O, Cano-Mollinedo MM, Terreehorst I, Lucendo AJ. Association between atopic manifestations and eosinophilic oesophagitis: a systematic review and meta-analysis. Ann Allergy Asthma Immunol 2017; 118(5):582– 90.e2.
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  • Molina-Infante J, Arias Á, Alcedo J, García-Romero R, Casabona-Frances S, Prieto-García A et al. Step-up empiric elimination diet for pediatric and adult eosinophilic oesophagitis: The 2-4-6 study. J Allergy Clin Immunol 2018; 141(4):1365–72.
  • Miehlke S, Alpan O, Schröder S, Straumann A. Induction of eosinophilic oesophagitis by sublingual pollen immunotherapy. Case Rep Gastroenterol 2013; 7(3):363–8.
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  • Arias Á, Pérez-Martínez I, Tenías JM, Lucendo AJ. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic ooesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther 2016; 43(1):3–15.
  • Navarro P, Arias Á, Arias-Gonzalez L, Laserna-Mendieta EJ, Ruiz-Ponce M, Lucendo AJ. Systematic review with meta-analysis: the growing incidence and prevalence of eosinophilic ooesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther 2019; 49(9):1116–25.
  • orpha.net. Orphan drugs in Australia. Available at www.orpha.net/consor/cgi-bin/Education_AboutOrphanDrugs.php?lng=EN&stapage=ST_EDUCATION_EDUCATION_ABOUTORPHANDRUGS_AUS. Accessed August 2022.
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  • Simon D, Cianferoni A, Spergel JM, Aceves S, Holbreich M, Venter C et al. Eosinophilic oesophagitis is characterized by a non-IgE mediated food hypersensitivity. Allergy 2016; 71(5):611–20.
  • Sharma A, Philpott H. Frontline Gastroenterology 2019;0:1–2. doi:10.1136/flgastro-2019-101245.
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  • Taft TH, Guadagnoli L and Edlynn. Anxiety and depression in Eosinophilic Esophagitis: A scoping review and recommendations for future research. J Asthma Allergy 2019:12; 389–399.
  • Schoepfer AM, Straumann A, Pancazk R et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology. 2014; 147(6):1255–66.e21.
  • Lucendo AJ, Molina-Infante J, Arias Á, von Arnim U, Bredenoord AJ, Bussmann C et al. Guidelines on eosinophilic oesophagitis: evidence based statements and recommendations for diagnosis and management in children and adults. United European Gastroenterol J 2017; 5(3):335–58.
  • Schoepfer AM, Safroneeva E, Bussmann C, Kuchen T, Portmann S, Simon HU et al. Delay in diagnosis of eosinophilic oesophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 2013; 145(6):1230–6.e1–2.
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