Approach

There are three major treatments for eosinophilic oesophagitis (EoO), and these treatments are often referred to as the 3 Ds:[1][3][28][99]

  • Drugs (pharmacological treatments)

  • Diet (dietary elimination)

  • Dilation (oesophageal dilation performed during endoscopy).

General principles of treatment

Guidelines recommend that either pharmacological or dietary therapy can be used as a first-line therapy.[1][3][4][28][99] The majority of patients (60% to 70%) will respond to either of these modalities, although no direct head-to-head comparative randomised trials have been performed to determine whether one approach is superior to another. In the absence of comparative data, the choice of initial treatment depends on patient preference, provider expertise, and local resources. 

The approach is the same for patients of any age, although very young children are almost always treated with dietary therapy first line. There are too few data about combination therapy (i.e., dietary therapy plus pharmacological treatment) to recommend this approach, but it can be considered in case of treatment failure, provided the patient can be carefully monitored and followed up by a multi-professional team, including a dietitian.[4]

Several pharmacological treatments for EoO have been studied. Topical/swallowed corticosteroids and proton-pump inhibitors (PPIs) are both considered first-line therapies.

The available options for dietary elimination include:

  • Targeted elimination diet

  • Empirical elimination diet (e.g., the six-food elimination diet)

  • Hypoallergenic elemental formula-based diet.

Both the pharmacological and dietary elimination therapies primarily target the oesophageal inflammation associated with EoO. Oesophageal dilation, however, targets oesophageal fibrostenotic remodelling, seen on endoscopy as strictures or narrowing. This is a mechanical approach that can increase oesophageal calibre, but does not impact the underlying inflammation. Currently, there are no pharmacological agents used for EoO that reverse fibrosis to the same degree. In many patients, treatments that target inflammation as well as those that address fibrostenosis must be used together.[4]

Pharmacological treatment

Topical/swallowed corticosteroids are the most extensively studied and used medications.

Choice of corticosteroid or PPI

  • Budesonide is commonly used for this indication. Randomised controlled trials show a marked reduction in eosinophilia in both adults and children with EoO.[100][101][102][103][104][105]

  • Fluticasone is commonly used and has been extensively studied for this indication. Randomised controlled trials have shown a marked reduction in oesophageal eosinophilia in both adults and children with EoO.[106][107][108][109][110][111]

  • The most studied PPI is omeprazole, but the choice of PPI is probably unimportant. Although PPI therapy is not licensed for EoO, current UK guidelines recommend giving omeprazole for 8-12 weeks with a clear explanation of the indication (EoO rather than gastro-oesophageal reflux disease [GORD]) given to the primary care team.[4]

Effectiveness

  • Network meta-analysis and retrospective data suggest that treatment with oral viscous budesonide improves endoscopic and histological outcomes compared with topical/swallowed fluticasone.[112][113] Longer mucosal contact time associated with use of oral viscous budesonide is believed to contribute to improve histological outcomes compared with topical/swallowed corticosteroids.[83][114]

  • One double blind, double-dummy RCT found that swallowed fluticasone (from a multi-dose inhaler) and oral viscous budesonide significantly decreased oesophageal eosinophil counts and improved dysphagia during initial treatment of EoO.​[115] There was no significant difference in the change in peak eosinophil count from baseline between swallowed fluticasone and oral viscous budesonide; either appears to be an acceptable treatment for EoO.

  • One short-term double-blind trial (14 days treatment, 2-week follow-up) reported histological remission in >90% of EoO patients randomised to orodispersible budesonide (compared with 0% in placebo recipients).[101] In one longer phase 3 randomised trial, a remission rate of 75% after 48 weeks' treatment was reported among patients receiving orodispersible budesonide, compared with a 4.4% remission rate with placebo.[116]

  • A parallel study of orodispersible budesonide versus placebo (6 weeks double-blind treatment followed by 6 weeks open label) demonstrated that treatment with orodispersible budesonide has a clear impact on clinical, as well as histological remission.[117]

  • Histological remission and symptom response mean that PPI treatment is considered effective in patients with EoO.[4] The response rates reported are 60% to 70% (clinical) and 50% (histological).​[118][119] Most studies assessed response after 8 weeks' treatment. 

Administration

  • Budesonide as an orodispersible tablet is specifically approved for use in adults with EoO, although it may not be universally available. The orodispersible tablet dissolves in the mouth over the course of 2 minutes and is gradually swallowed with saliva. Appropriate administration facilitates optimal exposure of the oesophageal mucosa to the active substance. In the UK and Europe, orodispersible budesonide is approved for use in adults with EoO. Orodispersible budesonide may also be beneficial for adolescents but may not be licensed for use in this age group.[4]

  • Topical administration of corticosteroids may be accomplished by modifying existing asthma formulations. For example, multi-dose inhaler (MDI) formulations of fluticasone, beclometasone, mometasone, and ciclesonide have all been used in EoO.[120][121][122][123][124][125][126][127] Budesonide has been used in the oral viscous form.[128][129][130] Oral viscous budesonide is prepared by mixing the budesonide aqueous inhalation solution (nebules) into a slurry with sucralose before being swallowed. Age-appropriate oral viscous budesonide formulations may be suitable as induction therapy for children with EoO.[4] MDIs can be puffed into the mouth during end-expiration and swallowed rather than inhaled. 

  • Patients should not eat or drink for 30-60 minutes after taking corticosteroids to prevent washing the medication out of the oesophagus.

  • There are no special administration requirements for PPIs.

Treatment duration

  • Previous recommendations were to treat with topical corticosteroids for 8 weeks, and then repeat oesophagogastroduodenoscopy (OGD) and biopsy to assess endoscopic and histological treatment response. Current UK guidelines suggest performing repeat OGD with biopsy every 8-12 weeks after starting treatment with either a topical corticosteroid or a PPI.[1][3][4][99]

  • Most patients will need maintenance therapy.[4] For topical corticosteroids, the principle is to use the lowest dose that continues to provide the best clinical, endoscopic, and histological response.[28] UK guidelines recommend orodispersible budesonide as a maintenance therapy for EoO in adults and adolescents (subject to approval), and tailored oral viscous budesonide as a maintenance therapy for EoO in children.[4]

  • For patients who initially have a good response (i.e., symptom improvement, endoscopic improvement, and histological improvement with the eosinophil count decreasing at least to <15 eosinophils per high-power microscopy field [eos/hpf]), the corticosteroid dose can be halved and a repeat OGD performed to confirm ongoing treatment response. If there is a relapse, the dose can be increased.

  • There are no randomised controlled trials to define the maintenance treatment strategy for PPIs, although PPI maintenance is considered an appropriate long-term treatment for EoO patients in clinical and histological remission.[4]

Non-responders

  • For patients who do not respond or who relapse, there are various options. The corticosteroid or PPI dose can be increased, the corticosteroid can be swapped for a PPI (or vice versa), or combination pharmacological treatment (corticosteroid plus a PPI) can be considered. Other treatment modalities can be tried, such as dietary elimination (most common), monoclonal antibodies, inclusion in clinical trials, or dilation.

  • The non-response rate ranges from <5% to 50% in randomised controlled trials, depending on factors such as the dose, agent, and definition of response. In the few real world studies that have examined predictors of response for these agents, non-response is seen in >40% of patients depending on the agent used and the definition of response.[8]

Monitoring

  • There are no recommendations to routinely monitor bone density or adrenal function in adult patients receiving topical corticosteroid therapy; however, this issue is controversial and is under study. Until further data are available, UK guidelines recommend monitoring for adolescents and children, especially for children receiving long-term topical corticosteroid therapy and if they are already receiving corticosteroids for another indication.[4]

  • There are no special monitoring requirements for PPIs.

Adverse effects

  • The systemic exposure to topical corticosteroid is thought to be very small because of poor absorption from the gastrointestinal tract (fluticasone), or a very high first-pass rate of hepatic metabolism (budesonide).

  • Some cases of adrenal insufficiency have been reported, mostly among patients on higher corticosteroid doses who use other inhaled or intranasal corticosteroids to treat concomitant atopic disease.[131][132] Long-term studies assessing the adrenal axis in both adults and children are needed, as well as additional data assessing the effect on growth and bone mineral density in children.[110]

  • Local irritation from medication deposition and oesophageal candidiasis are commonly reported adverse effects of corticosteroid therapy, but candidiasis generally resolves on treatment and doesn't require topical corticosteroids to be stopped.[116] These effects are seen in up to 15% to 20% of patients.[28]

  • Serious adverse events associated with PPIs are rare.

Systemic corticosteroids are not routinely used in the management of EoO and the UK guidelines do not recommend systemic corticosteroids for adult or paediatric patients with non-stricturing disease.[4] However, they may be considered in selected patients where rapid relief is required for severe symptoms such as dysphagia (which limits adequate nutrition or hydration), dehydration, weight loss, or where other treatments have failed.[133]

Anti-allergy drugs such as leukotriene receptor antagonists and mast-cell stabilisers are ineffective in EoO and not recommended.[4] Immune modulators and biologicals may have a role and continue to be studied, but data are generally not promising.[134] [ Cochrane Clinical Answers logo ] ​​ There is insufficient evidence to recommend immunomodulators and biologicals typically used for inflammatory bowel diseases in the management of EoO.[4]

Dietary elimination

If specific food triggers are identified and subsequently avoided, dietary elimination can be a long-term treatment approach with a durable response.

All paediatric and most adult patients require the support of a multidisciplinary team consisting of a gastroenterologist, an allergist, and a dietitian.[4] Education, support, and encouragement are all needed in motivated patients electing this treatment. 

After an initial diet is selected, patients remain on the diet for 8-12 weeks and then an OGD is performed to assess histological and endoscopic treatment response.[4] Elemental formula diets have, however, been shown to have a more rapid treatment effect, and repeat OGD may be performed 4 weeks into treatment.[39][133] Depending on the type of diet, individual foods are reintroduced and endoscopy is repeated in order to identify triggers and allow liberalisation of the diet with safe foods.

Empirical elimination diet

This diet involves removing the most common foods that are known to trigger EoO. The best-studied empirical elimination diet is the six-food elimination diet (SFED) where six foods are removed in the absence of, or regardless of, allergy test results. These six foods are the top triggers for EoO as determined by a number of studies: dairy, wheat, egg, soya, nuts, and seafood.[54][55][56][57]

Traditionally, patients on an SFED eliminate all six foods for a period of 6 weeks, and repeat OGD is performed to assess for histological and endoscopic response. If there is a good response (i.e., defined as improved symptoms, improved endoscopy, and improved histology with at least <15 eos/hpf) then the food reintroduction process is started.

Each individual food group is added back for 6 weeks and the OGD is repeated. If there is an ongoing response, that food is safe, the next food is added back for 6 weeks, and another OGD is performed. This process is repeated until all foods have been assessed. If there are signs that a food is a trigger (i.e., recurrent symptoms, recurrent endoscopic findings, and increased eosinophil counts, usually ≥15 eos/hpf), then that food is removed and, after a 2-week wash-out period, a new food is added. At the end of this process, a set of one or more food triggers is identified and, if these foods are removed from the diet, long-term durable treatment responses can be achieved.

There is no specific order for foods to be reintroduced, but based on expert opinion, most providers add back the least allergenic foods first. From a practical standpoint, the order would be seafood, nuts, soya, egg, wheat, and then dairy, which is the most common trigger.

The response rate for the SFED, based on a meta-analysis, is approximately 72%.[135] However, these data are largely from expert centres with multidisciplinary teams well versed in supporting patients through this process. In the real world, these response rates may be lower.[54][136]

The restrictive nature of the SFED means that it can have a big impact on health-related quality of life and eating behaviours, may result in nutritional deficits, and adherence is less likely in the long term. The great majority of responders to SFED are also shown ultimately on food re-challenge to have only one or two trigger foods; therefore, a more effective and less restrictive strategy, requiring fewer repeat endoscopies, may well be to start with a 4-, 2-, or even 1-food elimination diet.[58] Consideration may be given to a 4-food elimination diet (FFED), which removes dairy, wheat, egg, and soya; a 2-food elimination diet (TFED), which removes dairy and wheat or dairy and egg; and even a 1-food elimination where dairy is removed. In children, the FFED had response rates of approximately 60% to 70%, but this was lower in adults (approximately 50%).[137] In two studies of dairy elimination alone in children, response rates were approximately 60%.[138][139] One randomised, open-label trial comparing SFED with 1-food elimination diet (animal milk) reported similar histological remission rates and improvements in histological and endoscopic features with both 1-food and 6-food elimination. The study suggests eliminating animal milk as the first step in dietary management in patients with EoO.[140]​​

UK guidelines recommend following a 'step up' approach to dietary elimination, even though the SFED results in higher histological remission rates than the FFED and the TFED (79% remission for SFED, 60% for FFED and 43% for TFED).[141] Following a step up approach is also estimated to reduce endoscopy use by 20% and shorten the diagnostic process time.​[4][141]​ UK guidelines recommend that dietary treatments are supervised by an experienced dietitian and begin with a TFED (milk plus wheat or egg) before stepping up to the FFED (milk, wheat, egg, and soya) and finally the SFED (milk, wheat, egg, soya, fish/shellfish, and tree nuts/peanuts) if remission is not achieved.[4] Each exclusion diet should be adhered to for at least 8-12 weeks and assessed endoscopically and histologically, with endoscopy being repeated after the reintroduction of individual foods.[4]

Elemental formula diet

Elemental formulas are hypoallergenic and contain only amino acids, simple carbohydrates, and medium-chain triglycerides. The use of these formulas, with nearly universal response in children with EoO, was initially cited as evidence of the allergic basis of EoO and of the importance of food antigens.[37] Since that time, studies in children have shown response rates from 90% to 95%; one small study in adults reported a response rate of 72%.[31][38][39][135][142]

While treatment with elemental formulas is extremely effective in EoO, there are difficulties with their use outside of infants:

  • They are not palatable and a large volume must be administered every day, so some patients require enteral feeding tubes to obtain the required amount for adequate nutrition

  • It is a laborious process to attempt to identify safe foods when all foods have been removed from the diet

  • It is socially isolating for a patient of any age to be on an elemental formula

  • Formulas are very expensive.

For these reasons, use of this formula is typically limited to infants, patients with severe disease complicated by malnutrition, and patients who are refractory to all other treatments. UK guidelines only recommend elemental diets for selected patients with disease refractory to conventional treatments and after careful consideration by a multidisciplinary team.[4] It is a requirement to involve a dietitian in the care of the patient on these formulas to ensure adequate calories and macronutrients/micronutrients.

Elemental diets have a rapid treatment effect, and repeat OGD may be performed 4 weeks into treatment.[39][133]

Targeted elimination diet

This diet uses the results of allergy testing, most commonly skin prick tests but sometimes patch testing, to eliminate specific foods from the diet.

Efficacy of this approach ranges broadly depending on the centre and allergy test modality used. However, a systematic review and meta-analysis that included 1128 children and 189 adults, respectively, estimated the efficacy of this approach to be approximately 45%.[135] Food allergy testing-based elimination diets have low efficacy in patients with EoO because currently available allergy tests do not reliably identify food triggers.[55][57][143][144] Skin prick tests detect immediate immunoglobulin E (IgE) reactions, and patch testing detects delayed IgG-mediated responses. However, EoO is not a classic IgE- or IgG-mediated disease, and agreement between test-detected sensitisations and food triggers identified during reintroduction challenges is poor. In the UK, food-specific antibody testing (Ig-E or IgG-4) and antibody-directed dietary elimination are not recommended for patients with EoO.[4]

Endoscopic oesophageal dilation

For patients who have signs of oesophageal remodelling, specifically oesophageal strictures or narrowing, endoscopic dilation is an important adjunct treatment.[28][145] It is recommended in symptomatic patients with strictures that persist in spite of medical or dietary therapy, and initially in patients with severely symptomatic oesophageal stenosis.[3][4][99]

Dilation is a mechanical approach to stretching the oesophagus and disrupting scar tissue; it does not have any anti-inflammatory effect on the underlying eosinophilic process. However, patients experience rapid symptomatic improvement (despite no change in inflammation) because it effectively increases oesophageal calibre.

Large patient series of 8-9 years duration suggest that oesophageal dilation is safe, with a rate of perforation comparable to that for oesophageal dilation in other conditions such as peptic strictures (i.e, approximately 0.3%).[146][147][148][149][150][151][152][153][154][155][156][157] The pooled prevalence rates of perforation are 0.4% to 0.9% for oesophageal dilation in patients with EoO.​[158] The bleeding rate is 0.03% to 0.05%.[158]

While there have been no randomised controlled trials or prospective comparisons of the three different oesophageal dilation modalities (wire-guided bougie, non-wire-guided bougie, and through-the-scope balloon), all three have been reported to be safe and effective.​[4][28]

The key principle of dilation is to start low and go slow. Most patients have had oesophageal strictures for years, if not decades, and there is no need to reach a large dilation size right away. The endoscopist should carefully gauge the lumen of the oesophagus to choose an initial dilator size. The known diameter of the endoscope used can be helpful, particularly if a 9-mm scope does not pass but a 5-mm scope does. If there is a question, it is always better to start with a smaller diameter.

For bougies, a protocol where there is relook endoscopy after each dilator size is passed has been shown to be safe, and given the known mucosal fragility in EoO, this makes sense. If a balloon is used, direct visualisation and measurement of the oesophageal calibre is possible. The goal of dilation is to cause a mucosal tear, termed a dilation effect. While the extent of dilation effect has not been studied, the result of an adequate dilation is often a 5-10 mm wide rent with a length throughout the narrowed or strictured area. Serial dilation is often required in these patients to achieve a goal diameter of >15 mm. In addition, there are emerging data that control of inflammation with either medications or dietary elimination reduces the number of dilations needed to achieve this diameter. UK guidelines recommend use of anti-inflammatory medication in combination with endoscopic oesophageal dilation.[4]

When discussing dilation with patients, it is important to note that up to three-quarters of patients will have chest discomfort for several days post-dilation.[3][148] This does not portend a complication such as perforation, but patients should be informed of this likelihood and mild analgesics can be prescribed.

Maintenance therapy

When patients achieve a good response to treatment (i.e., resolution of oesophageal eosinophilia or a decrease in eosinophils to <15 eos/hpf (or <15 eos/0.3 mm²); resolution of or improvement in symptoms; normalisation of or improvement in the endoscopic appearance), most will need ongoing maintenance therapy. Because EoO is a chronic condition, symptoms and eosinophilia tend to recur when treatment is stopped.[125][128][159] At a minimum, patients who have had food impactions, fibrostenotic remodelling of the oesophagus with strictures or narrowing, or rapidly recurrent symptoms after stopping treatment, should be placed on maintenance therapy. However, guidelines recommend all patients with EoO should be considered for maintenance therapy, given the risk of possible progression to fibrostenosis with ongoing oesophageal eosinophilia.[3][28] For patients treated with topical corticosteroids or PPIs, the lowest dose that maintains remission should be used. For patients treated with dietary elimination, long-term avoidance of the identified food triggers is recommended.

Use of this content is subject to our disclaimer