Approach

Patients with eosinophilic oesophagitis (EoO) may be offered the following treatment options:​​[3][27][79]​​​​​[105]​​​​

  • Pharmacological treatments (e.g., topical corticosteroids, proton-pump inhibitors [PPIs], dupilumab)

  • Dietary elimination

  • 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.​​[2][3]​​[27][79]​​[105]​​​​ 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. An improvement in inflammatory features (i.e., furrows, exudates, and oedema) at each endoscopy is a desired endpoint of pharmacological or dietary therapy.[82]​ 

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.[2]

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.[3]​ 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.[2]

Several pharmacological treatments for EoO have been studied. Recommended treatment options include:[3][79]

  • Topical corticosteroids

  • PPIs

  • Dupilumab

Anti-allergy drugs such as leukotriene receptor antagonists and mast-cell stabilisers are ineffective in EoO and not recommended.[2]​ Immune modulators and biologicals may have a role and continue to be studied, but data are generally not promising.[106] [ Cochrane Clinical Answers logo ] ​ There is insufficient evidence to recommend immunomodulators and biologicals typically used for inflammatory bowel diseases in the management of EoO.[2]

Pharmacological treatment: topical corticosteroids

Guidelines recommend topical corticosteroids (e.g., budesonide, fluticasone) as first-line treatment for EoO.[3][79]​ Recommendations are based on the findings of randomised controlled trials (RCTs) which have found a marked reduction in oesophageal eosinophilia upon treatment with corticosteroids in both adults and children with EoO.[107][108][109][110][111][112][113][114][115][116][117][118]

General considerations

  • There are various topical corticosteroid formulations available, and availability depends on geographic location. Budesonide is commercially available for this indication as an oral suspension, or as an orodispersible tablet. An oral viscous formulation may also be prepared, and is an option for children who cannot receive the commercially available formulations. There is no commercially available formulation of fluticasone for this indication and existing asthma formulations must be used.

  • 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.[119]​ Orodispersible budesonide may also be beneficial for adolescents but may not be licensed for use in this age group.[2]

  • Budesonide oral suspension is approved in the US for patients aged ≥11 years with EoO, based on results from clinical trials.[120][121][122]​ Treatment up to 12 weeks is recommended.

  • Topical administration of corticosteroids may also 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.[123][124][125][126][127][128][129][130] Budesonide has been used in the oral viscous form.[131][132][133] 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.[2] 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 drugs out of the oesophagus.

  • Systemic corticosteroids are not routinely used in the management of EoO. UK guidelines do not recommend systemic corticosteroids for adult or paediatric patients with non-stricturing disease.[2] However, they may be considered may be considered as the initial treatment for oesophageal strictures before oesophageal dilation and 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.[79]

Monitoring

  • Guidelines suggest performing repeat oesophagogastroduodenoscopy (OGD) with biopsy every 8-12 weeks after starting treatment with a topical corticosteroid.​​[2][3]​​[105]​​

  • There are no recommendations to routinely monitor bone density or adrenal function in adult patients receiving topical corticosteroids. 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.[2]

  • Most patients will need maintenance therapy.[2] For topical corticosteroids, the principle is to use the lowest dose that continues to provide the best clinical, endoscopic, and histological response.[27] 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.[2]

  • 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.

  • For patients who do not respond or who relapse, the corticosteroid dose can be increased, the corticosteroid can be swapped for a PPI, or the combination of a corticosteroid plus a PPI can be considered. Other treatment modalities can be tried, such as dietary elimination (most common), dupilumab, inclusion in clinical trials, or dilation.

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).

  • Adrenal insufficiency has been reported, mostly among patients on higher corticosteroid doses who use other inhaled or intranasal corticosteroids to treat concomitant atopic disease.[134][135]​ 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.[117]

  • Local irritation from drug 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. These effects are seen in up to 15% to 20% of patients.[27]

Pharmacological treatment: PPIs

PPIs have been suggested as a treatment for EoO.[3]

General principles[2]

  • 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 omeprazole treatment for 8-12 weeks with a clear explanation of the indication (EoO rather than GORD) given to the primary care team.

Monitoring[2][3]​​[105]​​

  • Guidelines suggest performing repeat OGD with biopsy every 8-12 weeks after starting treatment with a PPI.

  • For patients who do not respond or who relapse, the PPI dose can be increased, the PPI can be swapped for a corticosteroid, or the combination of a corticosteroid plus a PPI can be considered. Other treatment modalities can be tried, such as dietary elimination (most common), dupilumab, inclusion in clinical trials, or dilation.

Adverse effects

  • Serious adverse events associated with PPIs are rare.

Pharmacological treatment: dupilumab

Dupilumab, an interleukin (IL)-4 receptor antagonist monoclonal antibody, is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of EoO in adults and children aged ≥1 year and weighing ≥15 kg body weight.[79][136][137][138]

General considerations

  • Early use of dupilumab may be considered for patients with comorbid atopic conditions (e.g., asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps), or for patients with a strong preference to avoid dietary restriction or topical corticosteroids.[139]​ Do not reduce or discontinue concurrent drug treatments for comorbid atopic conditions without specialist guidance. Dupilumab can also be considered as first-line therapy in patients presenting with severe EoO.[139]

  • Dupilumab may be considered as a step-up therapy under certain circumstances:[3][139]

    • Difficult to treat EoO

    • Failure to thrive, poor growth, or significant weight loss due to EoO

    • Patients with severe dietary restrictions

    • Patients with adverse effects to current therapy

    • Patients refractory to current therapy (PPI or corticosteroid): due to continued symptoms, persistent abnormal oesophageal inflammation, adverse effects of current therapy, intolerance of current therapy, or inability to adhere to current therapy. The American College of Gastroenterology (ACG) suggests dupilumab as a second-line or add-on therapy for patients with EoO who do not improve with PPI therapy.

    • Patients with clinically significant oesophageal strictures or narrow calibre oesophagus.

  • May be less preferred by some patients as it involves injections.[139]

​Monitoring[3]

  • Endoscopic assessment to monitor treatment response is recommended between 12 and 24 weeks based on clinical trial findings.

Adverse effects[139]

  • Injection site reactions are possible.

  • Conjunctivitis has been observed with the use of dupilumab in other conditions, although it has not been reported yet in EoO.

  • Broad cytokine block. This might help with other allergies, but long-term safety is still unclear.

Dietary elimination

The available options for dietary elimination include:

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

  • Hypoallergenic elemental formula-based diet

  • Targeted elimination diet

The ACG suggests empirical elimination diet for the treatment of EoO.[3]

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.[2] 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.[2] Elemental formula diets have, however, been shown to have a more rapid treatment effect, and repeat OGD may be performed 4 weeks into treatment.[38][79]​​ 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.[3][53][54][55][56]​​

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%.[140] 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.[53][141]

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.[57] 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%).[142] In two studies of dairy elimination alone in children, response rates were approximately 60%.[143][144] 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.[145]​​

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).[146] Following a step up approach is also estimated to reduce endoscopy use by 20% and shorten the diagnostic process time.​[2][146]​ 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.[2] 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.[2]

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.[36] 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%.[30][37][38][140][147]

While treatment with elemental formulas is extremely effective in EoO, there are difficulties with their use outside of infants:[3]

  • 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.[2] 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.[38][79]​​

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%.[140] Food allergy testing-based elimination diets have low efficacy in patients with EoO because currently available allergy tests do not reliably identify food triggers.[54][56][148][149]​ 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. UK and US guidelines do not recommend food-specific antibody testing (Ig-E or IgG-4) and antibody-directed dietary elimination for patients with EoO.[2][3]

Endoscopic oesophageal dilation

For patients who have signs of oesophageal remodelling, specifically oesophageal strictures or narrowing, endoscopic dilation is an important adjunct treatment.[3][27][150]​​​ 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.​[2][3]​​[105]​​

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%).[151][152][153][154][155][156][157][158][159][160][161][162] The pooled prevalence rates of perforation are 0.4% to 0.9% for oesophageal dilation in patients with EoO.​[163] The bleeding rate is 0.03% to 0.05%.[163]

While there have been no RCTs 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.​[2][27]

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 drugs or dietary elimination reduces the number of dilations needed to achieve this diameter. UK guidelines recommend use of anti-inflammatory therapy in combination with endoscopic oesophageal dilation.[2]

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.​[153] 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.[128][131][164] 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]​​[27]​​[105]

For patients treated with topical corticosteroids or PPIs, the lowest dose that maintains remission should be used. 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 patients with EoO patients in clinical and histological remission.[2]

For patients treated with dietary elimination, long-term avoidance of the identified food triggers is recommended.

For patients treated with dupilumab, it should be noted that treatment has demonstrated efficacy for up to 1 year. However, the optimal long-term management strategy remains to be determined, specifically regarding whether treatment frequency can be safely reduced or if concomitant EoO therapies can be withdrawn.[139]

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