Eosinophilic esophagitis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

There are three major treatments for eosinophilic esophagitis (EoE), and these treatments are often referred to as the 3 Ds:[1][3][28][101]

Drugs (pharmacologic treatments)

Diet (dietary elimination)

Dilation (esophageal dilation performed during endoscopy).

General principles of treatment

Guidelines recommend that either pharmacologic or dietary therapy can be used as a first-line therapy.[1][3][4][28][101] The majority of patients (60% to 70%) will respond to either of these modalities, although no direct head-to-head comparative randomized 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 pharmacologic 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 multiprofessional team, including a dietitian.[4]

Several pharmacologic treatments for EoE 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
Empiric elimination diet (e.g., the six-food elimination diet)
Hypoallergenic elemental formula-based diet.

Both the pharmacologic and dietary elimination therapies primarily target the esophageal inflammation associated with EoE. Esophageal dilation, however, targets esophageal fibrostenotic remodeling, seen on endoscopy as strictures or narrowing. This is a mechanical approach that can increase esophageal caliber, but does not impact the underlying inflammation. Currently, there are no pharmacologic agents used for EoE 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]

Pharmacologic treatment

Topical/swallowed corticosteroids are the most extensively studied and used medications. The use of corticosteroids for the treatment of EoE is off-label.

Choice of corticosteroid or PPI

Budesonide is commonly used for this indication. Randomized controlled trials show a marked reduction in eosinophilia in both adults and children with EoE.[102][103][104][105][106][107]
Fluticasone is commonly used and has been extensively studied for this indication. Randomized controlled trials have shown a marked reduction in esophageal eosinophilia in both adults and children with EoE.[108][109][110][111][112][113]
The most studied PPI is omeprazole, but the choice of PPI is probably unimportant. Although PPI therapy is not licensed for EoE, current UK guidelines recommend giving omeprazole for 8-12 weeks with a clear explanation of the indication (EoE rather than gastroesophageal reflux disease [GERD]) given to the primary care team.[4]

Effectiveness

Network meta-analysis and retrospective data suggest that treatment with oral viscous budesonide improves endoscopic and histologic outcomes compared with topical/swallowed fluticasone.[114][115] Longer mucosal contact time associated with use of oral viscous budesonide is believed to contribute to improve histologic outcomes compared with topical/swallowed corticosteroids.[83][116]
One double blind, double-dummy RCT found that swallowed fluticasone (from a multidose inhaler) and oral viscous budesonide significantly decreased esophageal eosinophil counts and improved dysphagia during initial treatment of EoE.[117] 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 EoE.
One short-term double-blind trial (14 days treatment, 2-week follow-up) reported histologic remission in >90% of EoE patients randomized to orodispersible budesonide (compared with 0% in placebo recipients).[103] In one longer phase 3 randomized 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.[118]
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 histologic remission.[119]
Histologic remission and symptom response mean that PPI treatment is considered effective in patients with EoE.[4] The response rates reported are 60% to 70% (clinical) and 50% (histologic).[120][121] Most studies assessed response after 8 weeks' treatment.

Administration

Topical administration of corticosteroids may be accomplished by modifying existing asthma formulations. For example, multi-dose inhaler (MDI) formulations of fluticasone, beclomethasone, mometasone, and ciclesonide have all been used in EoE.[122][123][124][125][126][127][128][129] Budesonide has been used in the oral viscous form.[130][131][132] 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 EoE.[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 esophagus.
There are no special administration requirements for PPIs.

Treatment duration

Previous recommendations were to treat with topical corticosteroids for 8 weeks, and then repeat esophagogastroduodenoscopy (EGD) and biopsy to assess endoscopic and histologic treatment response. Current UK guidelines suggest performing repeat EGD with biopsy every 8-12 weeks after starting treatment with either a topical corticosteroid or a PPI.[1][3][4][101]

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 histologic response.[28] UK guidelines recommend orodispersible budesonide as a maintenance therapy for EoE in adults and adolescents (subject to approval), and tailored oral viscous budesonide as a maintenance therapy for EoE in children.[4]

For patients who initially have a good response (i.e., symptom improvement, endoscopic improvement, and histologic 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 EGD performed to confirm ongoing treatment response. If there is a relapse, the dose can be increased.
There are no randomized controlled trials to define the maintenance treatment strategy for PPIs, although PPI maintenance is considered an appropriate long-term treatment for EoE patients in clinical and histologic remission.[4]

Nonresponders

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 nonresponse rate ranges from <5% to 50% in randomized 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, nonresponse 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.[133][134] 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.[112]

Local irritation from medication deposition and esophageal candidiasis are commonly reported adverse effects of corticosteroid therapy, but candidiasis generally resolves on treatment and doesn't require topical corticosteroids to be stopped.[118] 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 EoE and the UK guidelines do not recommend systemic corticosteroids for adult or pediatric patients with nonstricturing 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.[100]

Anti-allergy drugs such as leukotriene receptor antagonists and mast-cell stabilizers are ineffective in EoE and not recommended.[4] Immune modulators and biologics may have a role and continue to be studied, but data are generally not promising.[135] [ ] There is insufficient evidence to recommend immune modulators and biologics typically used for inflammatory bowel diseases in the management of EoE.[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 pediatric 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 EGD is performed to assess histologic and endoscopic treatment response.[4] Elemental formula diets have, however, been shown to have a more rapid treatment effect, and repeat EGD may be performed 4 weeks into treatment.[39][100] Depending on the type of diet, individual foods are reintroduced and endoscopy is repeated in order to identify triggers and allow liberalization of the diet with safe foods.

Empiric elimination diet

This diet involves removing the most common foods that are known to trigger EoE. The best-studied empiric 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 EoE as determined by a number of studies: dairy, wheat, egg, soy, nuts, and seafood.[54][55][56][57]

Traditionally, patients on an SFED eliminate all six foods for a period of 6 weeks, and repeat EGD is performed to assess for histologic 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 EGD is repeated. If there is an ongoing response, that food is safe, the next food is added back for 6 weeks, and another EGD 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 1 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, soy, 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%.[136] However, these data are largely from expert centers with multidisciplinary teams well versed in supporting patients through this process. In the real world, these response rates may be lower.[54][137]

The restrictive nature of the SFED means that it can have a big impact on health-related quality of life and eating behaviors, 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 soy; 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%).[138] In two studies of dairy elimination alone in children, response rates were approximately 60%.[139][140] One randomized, open-label trial comparing SFED with 1-food elimination diet (animal milk) reported similar histologic remission rates and improvements in histologic 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 EoE.[141]

UK guidelines recommend following a "step up" approach to dietary elimination, even though the SFED results in higher histologic remission rates than the FFED and the TFED (79% remission for SFED, 60% for FFED and 43% for TFED).[142] Following a step up approach is also estimated to reduce endoscopy use by 20% and shorten the diagnostic process time.[4][142] 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 EoE, was initially cited as evidence of the allergic basis of EoE 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][136][143]

While treatment with elemental formulas is extremely effective in EoE, 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 EGD may be performed 4 weeks into treatment.[39][100]

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 center 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%.[136] Food allergy testing-based elimination diets have low efficacy in patients with EoE because currently available allergy tests do not reliably identify food triggers.[55][57][144][145] Skin prick tests detect immediate immunoglobulin E (IgE) reactions, and patch testing detects delayed IgG-mediated responses. However, EoE is not a classic IgE- or IgG-mediated disease, and agreement between test-detected sensitizations 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 EoE.[4]

Endoscopic esophageal dilation

For patients who have signs of esophageal remodeling, specifically esophageal strictures or narrowing, endoscopic dilation is an important adjunct treatment.[28][146] It is recommended in symptomatic patients with strictures that persist in spite of medical or dietary therapy, and initially in patients with severely symptomatic esophageal stenosis.[3][4][101]

Dilation is a mechanical approach to stretching the esophagus 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 esophageal caliber.

Large patient series of 8-9 years duration suggest that esophageal dilation is safe, with a rate of perforation comparable to that for esophageal dilation in other conditions such as peptic strictures (i.e, approximately 0.3%).[147][148][149][150][151][152][153][154][155][156][157][158] The pooled prevalence rates of perforation are 0.4% to 0.9% for esophageal dilation in patients with EoE.[159] The bleeding rate is 0.03% to 0.05%.[159]

While there have been no randomized controlled trials or prospective comparisons of the three different esophageal dilation modalities (wire-guided bougie, nonwire-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 esophageal 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 esophagus 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 EoE, this makes sense. If a balloon is used, direct visualization and measurement of the esophageal caliber 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 esophageal 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][149] 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 esophageal eosinophilia or a decrease in eosinophils to <15 eos/hpf (or <15 eos/0.3 mm²); resolution of or improvement in symptoms; normalization of or improvement in the endoscopic appearance), most will need ongoing maintenance therapy. Because EoE is a chronic condition, symptoms and eosinophilia tend to recur when treatment is stopped.[127][130][160] At a minimum, patients who have had food impactions, fibrostenotic remodeling of the esophagus with strictures or narrowing, or rapidly recurrent symptoms after stopping treatment, should be placed on maintenance therapy. However, guidelines recommend all patients with EoE should be considered for maintenance therapy, given the risk of possible progression to fibrostenosis with ongoing esophageal 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.

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