Eosinophilic Esophagitis

Prevalence, Diagnosis, and Treatment in Childhood and Adulthood

Background: Eosinophilic esophagitis is a chronic, Th2 immune–mediated disease of the esophagus characterized by esophageal dysfunction and predominant eosinophilic inflammation. Its prevalence and incidence have risen in recent years and now stand at 16.1 per 100 000 persons and 1.7 per 100 000 persons per year.

Methods: This review is based on selected publications retrieved by a search in PubMed, Medline, and Google Scholar for clinical trials, reviews, and guidelines that were published between 2011 and 2024 in either English or German (search term, “eosinophilic esophagitis”).

Results: Eosinophilic esophagitis markedly impairs patients’ quality of life; its diagnosis is often delayed. It can be treated with an appropriately altered diet, pharmacotherapy, and/or endoscopic intervention (“diet, drugs, dilatation”). Elimination diets with the omission of 2, 4, or 6 food groups lead to histological remission in 43%, 60%, and 79% of patients, respectively. An entirely amino acid–based diet leads to histological remission in over 90% of patients, but can only be performed for a limited time. Topical corticosteroids lead to histological remission in 60–87% of cases, proton-pump inhibitors in 30–50%, and dupilumab (anti-IL-4Rα/IL-13Rα1) in 60–86%. These treatments differ widely in their side-effect profiles and in the restrictions they impose in everyday life, and their use must be considered individually for each patient. Because eosinophilic esophagitis is a chronic disease, remission maintenance therapy is needed over the long term.

Conclusion: Eosinophilic esophagitis was first described three decades ago. Effective treatments are available, but questions remain concerning the long-term course of the disease, remission maintenance therapy, and non-invasive markers of disease activity, among others. Delays in diagnosis should be avoided. The appropriate treatment and long-term care of the affected patients are needed to assure them an optimal quality of life.

Cite this as: Hoerning A, Steiss JO, Madisch A, de Laffolie J: Eosinophilic esophagitis: Prevalence, diagnosis, and treatment in childhood and adulthood. Dtsch Arztebl Int 2025; 122: 195–202. DOI: 10.3238/arztebl.m2025.0042

Since the first description of eosinophilic esophagitis (EOE) in the early 1990s (1, 2), chronic type 2 inflammation of the esophagus has become the second most common benign esophageal disease after gastroesophageal reflux disease (3). Other rarer differential diagnoses include acquired motility disorders such as diffuse eso-phageal spasm or achalasia.

The following presentation is based on publications (2011–2024) that were retrieved by a selective search in Medline, as well as selected older sources, on the topic of EoE in children and adults. The focus is on meta-analyses, reviews and randomized controlled trials; a few cohort studies are considered as well. Case descriptions were excluded.

Learning objectives

After reading this article, readers should:

• understand the basic characteristics of EoE
• know the diagnostic methods for identifying EoE
• have an overview of the various therapeutic approaches.

The frequency of EoE has not been studied in Germany to date. Switzerland, Denmark, and the Netherlands have seen an approximately 20-fold increase in incidence since the mid-1990s, without a simultaneous increase in endoscopy and esophageal biopsy rates (4, 5, 6). The reported disease frequencies vary geographically, with age, and over time: the prevalence and incidence range from 30.7 per 100,000 persons and 5.4 per 100 000 per year in North America to 16.1 per 100 000 and 1.7 per 100,000 per year in Europe. Men are affected 2 to 3 times more often than women, with 53.8 versus 20.1 cases per 100 000 persons; children and adolescents are affected somewhat less often (27 per 100 000) (3, 7, 8). Risk factors include a positive family history, a personal history of prior surgery for esophageal atresia (25% of cases), chronic intestinal failure (10% of cases), and pronounced atopy (9, 10). Many studies have shown an association with atopic type 2 inflammatory diseases such as bronchial asthma (27–60%), allergic rhinoconjunctivitis (57–70%), and atopic dermatitis (6–46%) (10, 11, 12, 13).

Pathogenesis

EoE is a non-IgE-mediated, Th2-helper lymphocyte-triggered, eosinophilic granulocyte-dominated chronic inflammatory disease of the esophageal mucosa. The cause is an abnormal interaction between genes and the environment; genetic risk factors include abnormalities of genes encoding ultrastructural components of the epithelial barrier, such as filaggrin and desmoglein, and mediators of allergic inflammation, such as TSLP (“thymic stromal lymphopoietin”) and the pro-inflammatory eotaxin-3 (14, 15, 16, 17). Harmful environmental factors such as ozone, microplastics, diesel exhaust fumes, premature birth, delivery by cesarean section, and early use of antibiotics in neonates are thought to be risk factors as well (18, 19). The most common food triggers are cow‘s milk, wheat, chicken eggs, soy, fish/seafood, and nuts/peanuts (20, 21). After prior barrier disruption of the esophageal mucosa, the allergens mentioned above enter the subepithelial space, either from the air via dissolution in saliva or directly in food, and evoke an immune reaction (22). Increased expression of eotaxin-3 in the esophageal mucosa recruits eosinophilic granulocytes. These, in turn, degranulate and cause chronic inflammation with fibrotic remodeling, followed by dysphagia and stenosis (23, 24).

In EoE, B-cell activation is only an epiphenomenon that can occur variably as part of the type-2 inflammation process. The use of non-invasive biomarkers for diagnosis (e.g. IgE antibodies) in EoE is not recommended because of their low sensitivity and specificity, as well as frequent misinterpretation (23).

In rare cases, de novo EoE occurs as a complication of sublingual immunotherapy (SLIT) or oral immunotherapy (OIT) in children and adults with an atopic predisposition. The prevalence is reported to be 2.7%; simply discontinuing both oral and sublingual immunotherapy usually brings about an improvement in symptoms (25).

In summary, genetic susceptibility combined with environmental factors and exposure to allergens, along with an underlying barrier disorder of the esophageal mucosa, leads to the development of EoE.

Clinical presentation and diagnostic evaluation

The diagnosis is often delayed because of the wide variety of presentations. In infants and toddlers, who cannot describe their symptoms verbally, the diagnostic latency is as long as 2–3 years; in one-third of affected adults, it is longer than 10 years even today (26, 27). The main symptoms differ depending on the age group (Box 1). Dysphagia and bolus obstruction dominate as typical cardinal symptoms in adolescents and adults; accompanying symptoms include retrosternal heartburn, epigastric pain, and thoracic pain.

Box 1

Age-specific differences in the manifestations of eosinophilic esophagitis

Some symptoms are often only reported when the patient is specifically asked about them, as they may not be prominent in everyday life. Many patients develop adaptive strategies to avoid discomfort when eating (28). Patients should, therefore, be asked about their eating habits—in particular, about the avoidance of certain foods, drinking after each bite, and chewing slowly – so that the extent of the symptoms can be more accurately assessed (Box 2) (29).

Box 2

Adaptation strategies of patients with eosinophilic esophagitis

A positive family history and a personal history of other atopic diseases can be important indicators; so can known gastrointestinal motility disorders or prior esophageal surgery. Most laboratory changes are non-specific, including systemic eosinophilia and an increase in total IgE. The general physical examination may reveal cutaneous signs of atopy; for children in particular, it is important to assess the patient’s nutritional status. The next step in the diagnostic evaluation is esophagogastroduodenoscopy (EGD), with at least two biopsies taken from the proximal, middle, and distal esophagus. Biopsies from the stomach and small bowel should always be taken at the first EGD to rule out competing diagnoses such as celiac disease, Crohn‘s disease, other eosinophilic gastrointestinal diseases (EGIDs), and infection. Histological evidence of at least 15 eosinophils per high-power field (HPF, standard size 0.3 mm2) confirms the diagnosis. In a few cases, an impedance measurement (measurement of the impedance of the esophageal contents over 24 h to assess reflux) may be necessary to distinguish EoE from gastroesophageal reflux disease (GERD). Typically, there is a clear gradient of eosinophils with a maximum in the distal esophagus.

EoE is often associated with a marked impairment of the quality of life and with accompanying psychosomatic disorders (30). Bolus impaction, fear of choking, frequent endoscopies, dietary restrictions, and the need for regular drug intake can cause anxiety, depression, and sleep disorders (20, 31, 32, 33, 34). Meta-analyses have shown that 9.8–12% and 9% of patients with EoE suffer from depression and anxiety, respectively (32). It was found in a large Danish registry study that adult patients with EoE take psychotropic drugs more often after diagnosis than the general population (hazard ratio 1.83 [1.6; 2.0]) (35).

Treatment

In principle, the treatment should be based on the guidelines of national and international medical specialty societies (29, 36, 37, 38). It is based on the three Ds (“diet, drugs, dilatation”), although the dilatation of stenoses is generally only needed by adolescent and adult patients, and not by children. Experienced (pediatric) gastroenterology centers can perform esophageal dilatation procedures with very rare complications (< 1%) (39).

Since clinical and histological recurrences are common, remission-maintaining therapy should be initiated after successful remission induction (23) (Figure).

Figure

The treatment of eosinophilic esophagitis in adulthood and in childhood and adolescence

Remission induction and long-term maintenance treatment

While dietary methods are recommended as first-line therapy in childhood and adolescence, on a par with proton pump inhibitors (PPI) and topical corticosteroids (TCS), they are considered only secondarily in adult medicine, in case budesonide does not bring about full remission or relapse occurs after it is discontinued (23). Elimination diet (EDs) range from the elimination of the most common food allergens as a 2-, 4– or 6-food elimination diet to an amino acid-based diet.

The 6-food elimination diet (6FED) (elimination of cow‘s milk protein, wheat/gluten, egg, soy, nuts, fish and seafood) has been well studied and reliably brings about clinical and histological remission in two-thirds to three-quarters of patients (children and adults) (20, 40). Once remission has been achieved, the eliminated foods are reintroduced one after the other, with serial endoscopy to identify the specific triggers. The dietary restrictions are burdensome. A distinction is drawn between top-down strategies (e.g., 6FED initially, then demonstration of histological remission, then stepwise reintroduction, with endoscopy each time) and step-up treatments (usually with elimination of cow‘s milk alone, or of cow‘s milk and wheat as 2FED, and the escalation to 4FED or 6FED if the histological abnormalities persist) (e1). When reintroduced, cow‘s milk causes a relapse in 85% of cases, eggs in 25%, wheat in 33%, and soy in 19% (e2). Since the vast majority of patients who respond to dietary therapy have only one or two food triggers, 6FED is often unnecessary (e3, e4). For example, 4-food elimination (milk, egg, wheat, soy) brings about remission in 60–64% of children with EoE (40, e2). In a prospective observational study, histological remission was achieved with 2FED, 4FED, and 6FED (step-up) in 43%, 60%, and 79% of 130 patients (including 25 children) (e1, e2).

The step-up strategy necessitated 35% fewer endoscopies than 6FE but met with more frequent problems of adherence.

One important aspect of wheat elimination is that gluten is not considered a relevant cause of EoE, and current knowledge thus clearly does not support a recommendation for eliminating all grains that contain gluten (i.e., wheat, barley, and rye) (e5). The data on 1FED are of clinical importance as they shown that this strategy meets with fewer problems of adherence. In a prospective observational study among children and adolescents, the elimination of cow‘s milk protein alone brought about histological remission in 51% of cases, endoscopic improvement in 59%, and improvement of previously reported symptoms in 61% (e3). In a direct, prospective comparison (RCT) of 4FED (milk, egg, wheat, soy) with the elimination of milk protein alone (1FED) in 63 children and adolescents with EoE, aged 6–17, 4FED was associated with a better clinical symptom score and a similar rate of histological remission (44 and 41%, respectively) (e4). Analogous findings were obtained in a randomized controlled trial in 129 adult patients with EoE, in which 1FED (elimination of cow‘s milk) was directly compared with 6FED (remission rates 34% and 40%, respectively) (e6).

Patients have trouble adhering to an amino acid-based elemental diet because of its highly restrictive nature and poor taste. A diet of this type is, therefore, mainly suitable for bridging, for infants, or for patients who can only be fed by tube. It is very effective, with a histological remission within a few weeks in over 90% of cases (e7, e8). Although no adverse drug effects are to be expected from nutritional therapy, the child‘s eating behavior can be affected, in some cases so severely as to constitute an avoidant/restrictive food intake disorder (ARFID) (e9). Many centers now recommend an initial 2FED or 4FED, generally with the elimination of cow‘s milk, wheat, and/or eggs (e10). All nutritional therapy should be supervised trained nutritionist and, if necessary, a (child) psychologist as part of a multidisciplinary treatment team (23).

In drug-induced induction therapy with proton pump inhibitors, the target dose is 2 mg/kg BW; half of this dose is given as maintenance therapy once histological remission has been achieved (23). The scientific data on the efficacy of proton pump inhibitors in the treatment of EoE are inconsistent, as a variety of different substance were used in non-uniform fashion and most of the pertinent studies have been retrospective cohort analyses. Published meta-analyses of prospectively and retrospectively collected case series indicate remission rates of 40% in children and 50% in adults (e11). Proton pump inhibitor therapy can be considered first-line treatment for EoE in children and adolescents. The lack of approval of PPI for this indication in Germany poses a dilemma for treatment teams.

Remission induction with TCS is performed with the administration of budesonide as an oral suspension or orodispersible tablet for 8–12 weeks (Table 1). Its efficacy has been well documented in multiple randomized, placebo-controlled trials and meta-analyses, and it brings about histological and clinical remission in most cases (60–87%) (e12, e13). As with PPI TCS are not approved for the treatment of EoE in children and adolescents. TCS therapy is not without side effects: esophageal candidiasis (in up to 10.5% of cases) (e14, e15) and secondary adrenal suppression (0–15%) (e16, e17) have been described in long-term therapy. TCS should, therefore, only be used to achieve histological remission; the dosage should then be halved for maintenance therapy (Table 1) (e18).

Dupilumab was approved in 2024 as subcutaneous injection therapy for intractable EoE in patients aged 1 and above. Dupilumab is a monoclonal antibody that blocks the IL-4 and IL-13-mediated signaling cascade and thereby inhibits type 2 inflammation. In the approval RCTs, dupilumab brought about histological remission at 16 and 52 weeks in 60%–84% and 100% of cases, respectively, and significantly improved disease symptoms and the health-related quality of life (e19, e20, e21, e22).

Further options that are now under study in phase 3 trials, such as targeted IL-5, IL-4, or IL-13 blockade and prostaglandin D2 receptor antagonists, have achieved variable rates of success, with good histological responses, but sometimes without any significant improvement of clinical symptoms (e23, e24). Mast cell stabilization with sodium cromoglycate, montelukast (a leukotriene receptor antagonist), or omalizumab (anti-IgE) was ineffective (e24).

Special aspects of long-term treatment in adulthood

Once a treatment has brought about remission, the same treatment is continued over the long term for maintenance (23). It is mandatory to monitor the success of treatment, both in adults and in children, with esophagogastroduodenoscopy including a biopsy after 8–12 weeks of treatment, as the clinical manifestations do not always correlate with the endoscopic and histologic findings (23). According to the management algorithm, patients with EoE should undergo clinical, gastroscopic, and histological examinations every 1–2 years, regardless of age.

As in induction therapy, orodispersible budesonide tablets have been found safe and effective for remission maintenance. In a randomized, controlled phase-3 trial, clinical-histologic remission was maintained in ca. 75% of patients at 48 weeks (Table 1). No clinically relevant changes in morning serum cortisol levels were observed. The rate of symptomatic, histologically confirmed esophageal candidiasis was ca. 5%. The drug was likewise safe and effective in the extension study, which was continued up to week 96 (e25).

Table 1

Table of evidence on the pharmacotherapy of EoE

Table 2

Evidence table on elemental and elimination diets for the treatment of eosiniophilic esophagitis (EoE)

The role of PPIs in long-term therapy is unclear, as there have been no controlled long-term studies, and this treatment therefore remains off label. In studies of prospective cohorts, remission has been found to be maintained in 31% of cases when high-dose PPI (omeprazole 2 × 40 mg) has been used to induce remission (remission in 33% after 8 weeks) and is continued thereafter at half the dose. With standard-dose PPI (omeprazole 20 mg), remission maintenance is expected in 15% of cases. These data suggest that PPI medication is not well suited for maintenance therapy and should only be used in exceptional cases (e26).

6FED is not well established as a treatment for maintaining remission. Although histological remission can be expected in 73% of cases after six weeks of strict 6FED, uncontrolled studies suggest that remission is maintained in only ca. 37% of cases one year, provided that allergen elimination has been continued without interruption (e27).

The main problem is that reintroduction of the previously eliminated food groups in adult patients generally leads to recurrent EoE (e27).

It was reported in other studies that 6FED led to sustained remission in 19% of cases. In 73% of cases, adherence problems were the main reason for recurrence, despite support from a dietician (e28).

In adults as in children, treatment with dupilumab was shown to bring about frequent remission up to week 52, with a highly favorable safety profile. The initial findings from the use of dupilumab in routine clinical practice include histological remission rates (<15 Eos/HPF) of 92% for dupilumab as first-line treatment, 85% as treatment of previously intractable disease, and 80% in patients with strictures, with subsequent improvement of the stenotic narrowing of the lumen (e29, e30).

Health care needs and outlook

There is an urgent need to identify noninvasively obtainable markers of disease activity, as repeated endoscopies are highly burdensome for patients, their families, and the health care system.

Clinical follow-up studies and disease data registries are needed so that clinical data on the manifestations, diagnostic evaluation, treatment, long-term course, and complications of EoE in children and adults can be collected and analyzed. This would enable comparisons across treatments and the development of a stratified therapeutic approach. For example, from the patient‘s point of view, primary treatment with biologic drugs appears reasonable if TCS carry a higher risk of side effects, or in cases of marked atopy or allergological comorbidity. In young children and infants, nutritional therapies are sometimes very successful; if the triggering allergen is identified early on, tolerance can develop later, enabling successful reintroduction.

Finally, there are many unanswered questions about the quality of life and about maintenance therapy. These, too, should be addressed as part of the EoE treatment initiatives that are now underway in the German-speaking countries.

Conflict of interest statement
JdL has received research funding and honoraria from Abbvie, Takeda, Falk, Danone, and Sanofi. He has served as a paid consultant for Abbvie, Takeda, Falk, Mirum, Sanofi, and Danone. He is a member of the advisory boards of Sanofi, Takeda, Abbvie, and Danone.

AH was a member of the advisory board of Sanofi, Takeda, and Danone. He has received lecture honoraria from Sanofi, Mirum, Albireo, Orphalan, Takeda, Abbvie, Hexal, Danone, and Pfizer.

JS has received lecture honoraria from Sanofi and Danone.

AM was a member of the advisory board of Sanofi and has received lecture honoraria from Sanofi and Falk.

Manuscript submitted on 11 September 2024, revised version accepted on 25 February 2025.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. André Hörning

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