Residency · Residency · Allergy Immunology

Eosinophilic Gastrointestinal Disorders

Overview

Eosinophilic gastrointestinal disorders (EGIDs) are chronic immune-mediated conditions characterized by pathologic eosinophilic infiltration of the gastrointestinal tract in the absence of secondary causes. The spectrum includes eosinophilic esophagitis (EoE), eosinophilic gastritis (EoG), eosinophilic gastroenteritis (EGE), and eosinophilic colitis (EoC). Eosinophilic esophagitis is by far the most common and best-characterized entity within this spectrum. Secondary causes of gastrointestinal eosinophilia that must be excluded before an EGID diagnosis is established include parasitic infections, inflammatory bowel disease, drug hypersensitivity reactions, connective tissue diseases, hypereosinophilic syndrome, and gastroesophageal reflux disease.

Eosinophilic Esophagitis (EoE)

Epidemiology

The prevalence of eosinophilic esophagitis is approximately 1 in 2,000 individuals overall, with both a true increase in incidence and improved recognition contributing to the rising number of diagnoses. There is a male predominance of approximately 3:1, with peak incidence in children and young adults in their twenties and thirties. A strong atopic association exists, with 50 to 80 percent of patients having comorbid allergic disease including allergic rhinitis, asthma, atopic dermatitis, or IgE-mediated food allergy. Genetic predisposition has been identified, with polymorphisms in genes encoding TSLP, calpain-14 (CAPN14), and eotaxin-3 (CCL26) associated with disease susceptibility.

Pathophysiology

Eosinophilic esophagitis is a type 2 immune-mediated disease driven by exposure to food and aeroallergens. The pathogenic cascade begins with epithelial barrier dysfunction, leading to release of the alarmins TSLP and interleukin-33 from esophageal epithelial cells. Interleukin-13 emerges as the central effector cytokine, driving multiple pathologic processes. It upregulates eotaxin-3 (CCL26), the most potent eosinophil chemoattractant and the most highly upregulated gene in EoE. IL-13 also downregulates desmoglein-1 (DSG1), disrupting the epithelial barrier; downregulates filaggrin expression in the esophageal epithelium; and induces periostin and TGF-beta, which promote subepithelial fibrosis.

Interleukin-5 contributes to eosinophil survival and activation, though it plays a less dominant role in EoE pathogenesis compared with IL-13. Interleukin-4 drives IgE class switching and contributes to food sensitization. The eosinophils recruited to the esophagus release a destructive array of mediators including major basic protein (MBP), eosinophil cationic protein (ECP), TGF-beta (promoting fibrosis), and IL-13 itself, creating a self-amplifying inflammatory loop. The natural history of untreated EoE is one of progression from a predominantly inflammatory phenotype to a fibrostenotic phenotype over years, with stricture formation representing the consequence of chronic, uncontrolled inflammation.

Clinical Presentation

The clinical presentation of EoE varies with age. Children typically present with feeding difficulties, vomiting, abdominal pain, failure to thrive, and food refusal. Adolescents and adults most commonly present with dysphagia (the most frequent presenting symptom), food impaction (which may be the initial presentation in 33 to 50 percent of cases), chest pain, and heartburn that is unresponsive to proton pump inhibitor therapy. Many patients develop subtle adaptive behaviors that may go unrecognized, including prolonged chewing, excessive water intake with meals, preferential avoidance of solid textures, and cutting food into very small pieces. Food impaction requiring emergent endoscopic disimpaction is a common mode of initial presentation in previously undiagnosed patients.

Diagnosis

The diagnosis of EoE requires both symptoms of esophageal dysfunction and histologic confirmation of 15 or more eosinophils per high-power field on esophageal biopsy. An important conceptual update is that PPI-responsive esophageal eosinophilia is now classified within the EoE spectrum rather than as a separate diagnostic entity.

Endoscopic findings are described using the EREFS scoring system: edema (manifesting as decreased vascular pattern), rings (concentric rings producing a "trachealized" or corrugated appearance), exudates (white plaques or microabscesses), furrows (longitudinal grooves), and stricture formation. Additional findings include crepe-paper mucosa, which is fragile and tears on passage of the endoscope. Importantly, the endoscopic appearance is normal in 10 to 25 percent of EoE patients, emphasizing that biopsies should be obtained whenever clinical suspicion exists, regardless of the macroscopic appearance. The biopsy protocol requires a minimum of 6 biopsies from at least 2 esophageal locations (proximal and distal), as eosinophilic infiltration is characteristically patchy.

<image>An endoscopic image composite showing the characteristic findings of eosinophilic esophagitis using the EREFS scoring system. Five panels arranged in a grid: (1) Rings/trachealization showing concentric mucosal rings giving a corrugated appearance, (2) White exudates/microabscesses appearing as scattered white plaques on esophageal surface, (3) Longitudinal furrows showing vertical grooves in the esophageal mucosa, (4) Edema with loss of vascular pattern compared to normal mucosa, (5) Stricture showing narrowed esophageal lumen. Each panel labeled with the EREFS component name and score (0, 1, or 2). Adjacent inset: histological image showing >=15 eosinophils per high-power field in esophageal squamous epithelium, with eosinophil microabscess and basal cell hyperplasia. Normal esophageal histology shown for comparison (0 eosinophils normally).</image>

Treatment

Pharmacologic Therapy

Proton pump inhibitor therapy has emerged as a first-line treatment in current guidelines. High-dose PPI (omeprazole 20 to 40 mg twice daily or equivalent) achieves histologic response (fewer than 15 eos/hpf) in 30 to 50 percent of patients. The mechanism extends beyond acid suppression: PPIs exert a direct anti-inflammatory effect by blocking eotaxin-3 expression in esophageal epithelial cells.

Topical (swallowed) corticosteroids represent the most effective pharmacologic therapy, achieving histologic response in 60 to 80 percent of patients. Fluticasone is administered by puffing from a metered-dose inhaler and swallowing (without a spacer) at doses of 440 to 880 micrograms twice daily in adults, though this represents off-label use. Budesonide viscous slurry is prepared by mixing budesonide respules with sucralose (Splenda) to form a viscous preparation at 1 to 2 mg twice daily. Budesonide orodispersible tablet (Jorveza) is approved in Europe at 1 mg twice daily for induction and 0.5 mg twice daily for maintenance. Patients should be instructed not to eat or drink for 30 minutes after administration. Side effects include esophageal candidiasis in 5 to 10 percent and rare adrenal suppression with long-term use. Relapse upon discontinuation is common, supporting the recommendation for ongoing maintenance therapy.

Dupilumab (Dupixent)

Dupilumab, an anti-IL-4Ralpha monoclonal antibody that blocks both IL-4 and IL-13 signaling, became the first FDA-approved biologic for EoE in 2022. It is indicated for patients aged 1 year and older (weighing at least 15 kg) with inadequate response to or intolerance of conventional therapy. Dosing is weight-based, with adults receiving 300 mg subcutaneously weekly. The TRIDENT studies demonstrated that 60 percent of patients achieved fewer than 6 eos/hpf at week 24 (compared with 5 percent with placebo), with significant improvements in the Dysphagia Symptom Questionnaire (DSQ), endoscopic appearance (EREFS scores), and histologic findings. Dupilumab is well tolerated, with injection site reactions as the primary adverse effect and no risk of esophageal candidiasis. A particular advantage is its ability to simultaneously treat EoE and comorbid atopic conditions.

Dietary Therapy

Dietary therapy provides an alternative to pharmacologic management. An elemental diet using amino acid-based formula achieves approximately 95 percent histologic remission but is impractical for long-term use. Empiric elimination diets follow a stepwise approach. The six-food elimination diet (6FED), removing milk, wheat, egg, soy, fish/shellfish, and tree nuts/peanuts, achieves approximately 70 percent histologic response. Sequential reintroduction of individual foods, one every 6 to 8 weeks with repeat endoscopy and biopsy after each, identifies the specific trigger. The four-food elimination diet (4FED), removing milk, wheat, egg, and soy, achieves 54 to 64 percent response. The two-food elimination diet (2FED), removing milk and wheat (the two most common triggers), achieves 40 to 43 percent response and may serve as the initial step in a step-up approach. Single food elimination of milk alone achieves approximately 30 percent response.

Milk is the most common EoE trigger food, identified in approximately 50 to 60 percent of patients, followed by wheat (30 percent), egg (20 percent), and soy (15 percent). A critical point is that skin prick testing and serum-specific IgE have poor predictive value for identifying EoE trigger foods because EoE is not purely IgE-mediated, and these tests should not serve as the sole guide for elimination diets. Atopy patch testing has been investigated but is not standardized and is not recommended in routine practice.

Monitoring and Long-Term Management

Endoscopy with biopsy is necessary to confirm histologic response after each therapeutic intervention, typically performed 6 to 12 weeks after initiating treatment. Symptom improvement may not correlate with histologic improvement, particularly in patients with established fibrostenotic disease in whom dysphagia persists due to fixed strictures despite resolution of active eosinophilic inflammation. Esophageal dilation is indicated for strictures and narrow-caliber esophagus and is generally safe with modern techniques. Long-term maintenance therapy, whether pharmacologic or dietary, is recommended to prevent disease progression from inflammatory to fibrostenotic phenotype.

Non-EoE Eosinophilic GI Disorders

Eosinophilic Gastritis (EoG) and Eosinophilic Gastroenteritis (EGE)

Eosinophilic gastritis and gastroenteritis are less common than EoE, with an estimated prevalence of 2 to 8 per 100,000. The clinical presentation depends on the layer of bowel wall involvement. Mucosal involvement, the most common pattern, produces abdominal pain, nausea, vomiting, diarrhea, malabsorption, and iron deficiency. Muscular layer involvement can cause bowel obstruction or pseudo-obstruction. Serosal involvement, the least common pattern, may produce eosinophilic ascites and pleural effusions. Diagnosis requires 30 or more eos/hpf on gastric biopsies, though no universally accepted threshold exists, and the normal stomach contains some eosinophils. Peripheral eosinophilia is present in 50 to 80 percent of cases. Treatment options include dietary elimination, systemic corticosteroids (prednisone 0.5 to 1 mg/kg), topical budesonide, and emerging biologic therapies (dupilumab and anti-IL-5 agents are under investigation).

Eosinophilic Colitis (EoC)

Eosinophilic colitis is the rarest EGID, and its diagnosis requires exclusion of inflammatory bowel disease (especially Crohn's disease), parasitic infection, and drug reactions. The normal colon contains resident eosinophils, with higher concentrations in the cecum and ascending colon, making diagnostic thresholds controversial (generally 40 to 60 eos/hpf in the right colon and 30 or more in the left colon are considered abnormal). Infantile eosinophilic colitis (allergic colitis) is the most common form, occurring in formula-fed or breastfed infants and presenting with bloody stools. It typically resolves with maternal dietary elimination or transition to a hypoallergenic formula.

<image>A schematic diagram of the GI tract showing the spectrum of eosinophilic gastrointestinal disorders. Anatomical illustration of esophagus, stomach, small intestine, and colon with highlighted regions for each EGID: EoE (esophagus), EoG (stomach), EGE (stomach and small intestine), EoC (colon). For each location, show: diagnostic biopsy threshold (eos/hpf), typical clinical presentation, treatment options, and prevalence estimate. Cross-sectional inset of bowel wall showing three patterns of eosinophilic infiltration: mucosal (surface), muscular (middle layer), and serosal (outer layer) with their respective clinical manifestations. Adjacent panel comparing normal eosinophil counts in different GI segments (esophagus: 0 normally; stomach: 2-10; small intestine: 10-26; cecum: up to 25) to emphasize that the esophagus normally has zero eosinophils.</image>

Key Clinical Pearls

• The esophagus normally has ZERO eosinophils; any eosinophils on esophageal biopsy are abnormal and >=15 eos/hpf confirms EoE diagnosis
• PPI-responsive esophageal eosinophilia is now classified within EoE, not as a separate entity; PPI is first-line therapy
• Milk is the most common EoE trigger food (~50-60%); SPT/sIgE testing has poor predictive value for identifying EoE triggers because EoE is not purely IgE-mediated
• Untreated EoE progresses from inflammatory to fibrostenotic phenotype; maintenance therapy is recommended to prevent stricture formation
• Dupilumab (anti-IL-4Ralpha) is the first FDA-approved biologic for EoE; achieves histologic remission in ~60% of patients
• Eotaxin-3 (CCL26) is the most upregulated gene in EoE; it is driven by IL-13 and is the key eosinophil chemoattractant in the esophagus
• Symptoms may not correlate with histologic disease activity in fibrostenotic EoE; endoscopic monitoring with biopsy is essential
• EoE can develop as a complication of oral immunotherapy for food allergy (2.7-8% incidence)

References

1. Dellon ES, et al. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis. Am J Gastroenterol. 2013;108(5):679-692.
2. Hirano I, et al. Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology. 2020;158(1):111-122.
3. Lucendo AJ, et al. Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations (UEG/EAACI/ESGE/ESPGHAN/EUREOS). United European Gastroenterol J. 2017;5(3):335-358.
4. Kagalwalla AF, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2006;4(9):1097-1102.
5. Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology. 2015;148(6):1143-1157.

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