Eosinophilic esophagitis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. Patients presenting with EoE have a history of elevated serum IgE levels, response to interventions such as diet restriction, history of food hypersensitivity. Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to vascular spaces. The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE. They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions. The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response. IL-5 and IL-13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation. IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue. IL-5 prolongs the survival of the eosinophils. The activated TH2 response leads to the recruitment and activation of Mast cells degranulate and cause tissue damage and repair. Cytokines produced by TH-1 cells are tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, TNF-α is expressed by the epithelial cells of the esophagus whereas the INF-γ is upregulated by the peripheral T cells. Delayed or type- IV hypersensitivity is the mechanism is involved in the EoE rather than the non-IgE. It is postulated that the EoE-defining endoscopic and histologic manifestations are a culmination of the disease process which, may have debilitating long-term effects including strictures and food impactions in untreated or poorly managed cases of EoE. CD34+ myeloid precursor cells in the bone marrow produce eosinophils and then the eosinophils develop granulation and migrate to vascular spaces. Eosinophils although present in all the layers of the esophagus in patients with EoE, they are predominant in the lamina propria and submucosa of the esophagus. The preformed granule proteins of the eosinophils are ECP- Eosinophil Cationic Protein, MBP- Major Basic Protein, EPO- Eosinophil Peroxidase, EDN- Eosinophil Derived Neurotoxin. Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues. Eosinophils synthesize and release cytokines such as IL-5, IL-13, Transforming growth factor (TGF)-α and -β, Chemokines (eotaxins and RANTES), Lipid mediators such as platelet activating factor (PAF) and leukotriene C4. IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils. Eosinophils cause inflammation in the EoE patients by the following mechanisms Angiogenic molecules from the eosinophils recruits the inflammatory cells and the increase the vascularity. Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling. MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophageal through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules. The above-mentioned processes lead to tissue remodeling eventually causing an overall esophageal dysfunction. TGF-β and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins. The importance of eosinophils in mediating tissue fibrosis is supported by evidence in both murine and human models. These findings not only highlight the importance of targeting fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling. There is no established system for the classification of Eosinophilic esophagitis (EoE).The causes of EoE are the food and pollen react with the lining of the esophagus, these allergens cause the multiplication of eosinophils in the layers of the esophagus and produce a protein that causes inflammation. The inflammation further cause scarring, excessive fibrous tissue deposition over the lining of the esophagus eventually leading to dysphagia. The dysphagia can sometimes worsen to cause food impaction and additional symptoms such as chest pain.Eosinophilic esophagitis must be differentiated from other diseases that cause dysphagia such as reflux esophagitis, esophageal carcinoma, systemic sclerosis, esophageal spasm, pseudoachalasia, stroke, esophageal candidiasis and chagas disease.The incidence Eosinophilic esophagitis (EoE) is approximately 10 per 100,000 individuals worldwide. The prevalence of EoE is approximately 50-100 per 100,000 individuals worldwide. Patients of all age groups may develop EoE. It usually affects individuals of the white race. Males are more commonly affected by EoE than females. EoE is a rare disease that tends to affect people with a history of European ancestry.The risk factors of EoE are as follows bimodal age distribution common in both children and adults, male gender, cold and dry climate, EoE is common in people with a history of European ancestry, summer and fall, positive family history of EoE, history of allergies such as asthma, industrial exposures, environmental allergies, chronic respiratory disease, food allergies and atopic dermatitis.There is insufficient evidence to recommend routine screening for Eosinophilic esophagitis (EoE). In patients with EoE, symptoms persist over years raising suspicion that a chronic inflammatory process is an underlying event responsible for it. The inflammatory activity is proportional to the density of the eosinophilic infiltration in the esophageal tissue. Similar to asthma, EoE has chronic persistent eosinophilic inflammation and can eventually lead to irreversible structural changes of the esophagus which is called re-modeling of the esophagus. The esophageal mucosa in patients with a longstanding EoE is characterized by a loss of elasticity. On histologic examination of the subepithelial compartments of the esophagus show an increase in the fibrous tissue. The endosonographic studies of the esophagus in patients with EoE shows following findings: Thickening of the mucosa, Thickening of the submucosal, and muscularis propria layers. In patients with EoE, the chronic eosinophilic inflammation leads to an increased deposition of the fibrous connective tissue which in turn causes the remodeling of the esophagus hindering the esophageal transport.*The complications of the EoE are as follows Scarring of esophagus-leading to dysphagia, Esophageal stenosis- causing food stuck. Tears or perforation during the endoscopy or retching leading to boerhaave syndrome.*The prognosis of the EoE is as follows: EoE is a relatively newly recognized disease, there is very limited data on the causes, natural history, prognosis, diagnosis and management of these patients. The long-term prognosis of the EoE is unclear but patients diagnosed with EoE have an unaffected lifespan. Patients should be counseled that although it is a chronic disease, it is a benign condition. Patients who are untreated or have discontinued the treatment have progression of their symptoms. The EoE patients with a narrow esophageal lumen are resistant to the corticosteroid treatment and require many esophageal endoscopic procedures. The dysphagia is common in patients with increased eosinophil count in the blood. The EoE is restricted only to the esophagus sparing the stomach and the duodenum. A common concern by patient and their families is what is the chance of that EoE may progress to a malignancy if untreated, EoE does not progress into metaplasia or dysplasia or esophageal cancer.The history and symptoms of eosinophilic esophagitis (EoE), dysphagia, regurgitation, cough, chest pain, food impaction, upper abdominal pain, vomiting. Clinical features in children are follows abdominal pain, nausea, emesis, failure to thrive. Clinical features in the adolescents and adults are as follows dysphagia, heartburn, food impaction, strictures.There are no specific diagnostic markers to diagnose the EoE patients. Although not specific, elevated serum IgE levels are identified in majority patients. An increased peripheral eosinophil count is also seen in majority patients. There are 3 main ways in which food allergies can be detected in EE are as follows skin prick testing, blood allergy testing, atopy patch testing.

Historical Perspective

In 1978, Landres et al reported an isolated case of vigorous achalasia and concluded that this was a variant of eosinophilic gastroenteritis in a patient with marked hypertrophy and eosinophilic infiltration of the esophagus. In 1981, Picus and Frank reported a case of a 16-year-old boy with progressive dysphagia for 1.5 years, endoscopic findings were suggestive of multiple 1-mm nodular filling defects in the esophagus in an area of stricture with dilatation above. The radiology showed a luminal narrowing, wall rigidity, and high circulating eosinophil count assumed to be a variant of eosinophilic gastroenteritis. In 1982 Münch et al and in 1983 Matzinger and Daneman both described isolated cases of esophageal eosinophilia with dysphagia in patients with assumed eosinophilic gastroenteritis. In 1985, Feczko et al reported 3 cases of eosinophilic infiltration of the esophagus, with 2 of the patients showing eosinophilic gastroenteritis. Two out of 3 patients developed esophageal stricture secondary to submucosal fibrosis. In 1985 reported eosinophilic infiltration in the esophageal mucosal biopsy in 11 patients with average age of 14.6 years - these patients had reflux symptoms and their eosinophil density was low. In retrospect, these were probably patients with gastroesophageal reflux disease (GERD). In 1989, Attwood et al described esophageal asthma an episodic dysphagia with eosinophilic infiltrates. These investigators compared a group of 15 adults who presented with dysphagia without esophageal obstruction and normal pH monitoring to a group of 100 adults with GERD as defined by increased acid exposure in the distal esophagus. In 1993, Attwood et al reported 12 adults with dysphagia, normal pH monitoring, and dense esophageal eosinophilia, seven patients had food hypersensitivity, and all required advanced intervention (dilatation and/or steroids in 1 case) for resolution of symptoms. In 1994, Straumann et al described a series of 10 patients with acute recurrent dysphagia seen over a 4-year period, who showed discrete endoscopic changes, and high concentrations of epithelial esophageal eosinophils, who improved following systemic steroid and antihistamine treatment. In 1995 the first publication in children was reported by Kelly et al, they identified 10 children who were diagnosed on clinical and histological grounds to have EoE. Six out of those 10 had been subject to antireflux therapy without any symptomatic improvement, two of these patients had already received fundoplication, and all responded well to amino acid formulas, suggesting an allergic etiology. The characteristics in pediatric EoE appeared to reflect greater amounts of regurgitation and failure to thrive, while the typical presentation in adults with EoE was dysphagia and food impaction. In 2003 the chronic nature of the natural history of EoE was described by Straumann et after the follow-up of 30 adults with EoE.

Classification

There is no established system for the classification of Eosinophilic esophagitis (EoE).

Pathophysiology

Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens. Patients presenting with EoE have a history of elevated serum IgE levels, response to interventions such as diet restriction, history of food hypersensitivity. Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to vascular spaces. The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE. They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions. The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response. IL-5 and IL-13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation. IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue. IL-5 prolongs the survival of the eosinophils. The activated TH2 response leads to the recruitment and activation of Mast cells degranulate and cause tissue damage and repair. Cytokines produced by TH-1 cells are tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, TNF-α is expressed by the epithelial cells of the esophagus whereas the INF-γ is upregulated by the peripheral T cells. Delayed or type- IV hypersensitivity is the mechanism is involved in the EoE rather than the non-IgE. It is postulated that the EoE-defining endoscopic and histologic manifestations are a culmination of the disease process which, may have debilitating long-term effects including strictures and food impactions in untreated or poorly managed cases of EoE. CD34+ myeloid precursor cells in the bone marrow produce eosinophils and then the eosinophils develop granulation and migrate to vascular spaces. Eosinophils although present in all the layers of the esophagus in patients with EoE, they are predominant in the lamina propria and submucosa of the esophagus. The preformed granule proteins of the eosinophils are ECP- Eosinophil Cationic Protein, MBP- Major Basic Protein, EPO- Eosinophil Peroxidase, EDN- Eosinophil Derived Neurotoxin. Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues. Eosinophils synthesize and release cytokines such as IL-5, IL-13, Transforming growth factor (TGF)-α and -β, Chemokines (eotaxins and RANTES), Lipid mediators such as platelet activating factor (PAF) and leukotriene C4. IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils. Eosinophils cause inflammation in the EoE patients by the following mechanisms Angiogenic molecules from the eosinophils recruits the inflammatory cells and the increase the vascularity. Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling. MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophageal through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules. The above-mentioned processes lead to tissue remodeling eventually causing an overall esophageal dysfunction. TGF-β and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins. The importance of eosinophils in mediating tissue fibrosis is supported by evidence in both murine and human models. These findings not only highlight the importance of targeting fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling.

Causes

The causes of EoE are the food and pollen react with the lining of the esophagus, these allergens cause the multiplication of eosinophils in the layers of the esophagus and produce a protein that causes inflammation. The inflammation further cause scarring, excessive fibrous tissue deposition over the lining of the esophagus eventually leading to dysphagia. The dysphagia can sometimes worsen to cause food impaction and additional symptoms such as chest pain.

Differentiating Eosinophilic esophagitis overview from Other Diseases

Eosinophilic esophagitis must be differentiated from other diseases that cause dysphagia such as reflux esophagitis, esophageal carcinoma, systemic sclerosis, esophageal spasm, pseudoachalasia, stroke, esophageal candidiasis and chagas disease.

Epidemiology and Demographics

The incidence Eosinophilic esophagitis (EoE) is approximately 10 per 100,000 individuals worldwide. The prevalence of EoE is approximately 50-100 per 100,000 individuals worldwide. Patients of all age groups may develop EoE. It usually affects individuals of the white race. Males are more commonly affected by EoE than females. EoE is a rare disease that tends to affect people with a history of European ancestry.

Risk Factors

The risk factors of EoE are as follows bimodal age distribution common in both children and adults, male gender, cold and dry climate, EoE is common in people with a history of European ancestry, summer and fall, positive family history of EoE, history of allergies such as asthma, industrial exposures, environmental allergies, chronic respiratory disease, food allergies and atopic dermatitis.

Screening

There is insufficient evidence to recommend routine screening for Eosinophilic esophagitis (EoE).

Natural History, Complications, and Prognosis

Natural History

The natural course of primary EoE is, in patients with EoE, symptoms persist over years raising suspicion that a chronic inflammatory process is an underlying event responsible for it. The inflammatory activity is proportional to the density of the eosinophilic infiltration in the esophageal tissue. Similar to asthma, EoE has chronic persistent eosinophilic inflammation and can eventually lead to irreversible structural changes of the esophagus which is called re-modeling of the esophagus. The esophageal mucosa in patients with a longstanding EoE is characterized by a loss of elasticity. On histologic examination of the subepithelial compartments of the esophagus show an increase in the fibrous tissue. In patients with EoE, the chronic eosinophilic inflammation leads to an increased deposition of the fibrous connective tissue which in turn causes the remodeling of the esophagus hindering the esophageal transport.

Complications

The complications of the EoE are as follows: Scarring of esophagus-leading to dysphagia, Esophageal stenosis, Tears or perforation during the endoscopy or retching leading to boerhaave syndrome.

Prognosis

The long-term prognosis of the EoE is unclear but patients diagnosed with EoE have an unaffected lifespan.

Diagnosis

Diagnostic Criteria

History and Symptoms

The history and symptoms of eosinophilic esophagitis (EoE), dysphagia, regurgitation, cough, chest pain, food impaction, upper abdominal pain, vomiting. Clinical features in children are follows abdominal pain, nausea, emesis, failure to thrive. Clinical features in the adolescents and adults are as follows dysphagia, heartburn, food impaction, strictures.

Physical Examination

The physical examination of the patients with EoE is usually normal.

Laboratory Findings

There are no specific diagnostic markers to diagnose the EoE patients. Although not specific, elevated serum IgE levels are identified in majority patients. An increased peripheral eosinophil count is also seen in majority patients. There are 3 main ways in which food allergies can be detected in EE are Skin prick testing, Blood allergy testing, Atopy patch testing.

Imaging Findings

The barium swallow of the esophagus shows multiple rings associated with eosinophilic esophagitis, There are no MRI nor CT scan findings associated with EoE. however, an MRI or a CT scan may be helpful in the diagnosis of complications of EoE such as tears, perforation strictures etc

Other Diagnostic Studies

Treatment

Medical Therapy

The optimal treatment of eosinophilic esophagitis remains uncertain. An eight-week course of therapy with topical corticosteroids (fluticasone or budesonide) may be used as the first-line pharmacologic therapy. Allergen elimination usually leads to improvement in dysphagia and reduction of eosinophil infiltration. Esophageal dilation of is generally reserved for refractory cases with esophageal stricture.

Surgery

Surgical intervention is not recommended for the management of Eosinophilic esophagitis.

Prevention

There are no established measures for the primary prevention of Eosinophilic esophagitis (EoE).

References

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