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Causes

• The causes of EoE are as follows:
• 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.

Risk factors

• EoE is associated with the following risk factors:
• Age- EoE has a bimodal age distribution common in both children and adults.
• Sex- Males are more prone to EoE than the females.
• Weather- Cold and dry climate triggers EoE.
• Location- EoE is common in people with a history of European ancestry.
• Season- Summer and fall, this is because people stay outdoors during this time and the higher levels of the pollen and the other allergens during these seasons.
• Family history- EoE runs in the family and it is more common in people with a positive family history of the EoE.
• History of allergies- EoE is very common in patient with a history of allergies such as asthma, industrial exposures, environmental allergies, chronic respiratory disease, food allergies and atopic dermatitis.

Historical Perspective

• The historical perspective of the EoE is as follows:
• 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 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 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 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.

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 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
  • Eosinophils
  • Mast cells
• 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.

Pathogenesis

• The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.
• IL-5 and 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.

Endoscopy

• Mucosal biopsies of the esophagus should be obtained in all patients in whom EoE is a clinical possibility regardless of the endoscopic appearance.
• Endoscopic abnormalities in patients with EoE are as follows:
  • Fixed esophageal ring which is corrugated
  • White exudates or plaques
  • Longitudinal furrows
  • Mucosal pallor
  • Diffuse esophageal narrowing
  • Mucosal fragility leading to esophageal lacerations during the endoscopy

However, because these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for EoE.