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Historical Perspective

• In 1989, Attwood et al published an abstract in Gut, describing “Oesophageal 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.
• Differences between the two groups were that the group without increased acid exposure was found to have significantly greater number of eosinophils than the group with GERD.
• The key finding of this case series was that it identified patients with dysphagia, with a range of severity up to complete bolus obstruction, presented with dense esophageal eosinophilia.
• In 1993, they published these key findings that described adults with dysphagia, normal pH monitoring and dense esophageal eosinophilia (>20 eos/HPF) and termed this Esophageal Eosinophilia with dysphagia.
• A distinct clinicopathological syndrome 10. Importantly, control patients with proven GERD had a mean of 3.3 eos/HPF in the esophageal epithelium. Endoscopic appearances using fiber optic technology likely limited descriptions of the full details now observed in this disease and may partially explain the fact that no endoscopic abnormalities were visualized in their series.
• Seven patients had food hypersensitivity, and all required advanced intervention (dilatation and / or steroids in one 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 treatment11.
• From this series it was clear that the endoscopic findings including rings, white exudates and furrows were variably expressed since some patient’s esophageal mucosae appeared relatively normal.
• He termed this Idiopathic Eosinophilic Esophagitis.
• Taken together, these 2 reports from 2 different continents, described key clinical findings observed in adults with dysphagia who had dense mucosal eosinophilia that was limited to the esophagus who did not have GERD.
• Importantly, endoscopic findings were variable, leading to the necessity of procuring endoscopic pinch biopsy to make the diagnosis.
• Since this practice was not widespread, because of the lack of diagnostic utility, larger recognition of this newfound disease remained somewhat limited.
• These two series, published by a gastroenterologist in private practice, Dr. Straumann and a surgeon, Dr. Attwood formed the beginnings their quest to define key clinical features and therapeutic approaches over the next 20 years.

• 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.